Entitled process for producing a fluorinated cyclopropane carboxylic acids
Technical field
[0001]
　The present invention relates to a method for producing a fluorine-containing cyclopropanecarboxylic acids.
Background technique
[0002]
　As a peripheral technique of fluorinated cyclopropane carboxylic acids, in Non-Patent Document 1, as a production method of cyclopropane diesters having no fluorine atom, the method using a compound having two leaving groups in a molecule as a raw material is reported It is (the following scheme).
[Formula 1]

[0003]
　The Non-Patent Document 2 manufacturing method via the sulfonium salt has been reported as a process for producing a fluorinated cyclopropane diesters (the following scheme).
[Formula 2]

[0004]
　The method in Non-patent document 3 using bromo trifluoropropene as synthesis of fluorinated cyclopropane monoesters are, Patent Document 1, a manufacturing method of a salt with difluoro acetaldehyde ethyl hemiacetal reported It is (the following scheme).
[Formula 3]

[0005]
　As a method for producing cyclopropane diesters, Non-patent document 4 a method of synthesizing a cyclic sulfate with malonic acid diester are reported (the following scheme).
[Formula 4]

[0006]
　Incidentally, the following formula:
[Formula 5]

fluorinated cyclopropane diester represented by, and the following formula:
[Formula 6]

Preparation of fluorinated cyclopropane monoester represented by is not known.
[0007]
　On the other hand, in the production of the fluorine-containing cyclopropanecarboxylic acid, as a prior art related to the process for producing a fluorinated cyclic sulfate is that of the starting material, the presence of imidazole in Patent Document 2, 1,1,1-trifluoro - how the 2,3-propanediol obtained by reacting sulfuryl chloride is known (the following scheme).
[Formula 7]

[0008]
　Further, a method of obtaining a fluorinated cyclic sulfate by using Patent Document 3, sulfuryl chloride and triethylamine and the diol compound is known (the following scheme).
[Of 8]

[0009]
　On the other hand, the following formula:
[Formula 9]

Preparation of fluorine-containing cyclic sulfate represented by is not known.
CITATION
Patent Literature
[0010]
Patent Document 1: U.S. Published Application No. 2015-0175626
Patent Document 2: JP 2006-328011 Patent Publication
Patent Document 3: JP 2008-230970 JP
Non-Patent Document
[0011]
Non-Patent Document 1:. J. Med Chem, 2004, No. 47, p.2511-2522.
Non-Patent Document 2: Synthesis, 2012 years, No. 44, p.3489-3495
Non-Patent Document 3:. Chem Commun. in 2003, p.536-537
non-Patent Document 4:.. J. Am Chem Soc , 1988 years, No. 110, p.7538-7539.
Disclosure of the Invention
Problems that the Invention is to Solve
[0012]
　An object of the present invention is to provide an industrial process for producing a fluorinated cyclopropanecarboxylic acids.
[0013]
　Although the method for producing a cyclopropane diesters is described in Non-Patent Document 1, the reference to this method, consider the manufacture of fluorinated cyclopropane carboxylic acids with a compound having two leaving groups of all the molecule but it was, could not be obtained the desired compound (Comparative example 4 described later, Comparative examples 6 and 8).
[0014]
　The method described in Non-Patent Document 2, a good yield is, it is considered that seemingly preferred method, the industrial implementation because it is the use of expensive iodonium salt had flame.
[0015]
　Further, the method described in Non-Patent Document 3, a good yield is, for it is believed that seemingly preferred method, the fluorine-containing cyclopropane monoesters obtained is a racemic mixture, if desired product is an optically active substance , the yield will be less than half the resolving the optical isomers of interest. Therefore, somewhat there is hardly to employ as industrial production process.
[0016]
　Described in Non-Patent Document 4, a method of using a malonic acid diester with cyclic sulfate is considered to seemingly preferred methods, the synthesis of the cyclic sulfate, the reaction is a two-stage, the use of expensive transition metal catalysts , the industrial implementation because using a higher carbon tetrachloride toxicity had flame.
[0017]
　Thus, process for producing a fluorinated cyclopropanecarboxylic acids, as that of the industrial scale, was not sufficiently satisfactory. In the present invention, the fluorine-containing cyclopropane carboxylic acids are important intermediates of medicines, and to provide an industrially feasible production process.
Means for Solving the Problems
[0018]
　The present inventors, in view of the above problems, as a result of intensive studies, found a manufacturing method shown in the following scheme, to complete the method of manufacturing industrially feasible fluorinated cyclopropane monoester salt. That is, to synthesize a fluorine-containing cyclic sulfate with a fluorine-containing diol compound and sulfuryl fluoride "cyclic sulfate of step", by reacting a fluorine-containing cyclic sulfate with malonic acid diester obtained in step with fluorine by way of obtaining a cyclopropane diester "cyclopropanation step" to obtain a fluorine-containing cyclopropane monoester fluorinated cyclopropane diester obtained in the step to hydrolyze "hydrolysis step", the prior art and to produce the monoester in conditions that may industrially easily employed than, further salts with fluorinated cyclopropane monoester and the amine as a mixture of fluorinated cyclopropane monoester and the amine obtained in the step formed, by going through the "recrystallization step" recrystallized purification, high chemical purity and optical purity It found to be able to produce fluorine-containing cyclopropanecarboxylic acids such as fluorinated cyclopropane monoester salts with, and completed the present invention.
[Of 10]

[0019]
　In the case where the steps adopted in the present invention against the Patent Documents 2 and 3, there are several problems.
[0020]
　For example, the method of Patent Document 2 because it is possible to obtain a fluorine-containing cyclic sulfate in high yield, and as seemingly preferable method. However, the present method is that you are using the highly toxic methylene chloride solvent, moreover partially fluorinated difluoromethyl group, trifluoromethyl group, i.e., when replacing the substrate of interest in the present invention, object it was not possible to obtain a compound (Comparative example of the present application. 1).
[0021]
　Further, since it is possible to obtain a fluorine-containing cyclic sulfate method of Patent Document 3 in high yield, and as seemingly preferable method. However, when replacing the trifluoromethyl group on a difluoromethyl group, it is impossible to obtain the desired compound (Comparative Example 10).
[0022]
　On the other hand, it is a substrate that is an object of the invention is a fluorine-containing cyclopropane carboxylic acids having a high optical purity, that once produced the "racemic fluorinated cyclopropanecarboxylic acids", prepared by optical resolution thereof it is also possible. However, when actually adopt it, optical resolution by recrystallization from the racemates efficiency also decreases poor yield. In contrast, the present invention is by using a pre-feed the optically active substance, since the process of optical resolution can be reduced, it is possible to perform efficient production.
[0023]
　Process for producing a fluorinated cyclopropane carboxylic acids employed in the present invention can solve the problems in the manufacturing process, industrially superiority is high.
[0024]
　Specifically, the present invention provides the following [Invention 1] - to provide a process for producing a fluorinated cyclopropane carboxylic acids described in the invention 16.
[0025]
　[Invention 1]
　general formula fluorinated diol compound represented by [1], alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, and the presence of at least one basic compound selected from the group consisting of alkaline earth metal bicarbonates, the general formula by reacting with sulfuryl fluoride [2] method for producing a fluorine-containing cyclic sulfate represented in.
[Formula 11]

wherein, R f represents a linear or branched fluoroalkyl group having 1 to 6 carbon atoms having more than one fluorine atom, and * represents an asymmetric carbon. ]
[Formula 12]

wherein, R f is the formula [1] represents the same substituents as, * represents an asymmetric carbon. ]
[0026]
　[Invention
　2] R f is difluoromethyl group (CF 2 H) or a trifluoromethyl group (CF 3 is), the method according to the invention 1.
[0027]
　[Invention 3]
　is a temperature of between -50 ~ + 50 ° C. when reacting sulfuryl fluoride, the method according to invention 1 or 2.
[0028]
　[Invention 4]
　The method according to any one of Inventions 1 to 3 The amount of sulfuryl fluoride is from 0.7 to 4.0 equivalents.
[0029]
　[Invention 5]
　invention to produce a fluorine-containing cyclic sulfate by a method according to any of 1 to 4, then the presence of the ester of an inorganic base, the general formula [3] malonic acid diester represented by the reaction It is to a method for producing a fluorine-containing cyclopropane diester represented by the general formula [5].
[Formula 13]

wherein, R 1 , R 2 having a carbon number of 1 are each independently 18 linear, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, the carbon number It represents from 6 to 18 aromatic ring group or a substituted aromatic ring group. ]
[Chemical Formula 14]

wherein, R f is the general formula [1 in the inventions 1] R in the f the same as. R 1 , R 2 R in the formula [3] 1 , R 2 the same as. * Represents an asymmetric carbon. ]
[0030]
　[Invention 6]
　inorganic bases alkali metal, alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides or alkaline earth metal hydroxide, the method according to the invention 5.
[0031]
　[Invention 7]
　The general formula malonic acid diester represented by the fluorine-containing cyclic sulfate ester represented by [2] and general formula [3], is characterized by adding a solvent containing an inorganic base, invention 5 or method according to the invention 6.
[0032]
　[Invention 8]
　to produce a fluorine-containing cyclopropane diester by the method according to any one of Inventions 5 to 7, then, the alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates into the diester, alkali earth metal carbonate, alkali metal bicarbonate, the presence of a quaternary ammonium hydroxide represented by the alkaline earth metal hydrogen carbonates or general formula [6], in the general formula [7] by carrying out the hydrolysis method for producing a fluorine-containing cyclopropane monoester represented.
Formula 15]

wherein, R 3 , R 4 , R 5 , R 6 are each independently, having 1 to 18 linear, branched alkyl or cyclic (in the case of 3 or more carbon atoms) It represents group, a substituted alkyl group, an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms. Also, R 3 , R 4 , R 5 , R 6 out of, or may be two or more forms part of the same aliphatic ring or aliphatic aromatic ring. ]
[Chemical Formula 16]

wherein, R f is the general formula [1 in the inventions 1] represents the same substituents as, R 2 represents the same substituents as the general formula [3] in the invention 5. * Represents an asymmetric carbon. ]
[0033]
　[Invention 9]
　temperature in the hydrolysis reaction is -30 ~ + 40 ℃, the method according to the invention 8.
[0034]
　[Invention 10]
　in the fluorine-containing cyclopropane monoesters represented by the general formula [7], the addition of an amine represented by the general formula [8], the fluorine-containing cyclopropane monoesters represented by the general formula [9] and to form salts with amines, further comprising the step of performing recrystallization purification method according to the invention 8 or 9.
[Formula 17]

wherein, R 7 , R 8 , R 9 are each independently hydrogen, C 1 -C 18 straight, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms. ]
[Formula 18]

wherein, R f is the general formula [1] represents the same substituents as, R 2 represents a same substituent as the general formula [3] in the invention 5, R 7 , R 8 , R 9 represent the same substituents as the general formula [8]. ]
[0035]
　[Invention 11]
　amine represented by the general formula [8] is an amine represented by the general formula [10] The method according to the invention 10.
[Formula 19]

wherein, R 7 , R 8 , R 10 are independently a hydrogen atom, C 1 -C 18 straight, branched alkyl or cyclic (in the case of 3 or more carbon atoms) group, a substituted alkyl group or an aromatic ring group having 6 to 18 carbon atoms, a substituted aromatic ring group, Ar 1 represents an aromatic ring group or a substituted aromatic ring group having 6 to 14 carbon atoms. Further, R 10 of, 1-18 linear, branched or cyclic alkyl group, a substituted alkyl group or an aromatic ring group having 6 to 18 carbon atoms (if 3 or more carbon atoms), substituted aromatic for Hajime Tamaki, * represents an asymmetric carbon. ]
[0036]
　[Invention 12]
　, comprising the steps manufacturing method for a salt of the general formula [11] fluorinated cyclopropane monoester represented by the 1-phenylethylamine.
[Formula 20]

wherein, R 2 represents the same substituents as the general formula [3] in the invention 5. * Represents an asymmetric carbon. ]
　[Cyclic sulfate step]
　in the fluorine-containing diol compound represented by the formula [12], an alkali metal hydride, alkali metal carbonates, by reacting an alkali metal hydrogen carbonate and sulfuryl fluoride in equation [13] obtaining a fluorinated cyclic sulfate according.
[Formula 21]

[formula 22]

wherein, * represents an asymmetric carbon. ]
　[Cyclopropanation step]
　in the fluorine-containing cyclic sulfate obtained in the cyclic sulfate step, the presence of an alkali metal or alkali metal hydride is reacted with malonic acid diester represented by the general formula [3] it is to obtain a fluorine-containing cyclopropane diester represented by the general formula [15].
Formula 23]

wherein, R 1 , R 2 are each independently a number from 1 to 18 linear carbon atoms, an alkyl group branched or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, It represents an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms. ]
[Chemical Formula 24]

wherein, R 1 , R 2Represent the same substituents as the general formula [3] in the invention 5, * represents an asymmetric carbon. ]
　[Hydrolysis step]
　The alkali metal hydroxide in the fluorine-containing cyclopropane diester obtained in cyclopropanation step, the presence of a quaternary ammonium hydroxide represented by the alkali metal carbonate or the general formula [6], hydrous obtaining a fluorine-containing cyclopropane monoesters represented by the general formula [16] by performing the decomposition.
Formula 25]

wherein, R 3 , R 4 , R 5 , R 6 are each independently, having 1 to 18 linear, branched alkyl or cyclic (in the case of 3 or more carbon atoms) group, a substituted aromatic ring group having optionally substituted alkyl group having a substituent on carbon, optional substituents on the carbons of the aromatic ring group or aromatic ring group having 6 to 18 carbon atoms in the alkyl group. The R 3 , R 4 , R 5 , R 6 out of, or may be two or more forms part of the same aliphatic ring or aliphatic aromatic ring. ]
[Chemical Formula 26]

wherein, R 2 is the general formula [3 in Invention 5] represents the same substituents as, * represents an asymmetric carbon. ]
　[Recrystallization process]
　The optically active 1-phenylethylamine was added to the fluorine-containing cyclopropane monoester obtained in the hydrolysis step, to form salts with the fluorinated cyclopropane monoester and 1-phenylethylamine of the formula [11], the step of performing the recrystallization purification operation.
[Formula 27]

[wherein, R 2 is R in the general formula [3] 2 same as. ]
[0037]
　[Invention 13]
　The fluorine-containing cyclic sulfate of the formula [13].
[Formula 28]

wherein, * represents an asymmetric carbon. ]
[0038]
　[Invention 14]
　salts with fluorinated cyclopropane monoester with an amine of the formula [17].
[Formula 29]

In the formula, R 11 represents a straight-chain or branched-chain on the alkyl group having 1 to 6 carbon atoms, R 12 , R 13 , R 14 are each independently a hydrogen atom, C 1 -C represents a straight or branched chain alkyl group of ~ 6, Ar 2 represents an aromatic ring group or a substituted aromatic ring group having 6 to 10 carbon atoms. Further, R 14 of, for straight-chain or branched alkyl group having 1 to 6 carbon atoms, * the amine represents an asymmetric carbon. ]
[0039]
　[Invention 15]
　salts with fluorinated cyclopropane monoester and 1-phenylethylamine of the formula [18].
Formula 30]

wherein, Et represents an ethyl group. ]
[0040]
　[Invention 16]
　salts with fluorinated cyclopropane monoester and 1-phenylethylamine of the formula [19].
Formula 31]

wherein, Et represents an ethyl group. ]
[0041]
　The present invention has an effect that can be produced fluorinated cyclopropanecarboxylic acids such as fluorinated cyclopropane monoester salt industrially feasible embodiment.
DESCRIPTION OF THE INVENTION
[0042]
　The present invention will be described in detail. Hereinafter will be described an embodiment of the present invention, the present invention is not limited to the following embodiments, without departing from the spirit of the present invention, based on the ordinary knowledge possessed by those skilled in the art, as appropriate implementation can do.
[0043]
　The present invention provides a process for producing a fluorinated cyclopropane carboxylic acids, fluorinated cyclic sulfate represented by the general formula [2] with the formula fluorinated diol compound and sulfuryl fluoride represented by [1] manufacturing method for obtaining a (cyclic sulfate step) the process of obtaining a fluorine-containing cyclopropane diester represented by the fluorine-containing cyclic sulfate with malonic acid diester obtained by the above method is reacted general formula [5] is (cyclopropanation step), a manufacturing method of obtaining a fluorine-containing cyclopropane monoesters represented by the general formula [7] with a fluorinated cyclopropane diester obtained in the above manner is hydrolyzed (hydrolysis step) .
[0044]
　Furthermore, by reacting amine fluorinated cyclopropane monoester obtained by the aforementioned method to form a fluorine-containing cyclopropane monoester salt represented by the general formula [9], the step of performing recrystallization purification (recrystallization process) may further comprise a.
[0045]
　[Cyclic sulfate step]
　First, a description will be given cyclic sulfate process. This step formula fluorinated diol compound represented by [1] is a step of synthesizing a fluorine-containing cyclic sulfate of a basic compound and with sulfuryl fluoride represented by the general formula [2].
[0046]
　R fluorinated diol compound represented by the general formula [1] f is a linear or branched fluoroalkyl group having 1 to 6 carbon atoms containing a fluorine atom one or more. Specific compounds, trifluoromethyl group, pentafluoroethyl group, heptafluoropropyl group, a nonafluorobutyl group, difluoromethyl group, 1,1-difluoroethyl group, 2,2-difluoroethyl group, 1,1 - difluoropropyl group, 2,2-difluoro-propyl, 3,3-difluoro-propyl, 1,1-difluoro butyl group, 2,2-difluoro butyl group, 3,3-difluoro butyl group, 4,4-difluoro butyl group, monofluoromethyl group, 1-mono-fluoroethyl group, 2-monofluoroethyl group, 1-mono-fluoropropyl group, 2-mono-fluoropropyl group, 3-monofluoromethyl-propyl, 1-mono-fluoro butyl group, 2-monofluoromethyl-butyl group, 3-monofluoromethyl-butyl group, and 4-monofluoromethyl-butyl There, a trifluoromethyl group, among them, pentafluoroethyl group, heptafluoropropyl group, a nonafluorobutyl group, difluoromethyl group are preferable, a trifluoromethyl group, difluoromethyl group is particularly preferable. Fluorinated diol compound represented by the general formula [1], for example reference example 2 described below, can be prepared as described in Reference Example 7 and Reference Example 11.
[0047]
　The basic compound used to prepare the fluorinated cyclic sulfate represented by the general formula [2], alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, alkaline earth metal hydrosulfide oxides, alkali metal carbonates, alkaline earth metal carbonates, include alkali metal hydrogen carbonates or alkaline earth metal hydrogen carbonates, in this, an alkali metal hydride, alkali metal hydroxides, alkali metal carbonates salts, alkali metal hydrogen carbonates, alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates preferably, alkali metal hydrides, alkali metal carbonates, alkali metal bicarbonates are particularly preferred. Specifically lithium hydride, sodium hydride in, potassium hydride, rubidium hydride, hydride, cesium, magnesium hydride, calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, hydroxide cesium, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogencarbonate , magnesium bicarbonate, include calcium hydrogen carbonate, among them lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, charcoal Potassium, rubidium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate are preferred, sodium hydride, potassium carbonate, cesium carbonate, potassium hydrogen carbonate , cesium hydrogen carbonate is particularly preferred.
[0048]
　In this step, the presence of a fluorine-containing diol compound basic compound, there is no particular limitation on the charging order of reagent during the reaction with sulfuryl fluoride, for example, as shown in the Examples below, initially containing fluorine diol compound and the basic compound, and after the preparation of the reaction solution was stirred it was charged and the reaction solvent in the reaction vessel, it is preferable to introduce sulfuryl fluoride. There is no particular restriction on the reaction temperature in the preparation of a reaction solution containing a fluorine-containing diol compound and the basic compound as referred to herein may be a -70 ~ 50 ° C., preferably -50 ~ 40 ° C., - particularly preferred is 30 ~ 30 ℃. The reaction temperature is slower reaction rate too low than -70 ° C., industrially difficult employed.
[0049]
　The reaction time in adjusting the reaction solution containing a fluorine-containing diol compound and the basic compound is not particularly limited, usually, after reacting the two starting materials, gas chromatography, liquid chromatography, NMR, etc. by means, it is preferable that the end point of time when the fluorine-containing diol compound almost disappeared.
[0050]
　The solvent used in this reaction include aprotic solvents having a polarity, ether solvents, nitrile solvents, amide solvents, ester solvents, sulfur-containing solvents are preferred, nitrile solvents are particularly preferred. Specifically, diethyl ether, diisopropyl ether, dibutyl ether, t- butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethylformamide, methyl acetate, ethyl acetate, propyl acetate, t-butyl, dimethyl sulfoxide , sulfolane and the like, diisopropyl ether, dibutyl ether, methyl -tert- butyl ether, cyclopentyl methyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethylformamide, ethyl acetate, preferably dimethyl sulfoxide, acetonitrile is particularly preferred. These solvents may be used alone or in combination.
[0051]
　The temperature for reaction by adding sulfuryl fluoride in a reaction solution containing a fluorine-containing diol compound and the basic compound may be any -50 ~ + 50 ℃, preferably -40 ~ + 40 ℃, particularly preferably -30 ~ + 30 ° C. . Temperature slows the reaction rate too low than -50 ° C., industrially difficult employed. On the other hand, the temperature is not preferable because the increase of impurities by side reactions too high than 50 ° C..
[0052]
　May be carried out in the range of 0.001 ~ 2.0 MPa as the pressure conditions for the reaction by the addition of sulfuryl fluoride, preferably 0.001 ~ 1.5 MPa, and particularly preferably 0.001 ~ 1.0 MPa. Pressure is too the reaction rate becomes slow low, industrially difficult employed. The pressure mentioned here indicates that the absolute pressure. The amount of sulfuryl fluoride, it is sufficient from 0.7 to 4.0 equivalents of the fluorine-containing diol compound, preferably 1 to 3.0 equivalents, particularly preferably 1 to 2.0 equivalents. If 0.7 is less than equivalent, adversely affect yield, when 4.0 more than equivalent, may adversely affect the selectivity of the reaction.
[0053]
　Take the form of blowing sulfuryl fluoride dip tube in the reaction solution in the form of introducing sulfuryl fluoride, it may be in a form to be introduced into a sealable autoclave reactor.
[0054]
　The reaction time for the reaction by the addition of sulfuryl fluoride is not particularly limited, usually, after the introduction of the sulfuryl fluoride has been completed, gas chromatography, liquid chromatography, by means of NMR, etc., of the product it is preferable that the time when the change in the amount is used up as the end point.
[0055]
　The reaction vessel used in the reaction, stainless steel, Monel TM , Hastelloy TM , nickel, or these metals or polytetrafluoroethylene, etc. lined reaction vessel with a fluororesin such as perfluoropolyether resin.
[0056]
　Post-processing by adopting the common operations in organic synthesis, the general formula [2] The fluorine-containing cyclic sulfate represented by can be obtained. The crude product is activated carbon treatment as needed, fractional distillation can be purified to a high purity by column chromatography or the like.
[0057]
　Also after producing a fluorine-containing cyclic sulfate, although the desired product may be isolated, it can be used a solution immediately after the reaction as described in Examples below to the next cyclopropanation step. Adopting this method is advantageous in terms of operability, it cited as one of the preferred forms.
[0058]
　By carrying out the invention described process can produce a fluorine-containing cyclic sulfate of the formula [13] (Note that the ester can be converted to various compounds having a difluoromethyl group, useful compounds is there).
[Of 32]

[0059]
　[Cyclopropanation step]
　is described next cyclopropanation step. Fluorinated cyclic sulfate obtained in this step before step (cyclic sulfates step), the presence of an inorganic base, with a malonic acid diester represented by the general formula [3] are reacted, the general formula [5 is a process for producing a fluorine-containing cyclopropane diester represented by. Detailed reaction of this step is shown in the following scheme.
[Of 33]

[0060]
　Note that this step, via an intermediate material (malonic acid ester adduct) shown in the above scheme, reaction cyclization of the adduct proceeds in series, fluorine-containing cyclopropane diester is obtained as the result. To explain this process in detail, the present process is the "first stage", "second stage", describing the "inorganic base" as "inorganic base 1", "an inorganic base 2". Incidentally, one embodiment in this manner present even when subjected to stepwise reaction process, this aspect is of course included in the invention of the present process.
[0061]
　R malonic acid diester represented by the general formula [3] 1 , R 2Carbon atoms of 1 each independently 18 linear, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms represent. Substituted alkyl group, any halogen atom on a carbon of the alkyl group, an alkyl group having a substituent such as an aromatic ring group, substituted aromatic ring group halogen atoms on any carbon of the aromatic ring group, aromatic ring group, a nitro group, aromatic ring group having a substituent such as an alkoxy group having 1 to 6 carbon atoms. A methyl group, an ethyl group, a propyl group, an isopropyl group, 1-butyl, 2-butyl, isobutyl, tert- butyl group, 1-pentyl, 2-pentyl, 3-pentyl, 2 - methyl-1-butyl, 2-methyl-2-butyl group, 3-methyl-1-butyl group, 3-methyl-2-butyl group, neopentyl group, 1-hexyl, 2-hexyl, 3- hexyl, 2-methyl-1-pentyl group, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4- methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,2-dimethyl-1-butyl group, 2,3-dimethyl-1-butyl group, 3,3 - dimethyl-1-butyl group, 2,3-di Chill-2-butyl group, 3,3-dimethyl-2-butyl group, 2-ethyl-1-butyl group, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, 1-undecyl group, 1-dodecyl group, 1-tridecyl group, 1-tetradecyl group, 1-pentadecyl group, 1-hexadecyl group, 1-heptadecyl group, 1-octadecyl group, 1-cyclopropyl group, 1-cyclopentyl, 1- cyclohexyl group, a benzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-bromobenzyl group, 3- bromobenzyl group, 4-bromobenzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, a naphthyl group, Ann Toraseniru group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4- bromophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, a 4-methoxyphenyl group, and a methyl group. among this, ethyl , propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert- butyl group, 1-pentyl, 1-hexyl, 1-heptyl, 1-octyl, 1-nonyl group, 1-decyl, 1-cyclohexyl group, a benzyl group, a phenyl group, a naphthyl group are preferable, methyl group among these, Ethyl group, a propyl group, an isopropyl group, 1-butyl group, isobutyl group, tert- butyl group, 1-cyclohexyl group, a benzyl group, a phenyl group is particularly preferred.
[0062]
　General formula [3] malonic acid Specific compounds of malonic acid diester represented by dimethyl, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, malonate, di-2-butyl, diisobutyl malonate , malonate tert- butyl group, dipentyl malonate, dihexyl malonate, diheptyl malonate, dioctyl malonate, dinonyl malonic acid, didecyl malonate, dicyclohexyl malonate, dibenzyl malonate, diphenyl malonate, dinaphthyl malonic preferably , dimethyl malonate among them, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, diisobutyl malonate, malonate tert- butyl, dicyclohexyl malonate, dibenzyl malonate, diphenyl malonate Alkylsulfonyl is particularly preferred.
[0063]
　The equivalent of malonic acid diester represented by the general formula [3] may be a 1-5 equivalents of the fluorine-containing cyclic sulfate, preferably 1 to 3 equivalents, particularly preferably 1 to 1.5 equivalents. 1 less than equivalent and yield is lowered, 5 malonic acid diester would remain as using an impurity of an amount exceeding the equivalent of a chemical purity may be decreased.
[0064]
　The inorganic base used in this step (corresponding to say in the scheme "inorganic base 1", and "inorganic bases 2 '), an alkali metal, alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides , using an alkaline earth metal hydroxide. Alkali metal in this alkali metal hydrides are preferred. Specifically lithium, sodium, potassium, lithium hydride, sodium hydride, potassium hydride, rubidium hydride, hydride, cesium, magnesium hydride, calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, include calcium hydroxide, among others, lithium, sodium, lithium hydride, sodium hydride, potassium hydride are preferred, sodium, sodium hydride is particularly preferred. Incidentally, an inorganic base may be the same or different.
[0065]
　Equivalents of the inorganic base may be two equivalents or more to the malonic acid diester represented by the general formula [3]. 2 less and yields than equivalent may be lowered. Note that when adding stepwise inorganic base as described above scheme, the "first step" by adding an inorganic base 1, the addition of an inorganic base 2 in the "second stage", so that a total of 2 equivalents or more it may in addition be in.
[0066]
　Ether solvents as the reaction solvent in this step, an amide solvent, aliphatic hydrocarbon solvents, and aromatic hydrocarbon solvents. Specifically, diethyl ether, diisopropyl ether, dibutyl ether, methyl -tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, dimethylformamide, dimethylacetamide, n- hexane, cyclohexane, n- heptane, n - nonane, n- octane, toluene, xylene and the like, diethyl ether among them, diisopropyl ether, methyl -tert- butyl ether, tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, dimethylformamide, n- hexane, n- heptane, toluene, xylene are preferred, diisopropyl ether, methyl -tert- butyl ether, tetrahydrofuran, dimethoxy Ethane, dimethylformamide, n- heptane, toluene especially preferred. Note that this step, the first step as described above scheme, even these reaction solvents is reacted in the second stage can be applied. These solvents may be used alone or in combination of two or more solvents.
[0067]
　A preferred embodiment of this step, the fluorine-containing cyclic sulfate, the presence of an inorganic base, although it is made to react with malonic acid diester is not particularly limited in embodiments, for example, gas chromatography, such as NMR analysis unit, the progress of the reaction is followed, it is preferable that the raw material to terminate the reaction at the time when almost disappeared. Further, when advancing the stepwise reaction as above scheme, after the inorganic base 1 was added in the first step, gas chromatography, analytical means such as NMR, to track the progress of the reaction is the intermediate confirmed the production of malonic acid ester adduct, the time fluorinated cyclic sulfate has almost disappeared as a raw material or when no change is observed in the conversion of the ester, an inorganic base 2 and / or to the reaction system it is possible to react by adding a reaction solvent.
[0068]
　It is also possible to inorganic bases 1 was excessively added in the first step utilizes the unreacted inorganic base 2. In this case, the amount of inorganic base 2 is equivalent to minus excess inorganic base 1 is a guide, separately may be added an inorganic base, if necessary.
[0069]
　Described preferred reaction temperature at this step. Typically reaction temperature is -80 ° C. ~ 170 ° C., preferably from -50 ° C. ~ 120 ° C., more preferably Although the reaction proceeds in a temperature range of -30 ~ 100 ° C., for example, as shown in the above scheme, when the reaction of this step stepwise, the preferred embodiments below, state.
[0070]
　First, the temperature when carrying out the reaction in the first stage may be at -70 ° C. or higher but, -50 ° C. ~ 40 ° C., preferably may be carried out at -30 ℃ ~ 30 ℃. The end point of the reaction gas chromatography, analytical means such as NMR, to track the progress of the reaction, when the raw material has almost disappeared or, may promote the reaction of the second stage at the time the progress of the reaction is stopped. Since the solid when carrying out the reaction of the first stage large quantities deposited, it is preferable to adjust the concentration of the reaction solution so that 2M 0.1, particularly preferably 1.5M 0.2. Concentration becomes difficult to stir higher than 2M, lower than 0.1M and productivity greatly decreases. Next, the second stage reaction by raising the temperature of the reaction solution. The reaction temperature of the second stage 40 ~ 0.99 ° C., preferably about 40 ~ 120 ° C., more preferably may be performed at 50 ~ 100 ° C.. At temperatures below 40 ° C., the cyclization reaction is hard to proceed, it may be necessary a long time for the reaction. Meanwhile, if the temperature exceeds 0.99 ° C., the reaction itself can proceed, product or the like is decomposed, there is a possibility that a side reaction occurs. Will easily be stirred gradually solid disappeared when the second stage reaction proceeds.
[0071]
　No particular limitation is imposed on the charging method in the reaction of this step, for example, as shown in the Examples below, the first, after the reaction solvent and the inorganic base and the charged liquid mixture in the reaction system, the mixture it is preferred to add a malonic acid diester and a fluorine-containing cyclic sulfate of raw materials in the liquid. In this case, after the mixture was mixed with malonic acid diester and a fluorine-containing cyclic sulfate, it is also possible to add to the mixture prepared above, also mixed with malonic acid diester and a fluorine-containing cyclic sulfate to not let, it may be added each separately. Further, with respect to malonic acid diester and / or a fluorine-containing cyclic sulfate, was added to the reaction solvent, if necessary, may be added dropwise to the mixture prepared above, those skilled in the art can be appropriately adjusted.
[0072]
　Here, when the mixture was mixed with malonic acid diester and a fluorine-containing cyclic sulfate, induction time of the malonic acid diester and a fluorine-containing cyclic sulfate to the reaction system in the long or longer and 30 minutes or 48 hours good, preferably 40 minutes or less than 24 hours, and particularly preferably 1 hour or more 12 hours. In less than 30 minutes may solids resulting in large quantities precipitated, whereas sometimes the productivity is bad at over 48 hours.
[0073]
　[Hydrolysis Step]
　described next hydrolysis step. This step is a step of obtaining a fluorine-containing cyclopropane monoesters represented by the general formula [7] is hydrolyzed fluorinated cyclopropane diester obtained in the step.
[0074]
　Formula alkali metal hydroxide as the base used in the hydrolysis of fluorinated cyclopropane diesters represented by [5], an alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen salts, quaternary ammonium hydroxide represented by the alkaline earth metal hydrogen carbonates or general formula [6] (in the present process, these compounds may be simply referred to as "base").
Formula 34]

wherein [6], R 3 , R 4 , R 5 , R 6 are each independently from 1 to 18 carbon atoms of straight, branched alkyl or cyclic (in the case of 3 or more carbon atoms) group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group having 6 to 18 carbon atoms. Substituted alkyl group, any halogen atom on a carbon of the alkyl group, aromatic ring group, an alkyl group having a substituent such as a hydroxyl group, a substituted aromatic ring group halogen atoms on any carbon of the aromatic ring group an aromatic group having an aromatic ring group, a nitro group, a substituent such as an alkoxy group having 1 to 6 carbon atoms. The R 3 , R 4 , R 5 , R 6 out of, or may be two or more forms part of the same aliphatic ring or aliphatic aromatic ring.
[0075]
　Alkali metal hydroxide in this, alkali metal carbonates, alkali metal hydrogen carbonates, quaternary ammonium hydroxide are preferred, alkali metal hydroxides, quaternary ammonium hydroxide is particularly preferred. Specifically sodium lithium hydroxide, the potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium hydrogen, sodium bicarbonate, potassium bicarbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutyl ammonium hydroxide, tetrapentyl ammonium hydroxide, tetrahexyl ammonium hydroxide, heptyl ammonium hydroxide to tetra, dimethyl dioctylcarbamoyl Ammonium hydroxide, trioctylmethylammonium hydroxide, tetra-octyl ammonium hydroxide, decyl trimethylammonium hydroxide, dodecyl trimethylammonium hydroxide, dilauryl dimethyl ammonium hydroxide, dimethyl dioctadecyl ammonium hydroxide, benzyl trimethylammonium hydroxide, benzyl triethylammonium hydroxide, benzyltrimethylammonium ammonium hydroxide, benzyl tributyl ammonium hydroxide, benzyltrimethylammonium heptyl ammonium hydroxide, benzyltrimethylammonium hexyl ammonium hydroxide, benzyltrimethylammonium heptyl ammonium hydroxide, benzyl trioctyl ammonium hydroxide, Torimechirufe Le ammonium hydroxide, triethyl phenyl ammonium hydroxide, tripropyl phenyl ammonium hydroxide, tributylphenyl ammonium hydroxide, tri-pentylphenyl ammonium hydroxide, Toriheki Sill phenyl ammonium hydroxide, tri heptylphenyl ammonium hydroxide, tri-octylphenyl ammonium hydroxide, dimethylpiperidinium hydroxide, ethyl - methyl piperidinium hydroxide, methyl - propyl piperidinium hydroxide, butyl - Mechirupiperiji onium hydroxide, diethyl piperidinium hydroxide, ethyl - propyl piperidinium hydroxide, butyl - ethyl piperidinium hydroxide, dipropyl piperidinium hydroxide, butyl - propyl piperidinium hydroxide, dibutyltin Lupi piperidinium bromide hydroxide, 2-hydroxyethyl trimethylammonium hydroxide, tris (2-hydroxyethyl) include methyl ammonium hydroxide, among others Lithium oxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, tetra-hexyl ammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, trimethylphenyl ammonium hydroxide, triethyl phenyl ammonium hydroxide, butyl - methyl piperidinium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide favored Properly, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide particularly preferred. Le - methylpiperidinium hydroxide, methyl - propyl piperidinium hydroxide, butyl - methyl piperidinium hydroxide, diethyl piperidinium hydroxide, ethyl - propyl piperidinium hydroxide, butyl - ethyl piperidinium hydroxy de, dipropyl piperidinium hydroxide, butyl - propyl piperidinium hydroxide, dibutyltin Lupi piperidinium onium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide, tris (2-hydroxyethyl) include methyl ammonium hydroxide, Of these lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, calcium carbonate, hydrogen carbonate Na Potassium, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, tetra-hexyl ammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, trimethyl phenyl ammonium hydroxide, triethyl phenyl ammonium hydroxide, butyl - methyl piperidinium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, tetramethylammonium hydroxide , tetraethylammonium hydroxide, 2-hydroxyethyl trimethinecyanine Chill ammonium hydroxide is particularly preferred. Le - methylpiperidinium hydroxide, methyl - propyl piperidinium hydroxide, butyl - methyl piperidinium hydroxide, diethyl piperidinium hydroxide, ethyl - propyl piperidinium hydroxide, butyl - ethyl piperidinium hydroxy de, dipropyl piperidinium hydroxide, butyl - propyl piperidinium hydroxide, dibutyltin Lupi piperidinium onium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide, tris (2-hydroxyethyl) include methyl ammonium hydroxide, Of these lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, calcium carbonate, hydrogen carbonate Na Potassium, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, tetra-hexyl ammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, trimethyl phenyl ammonium hydroxide, triethyl phenyl ammonium hydroxide, butyl - methyl piperidinium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, tetramethylammonium hydroxide , tetraethylammonium hydroxide, 2-hydroxyethyl trimethinecyanine Chill ammonium hydroxide is particularly preferred. Lysine onium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide, tris (2-hydroxyethyl) include methyl ammonium hydroxide, among others lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, tetra-hexyl ammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, trimethylphenyl ammonium arsenate Rokishido, triethyl phenyl ammonium hydroxide, butyl - methyl piperidinium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide is particularly preferred. Lysine onium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide, tris (2-hydroxyethyl) include methyl ammonium hydroxide, among others lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, hydrogen carbonate, rubidium, cesium hydrogen carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, tetra-hexyl ammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, trimethylphenyl ammonium arsenate Rokishido, triethyl phenyl ammonium hydroxide, butyl - methyl piperidinium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, tetramethylammonium hydroxide, tetraethylammonium hydroxide, 2-hydroxyethyl trimethylammonium hydroxide is particularly preferred.
[0076]
　The reaction temperature of the hydrolysis may, if -30 ~ + 40 ℃, preferably -20 ~ + 30 ℃, particularly preferably -10 ~ + 20 ℃. May hydrolysis reaction is slow at temperatures below -30 ° C., whereas, at temperatures above 40 ° C., side reactions tend to occur.
[0077]
　Equivalent of base is as long 1-5 equivalents, preferably 1 to 3 equivalents, particularly preferably 1 to 2 equivalents. 1 is less than the equivalent weight may result in yield is reduced, while the amount of base in excess of 5 equivalents, of the fluorine-containing cyclopropane diesters, two ester moiety side reactions such as being hydrolyzed results Sometimes.
[0078]
　As the reaction solvent such as water, alcohol solvents can be employed. Specifically mentioned water, methanol, ethanol, propanol, isopropanol, butanol, water, methanol, ethanol, propanol, isopropanol is preferably water, methanol, ethanol is particularly preferred. These solvents may be used alone or in combination of two or more.
[0079]
　Hydrolysis for fluorinated cyclopropane diesters, of the two ester moiety of the ester has, R f away from the base sterically one ester (ester taking the trans position) is preferentially hydrolyzed. For example, Org. Process Res. Dev. , 2011 year, No. 15, although selective hydrolysis of analogous compounds has been reported in P.1207-1211, thus, the ester is selectively hydrolyzed fluorinated cyclopropane monoesters represented by the general formula [7] in Rukoto is a compound having two asymmetric carbon. In this case R f when the configuration of the carbon α-position of the group of S, the other it is S or R becomes asymmetric centers, R f carbon in α position of group is configuration For R, the other it is R or S chiral center.
[0080]
　After post-treatment after the reaction was acidified reaction solution by adding an acid, by employing a common operation in ordinary organic compound synthesis such as extraction, fluorinated cyclopropane mono represented by the general formula [7] it is possible to obtain the ester. The crude product is activated carbon treatment as needed, fractional distillation can be purified to a high purity by column chromatography or the like. When the extraction operation, it is necessary to add an acid to the solution to acidic, the acid added is not particularly limited, boric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, nitric, inorganic acids such as sulfuric acid, formic acid, acetic acid, oxalic acid, benzoic acid, benzenesulfonic acid, and organic acids such as p-toluenesulfonic acid.
[0081]
　[Recrystallization step]
　for the last recrystallization step is explained. In this step, the fluorine-containing cyclopropane monoesters represented by the general formula [7], a fluorine-containing cyclopropane monoester by adding an amine represented by the general formula [8] represented by the general formula [9] form salts with amines, a process of recrystallization purification.
[0082]
　Formula of the amine represented by [8] R 7 , R 8 , R 9Each independently represent a hydrogen atom, C 1 -C 18 straight, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, aromatic ring group or a substituted aromatic having 6 to 18 carbon atoms It represents a ring group. Substituted alkyl group, any halogen atom on a carbon of the alkyl group, amino group, hydroxy group, an alkyl group having a substituent such as an aromatic ring group. Substituted aromatic ring group is an aromatic ring group having any halogen atom on the carbon atoms, a nitro group, an alkyl group having 1 to 6 carbon atoms, a substituent such as an alkoxy group having 1 to 6 carbon atoms of the aromatic group . Specifically, a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, 1-butyl, 2-butyl, isobutyl, tert- butyl group, 1-pentyl, 2-pentyl, 3-pentyl group, 2-methyl-1-butyl, 2-methyl-2-butyl group, 3-methyl-1-butyl group, 3-methyl-2-butyl group, neopentyl group, 1-hexyl, 2-hexyl group , 3-hexyl, 2-methyl-1-pentyl group, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group , 4-methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,2-dimethyl-1-butyl group, 2,3-dimethyl-1-butyl group, 3,3-dimethyl-1-butyl group, , 3-dimethyl-2-butyl group, 3,3-dimethyl-2-butyl group, 2-ethyl-1-butyl group, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl group, 1-undecyl, 1-dodecyl group, 1-tridecyl group, 1-tetradecyl group, 1-pentadecyl group, 1-hexadecyl group, 1-heptadecyl group, 1-octadecyl group, 1-cyclopropyl group, 1-cyclopentyl , 1-cyclohexyl group, a chloromethyl group, bromomethyl group, cyanomethyl group, 2-hydroxyethyl group, 2-aminoethyl group, 2-chloroethyl group, a benzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4- chlorobenzyl group, 2-fluorobenzyl group, 3-Furuorobe Njiru group, 4-fluorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, a 1-naphthyl group, 2-naphthyl group, a 1-anthracenyl group, 9-anthracenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4- methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, and a 4-methoxyphenyl group Is hydrogen Among them, a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, 1-butyl group, 1-pentyl, 1-hexyl, 1-heptyl, 1-octyl, 1-nonyl group, 1-decyl, 1-cyclohexyl group, a benzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, a naphthyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl , 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group, a hydrogen among them, a methyl group, an ethyl group, a propyl group, an isopropyl group, 1-butyl group, 1-cyclohexyl group, benzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, 1- (1-naphthyl) ethyl group is particularly preferred. , 4-bromophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3 - methoxyphenyl group, and a 4-methoxyphenyl group, a hydrogen among them, a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, 1-butyl group, 1-pentyl, 1-hexyl, 1-heptyl group, 1-octyl, 1-nonyl, 1-decyl, 1-cyclohexyl group, a benzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, a naphthyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) represents an ethyl group, a hydrogen among them, a methyl group, Ethyl group, a propyl group, an isopropyl group, 1-butyl group, 1-cyclohexyl group, a benzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, 1- (1-naphthyl) ethyl group is particularly preferred. , 4-bromophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3 - methoxyphenyl group, and a 4-methoxyphenyl group, a hydrogen among them, a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, 1-butyl group, 1-pentyl, 1-hexyl, 1-heptyl group, 1-octyl, 1-nonyl, 1-decyl, 1-cyclohexyl group, a benzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, a naphthyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) represents an ethyl group, a hydrogen among them, a methyl group, Ethyl group, a propyl group, an isopropyl group, 1-butyl group, 1-cyclohexyl group, a benzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, 1- (1-naphthyl) ethyl group is particularly preferred.
[0083]
　Salts with fluorinated cyclopropane monoester with an amine represented by the general formula [9], it is possible to improve the optical purity by performing recrystallization purification. For example, according to International Publication No. 2010/041739, by performing the recrystallization purification using chiral amine, optical purity of similar compounds have been reported to increase.
[0084]
　General formula R amine represented by [8] 7 , R 8 , R 9 if the there is a chiral center, the use of optically active amine is a preferred embodiment since it facilitates the improvement of the optical purity by recrystallization is there. That is, among the general formula [8], amines specifically represented by the general formula [10] is particularly preferred. R in the amine 7 , R 8 , R 10Is hydrogen, C 1 to 18 straight, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group or an aromatic ring group or a substituted aromatic ring group having 6 to 18 carbon atoms represent. Specifically hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, 1-butyl, 2-butyl, isobutyl, tert- butyl group, 1-pentyl, 2-pentyl, 3-pentyl , 2-methyl-1-butyl, 2-methyl-2-butyl group, 3-methyl-1-butyl group, 3-methyl-2-butyl group, neopentyl group, 1-hexyl, 2-hexyl group, 3-hexyl, 2-methyl-1-pentyl group, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,2-dimethyl-1-butyl group, 2,3-dimethyl-1-butyl group, 3 , 3-dimethyl-1-butyl group, 2, - dimethyl-2-butyl group, 3,3-dimethyl-2-butyl group, 2-ethyl-1-butyl group, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, 1- undecyl, 1-dodecyl group, 1-tridecyl group, 1-tetradecyl group, 1-pentadecyl group, 1-hexadecyl group, 1-heptadecyl group, 1-octadecyl group, 1-cyclopropyl group, 1-cyclopentyl, 1 - cyclohexyl group, chloromethyl group, bromomethyl group, cyanomethyl group, 2-hydroxyethyl group, 2-aminoethyl group, 2-chloroethyl group, a benzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl , 4-bromobenzyl group, 1-phenylethyl, 2-phenylethyl group, a phenyl group, 1-naphthyl, 2-naphthyl, 1-anthracenyl group, 9-anthracenyl group, 2-chlorophenyl group, a 3-chlorophenyl group,
[0085]
　Incidentally, R 10 for the groups other than a hydrogen atom, i.e., having 1 to 18 linear carbon atoms, an alkyl group, a substituted alkyl group or a C 6 to branched chain or cyclic (in the case of 3 or more carbon atoms) for 18 aromatic ring group, an amine represented by the general formula [10] has an asymmetric center, form salts with a fluorinated cyclopropane monoester and amine as optically active amine.
[0086]
　Ar 1 represents an aromatic ring group or a substituted aromatic ring group having 6 to 14 carbon atoms. Substituent in the substituted aromatic ring groups have any halogen atoms in the carbon of the aromatic ring group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an an alkoxy group having 1 to 6 carbon atoms. Specifically, phenyl group, 1-naphthyl, 2-naphthyl, 1-anthracenyl group, 9-anthracenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluoro phenyl, 3-fluorophenyl group, 4-fluorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group , 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, a 4-methoxyphenyl group and the like, a phenyl group among them, 1-naphthyl group, 2-naphthyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group, 2-meth Shifeniru group, 3-methoxyphenyl group, a 4-methoxyphenyl group are preferred, a phenyl group, 1-naphthyl, 2-naphthyl are particularly preferred.
[0087]
　The amine represented by the general formula [8] Specifically, 1-phenylethylamine, 1- phenylpropylamine, 4-phenyl-2-butylamine, 2-methyl-1-phenylpropylamine, 1- (2-methylphenyl) ethylamine, 1- (3-methylphenyl) ethylamine, 1- (4-methylphenyl) ethylamine, 1- (4-ethylphenyl) ethylamine, N- methyl-1-phenylethylamine, N- methyl-1-phenylpropylamine, N- methyl-1- (4-methylphenyl) ethylamine, 1- (2-naphthyl) ethylamine, 1- (2-naphthyl) propylamine, N- methyl-1- (2-naphthyl) ethylamine, N- methyl - 1- (2-naphthyl) propylamine, 1- (1-naphthyl) ethylamine and the like, But 1-phenylethylamine, 1- phenylpropylamine, 1- (4-methylphenyl) ethylamine, 1- (4-ethylphenyl) ethylamine, N- methyl-1-phenethylamine, 1- (2-naphthyl) ethylamine, 1- (2-naphthyl) propylamine, 1- (1-naphthyl) ethylamine are particularly preferred.
[0088]
　General formula [10] at the indicated by the amine * represents an asymmetric carbon, the fluorine-containing cyclopropane monoesters represented by the general formula [7], may take either the R or S as a configuration.
[0089]
　The solvent used for recrystallization purification, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, ketone solvents, ester solvents, nitrile solvents, alcohol solvents, water and the like. Of these, aliphatic hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, ketone solvents, ester solvents, nitrile solvents, alcohol solvents, water is preferable, aliphatic hydrocarbon solvents, ketone system solvent, nitrile solvent, an alcohol solvent, water is particularly preferred. Specifically n- pentane, n- hexane, cyclohexane, n- heptane, methylcyclohexane, benzene, toluene, ethylbenzene, xylene, mesitylene, methylene chloride, chloroform, 1,2-dichloroethane, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl -tert- butyl ether, cyclopentyl methyl ether, acetone, methyl ethyl ketone, methyl i- butyl ketone, ethyl acetate, n- butyl, acetonitrile, propionitrile, methanol, ethanol, n- propanol, isopropanol, n- butanol, isobutanol, etc. and the like. Wherein at even n- hexane, methylcyclohexane, n- heptane, methylene chloride, diisopropyl ether, tetrahydrofuran, methyl -tert- butyl ether, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, methanol, ethanol, n- propanol, isopropanol and water Preferably, In particular n- hexane, methylcyclohexane, n- heptane, acetone, acetonitrile, methanol, ethanol, n- propanol, isopropanol, diisopropyl ether and water are more preferred. These recrystallization solvents can be used singly or in combination.
[0090]
　The amount of solvent used for recrystallization purification may respect the general formula [9] represented by the fluorinated cyclopropane monoester and crude crystals 1g salts with amines, using normal 1ml above, 1 100ml are preferred, 1 ~ 50 ml is more preferred.
[0091]
　In this recrystallization purification, it can be precipitated smoothly and efficiently crystals by adding seed crystals. The amount of the seed crystal may be the general formula [9] in the normal 0.0001g above the crude crystals 1g of the salt with a fluorinated cyclopropane monoester and amine represented used, 0.0001 to 0 .1g are preferred, particularly 0.001 ~ 0.05 g is more preferable.
[0092]
　The temperature condition can be appropriately determined by the boiling point and freezing point of the recrystallization solvent used, usually dissolved before purification of the crude crystals at a temperature near the boiling point of the recrystallization solvent from about 30 ° C., still standing or stirring lower, to precipitate crystals while gradually cooling and finally cooled to -20 ° C. ~ room temperature (25 ° C.).
[0093]
　In this recrystallization purification, the precipitation chemical purity and optical purity of the crystals is improved by the precipitated crystals are recovered by filtration or the like, represented by a high chemical purity and optical purity of the general formula [9] including salts with fluorine cyclopropane monoesters and amines can be obtained. Further by repeating the recrystallization procedure, a higher chemical purity and can be obtained as the optical purity. Also before purification the crude crystals may be decolorized by activated carbon treatment is dissolved in the recrystallization solvent.
[0094]
　As the purification time is is usually from 0.1 to 120 hours, for different purification conditions, it precipitated chemical purity of crystals, in optical purity and monitoring analysis to high chemical purity and optical purity precipitated amount of the crystal yield it is preferable that the could be recovered when the end point.
[0095]
　The resulting crystals rotary evaporator, the vibration dryer, conical dryer, etc. to remove the solvent adhering to the crystals, such as tray dryer can be obtained more what chemical purity is high. The conditions for drying usually vacuum degree at a temperature in the region of 30 ~ 100 ° C. can be dried at atmospheric pressure (0.1 MPa) from 0.0001 MPa.
[0096]
　It may be a 1-7 times as the number of times to carry out the recrystallization purification is preferably 1 to 5 times, particularly preferably 1 to 3 times. And fewer times to carry out the recrystallization purification does not increase the optical purity enough, unfavorably reduced yield when the number of times to implement is too much.
[0097]
　The optical purity of the raw material purified by recrystallization, but what can be purified by recrystallization from any purity, high purification efficiency higher. For recrystallization purification from the racemic mixture is inefficient, raw optical purity is preferably at least 30% ee, particularly preferably ee 70%.
[0098]
　Among salts with fluorinated cyclopropane monoester with an amine represented by the general formula [17], R 11 represents a linear or branched alkyl group having 1 to 6 carbon atoms. A methyl group, an ethyl group, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert- butyl group, 1-heptyl group, a 1-hexyl group, methyl among them group, an ethyl group, 1-propyl, 2-propyl, 1-butyl, 2-butyl group, a tert- butyl group preferably a methyl group, an ethyl group are particularly preferred.
[0099]
　Also, R 12 , R 13 , R 14 each independently represents an hydrogen atom, a linear or branched chain on the alkyl group having 1 to 6 carbon atoms. Specifically hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert- butyl group, 1-heptyl group, a 1-hexyl group, the Above all hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl group, a tert- butyl group, more preferably a hydrogen, a methyl group, an ethyl group it is particularly preferred.
[0100]
　Further, Ar 2 represents an aromatic ring group or a substituted aromatic ring group having 6 to 10 carbon atoms. Substituent in the substituted aromatic ring groups have any halogen atoms on the carbons of the aromatic ring group, a nitro group, an alkyl group having 1 to 6 carbon atoms, a substituent such as an alkoxy group having 1 to 6 carbon atoms. Specifically, phenyl group, 1-naphthyl, 2-naphthyl, 1-anthracenyl group, 9-anthracenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3- fluorophenyl group, 4-fluorophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, a 4-methoxyphenyl group and the like, a phenyl group among them, 1-naphthyl, 2-naphthyl, 2-chlorophenyl group, 4-chlorophenyl group, 2-nitrophenyl group, 4- nitrophenyl group, 2-methoxyphenyl group, a 4-methoxyphenyl group are preferred, a phenyl group, 1- Fuchiru group, 2-naphthyl group is particularly preferred.
[0101]
　Incidentally, R 14 for the definition of, for straight-chain or branched alkyl group having 1 to 6 carbon atoms, amine has an asymmetric center, salts with fluorinated cyclopropane monoester and amine as optically active amine to form.
[0102]
　Salts with fluorinated cyclopropane monoester with an amine represented by the obtained formula [9], for example, is a useful compound as a pharmaceutical intermediate. For example, converting a cyclopropane monoester salts are ammonium salts as in Reference Example 12 After removal, the fluorine-containing cyclopropane amino acids by Curtius rearrangement reaction and hydrolysis reaction. This compound is an intermediate of hepatitis C treatment as reported in e.g. WO 2009/134987 Patent Report.
Example
[0103]
　The present invention will hereinafter be described in detail by way of Examples, but the present invention is not limited to these examples. Here, "%" in the analysis value represents "area%" of the composition obtained by measuring the nuclear magnetic resonance spectra (NMR) or gas chromatograph mass spectrometer.
[0104]
　[Example
　1] acetonitrile in a stainless steel autoclave reactor 200 ml (100 ml), 3,3-difluoro-1,2-propanediol (a racemic mixture represented by the following formula, purity: 96.6wt%, 11.6g was 100 mmol) and potassium carbonate (15.2 g, 110 mmol) put and stirred at room temperature for one hour.
Formula 35]

The reactor sulfuryl fluoride Upon cooling at -10 ℃ (16.6g, 163mmol) was slowly introduced. Internal temperature at this time was -5 ~ 2 ° C.. Introduction of sulfuryl fluoride was stirred for 2.5 hours at an internal temperature of -5 ~ 0 ° C. when finished. Thereafter, the temperature was raised to room temperature over 30 minutes. The resulting reaction solution 19 was analyzed by F-NMR, the fluorinated cyclic sulfate of interest 69.4% yield, 69.45Mmol. The resulting reaction solution to remove solids which had precipitated by suction filtration, and the filtrate concentrated on a rotary evaporator. Fluorinated cyclic sulfate of the resulting residue purpose represented by the following formula by subjecting to column chromatography 58.2% yield, 58.3 mmol.
Formula 36]

of the object 1 H-NMR (deuterated solvent: CD 3 CN, reference material: tetramethylsilane), δppm: 4.89 (dq, 2H), 5.25 (m, 1H), 6.19 (dt, IH), 19 F-NMR (deuterated solvent: CD 3 CN, standard: setting the hexafluorobenzene -162.2ppm), - 131.9 (ddd, 1F), - 130.6 (ddd, 1F).
[0105]
　[Example 2]
　thermowell, a Dimroth condenser, sodium hydride and dimethoxyethane (31.2 ml) three-necked flask 200ml of internal equipped with a septum was purged with nitrogen (3.93g, 98.3mmol) and put was cooled with ice water. Then diethyl malonate (7.49 g, 46.8 mmol) and a mixture of dimethoxyethane (31.2 ml) was added slowly over 10 minutes. This time the temperature was 2 ~ 14 ° C.. Addition was stirred for 30 minutes while cooled in ice water when finished. Then fluorine-containing cyclic sulfate (8.48 g, 41.3 mmol) represented by the following formula and benzotrifluoride dimethoxyethane (31.2 ml) is an internal standard substance (1.50g, 10.27mmol) A mixture of It was added slowly over a period of 5 minutes.
Formula 37]

This time the temperature was 3 ~ 17 ° C.. Addition was stirred for 30 minutes while cooling with ice water when finished. It was then stirred for 2.5 hours and heated to near the internal temperature 80 ° C. in an oil bath. Heating was cooled to room temperature when you are finished. The solvent was then removed and the solution on a rotary evaporator, the weight of the solution was carried out concentrated to 29.3 g. Was diluted by adding diisopropyl ether 93.6ml to the concentrate, then the solution cooled sulfuric acid (0.73 g, 7.4 mmol) was added slowly to the mixture of water (119 ml). Internal temperature at this time was 5 ~ 7 ° C.. The solution was then separated into two layers, the aqueous layer was extracted with diisopropyl ether (78ml × 2). It was combined all organic layer obtained was concentrated on a rotary evaporator. The residue obtained on concentration than be subjected to column chromatography to obtain a fluorine-containing cyclopropane diesters of interest represented by the following formula 8.85 g, with (content 22.0 mmol), 53% yield.
[Of 38]

of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 1.29 (td, 6H), 1.54 (m, 1H), 1.75 (m, 1H), 2.35 (m, IH), 4.23 (m, 4H), 5.72 (td, IH), 19 F-NMR (deuterated solvent: setting a hexafluorobenzene -162.2Ppm: heavy chloroform, standard substance), -117.8 (ddd, 1F), - 111.6 (ddd, 1F).
[0106]
　[Example
　3] 50 ml stainless steel autoclave reactor THF (17 ml) and sodium hydride (0.89 g, 22.3 mmol) placed was cooled in an ice-water are then represented by the following formula 3,3 - difluoro-1,2-propanediol (a racemic mixture, 1.0 g, 8.9 mmol) was added portionwise.
Formula 39]

was stirred for 20 minutes while cooling with ice water and the lid to the reactor once the addition is complete. The reactor of dry ice and a mixture of acetonitrile reactor internal Upon cooling at (-45 ° C.) was degassed to approximately 0.001MPa a vacuum pump. Then, it was introduced slowly over a period of sulfuryl fluoride (1.1g, 10.8mmol) for about an hour. The pressure was increased to 0.2MPa. Introduction was stirred for 2 hours while cooling When complete, was stirred overnight at room temperature. The resulting reaction solution 19 was analyzed by F-NMR, the fluorinated cyclic sulfate of interest represented by the following formula Yield: 50.7%, was obtained 4.5 mmol.
[Of 40]

[0107]
　[Example 4]
　thermowell, was cooled with ice water was poured diethyl malonate three-necked flask 50ml equipped with a Dimroth condenser and a septum (0.80 g, 5.0 mmol) and THF with (13 ml). Then sodium hydride (0.45 g, 11.3 mmol) was charged portionwise. This time the temperature was 8 ~ 9 ° C.. Charged is fitted with a dropping funnel into the reactor when finished, was slowly added dropwise and the reaction solution containing a fluorinated cyclic sulfate represented by the following formula obtained in Example 3 in a dropping funnel.
Formula 41]

This time the temperature was 3 ~ 7 ° C.. It was stirred for two hours while cooled in ice water. The reaction mixture was allowed to react for one hour at around an internal temperature 68.8 ° C. and heated in an oil bath (reflux). After filtering the resulting reaction solution, and the precipitated solid was washed with diisopropyl ether 15 ml. And concentrated on a rotary evaporator and the combined filtrate and washings. As a result, to obtain a crude product of the fluorine-containing cyclopropane diesters of interest represented by the following formula 5.3 g, at (content 2.4 mmol), 54% yield.
[Of 42]

[0108]
　[Example
　5] acetonitrile (100ml) in a stainless steel autoclave reactor 200 ml, represented by the following formula (S)-3,3-difluoro-1,2-propanediol (chemical purity: 91.6wt%, optical purity: 82.0% ee, 12.2g, was 100 mmol) and potassium carbonate (16.6 g, 120 mmol) put and stirred at room temperature for one hour.
Formula 43]

When reactor was then cooled to an internal temperature of -5 ° C. was introduced slowly sulfuryl fluoride (14.9 g, 146 mmol). Internal temperature at this time was -5 ~ 4 ° C.. Was stirred for 3 hours at an internal temperature of -5 ~ 0 ° C. After the introduction of the sulfuryl fluoride is completed. Thereafter, the temperature was raised to room temperature over 15 minutes. The resulting reaction solution 19 was analyzed by F-NMR, the fluorinated cyclic sulfate of interest represented by the following formula Yield: 77.1%, were obtained 77.1 mmol.
Formula 44]

obtained reaction mixture to remove solids which had precipitated by suction filtration, the filtrate was washed with toluene 30 ml. And concentrated on a rotary evaporator and the combined filtrate and washes. The resulting residue extracted toluene was added to 65ml of water 39 ml, and the two layers separated. The aqueous layer was extracted again with toluene 26 ml. Extraction solution result of the concentration and azeotropic dehydration together, 12.8 g of fluorine-containing cyclic sulfate of interest, 65.4% yield, 65.4 mmol. Of the desired product 1 H-NMR (deuterated solvent: CD 3 CN, reference material: tetramethylsilane), δppm: 4.89 (dq, 2H), 5.25 (m, 1H), 6.19 (dt, 1H ), 19 F-NMR (deuterated solvent: CD 3CN, reference material: Set the -162.2ppm hexafluorobenzene), - 131.9 (ddd, 1F), - 130.6 (ddd, 1F).
[0109]
　Example 6
　thermowell, a Dimroth condenser, sodium hydride and THF (25 ml) three-necked flask 200ml of internal equipped with a septum was purged with nitrogen (2.25 g, 56.2 mmol) Put ice in was cooling. Then diethyl malonate (4.09 g, 25.6 mmol) and was added the mixture slowly over 30 minutes THF (17 ml). This time the temperature was 3 ~ 5 ° C.. Addition was stirred for 30 minutes while cooled in ice water when finished. Then fluorine-containing cyclic sulfate represented by the following formula obtained in Example 5 (5.0g, 25.6mmol) and THF (9 ml) as an internal standard in which benzotrifluoride (1.47 g, 10 mmol) of the mixture was added slowly over 30 minutes.
Formula 45]

This time the temperature was 3 ~ 4 ° C.. Addition was stirred for 3.5 hours while cooling with ice water when finished. Then in THF (34 ml) was added and stirred for 3 hours by heating in the vicinity of an internal temperature 70 ° C. in an oil bath. Heating and cooled to room temperature When finished, the solution was cooled sulfuric acid (0.40 g, 4.1 mmol) was added slowly to the mixture of water (85 ml). Internal temperature at this time was 3 ~ 5 ° C.. The solution was then separated into two layers, the aqueous layer was extracted with diisopropyl ether (twice with 100 ml, once with 50ml). It was combined all organic layer obtained was concentrated on a rotary evaporator. The residue obtained on concentration than be subjected to column chromatography to obtain a fluorine-containing cyclopropane diesters of interest represented by the following formula Yield 4.5 g, content 17.1 mmol, 67% yield.
[Of 46]

of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 1.29 (td, 6H), 1.54 (m, 1H), 1.75 (m, 1H), 2.35 (m, IH), 4.23 (m, 4H), 5.72 (td, IH), 19 F-NMR (deuterated solvent: setting a hexafluorobenzene -162.2Ppm: heavy chloroform, standard substance), -117.8 (ddd, 1F), - 111.6 (ddd, 1F).
[0110]
　Example 7
　thermowell, Dimroth condenser, THF internal equipped with a septum in the three-necked flask 200ml substituted with nitrogen (17 ml) and sodium hydride (2.87 g, 71.8 mmol) Put ice in was cooling. Then malonic acid dipropyl (6.49 g, 34.5 mmol) and the mixture was slowly added over 40 minutes of THF (19 ml). Internal temperature at this time was 4 ~ 5 ° C.. Addition was stirred for 30 minutes while cooled in ice water when finished. Then fluorine-containing cyclic sulfate represented by the following formula was synthesized in Example 5 (5.0g, 28.7mmol) with a mixture of THF (19 ml) and the internal standard substance benzotrifluoride (1.46 g, 10 mmol) It was added slowly over a period of 30 minutes.
Formula 47]

This time the temperature was 3 ~ 4 ° C.. Addition was stirred for 1.5 hours while cooling with ice water when finished. It was then stirred for 1.5 hours and heated to near the internal temperature 65 ° C. in an oil bath. Heating and cooled to room temperature When finished, the solution cooled sulfuric acid (0.89 g, 9.1 mmol) was added slowly to the mixture of water (57 ml). Internal temperature at this time was 3 ~ 5 ° C.. The solution was then separated into two layers, water 20ml was added to the aqueous layer was extracted with diisopropyl ether 100 ml. It was combined all organic layer obtained was concentrated on a rotary evaporator. The residue obtained on concentration than be subjected to column chromatography to obtain a fluorine-containing cyclopropane diesters of interest represented by the following formula Yield 6.52 g, content 11.9 mmol, 43% yield.
[Of 48]

of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 0.96 (t, 6H), 1.55 (m, 1H), 1.69 (m, 5H), 2.35 (m, IH), 4.13 (q, 4H), 5.71 (td, IH), 19 F-NMR (deuterated solvent: setting a hexafluorobenzene -162.2Ppm: heavy chloroform, standard substance), -117.7 (ddd, 1F), - 111.5 (ddd, 1F).
[0111]
　Example
　8 acetonitrile (100ml) in a stainless steel autoclave reactor 200 ml, represented by the following formula (R)-3,3-difluoro-1,2-propanediol (chemical purity: 89.5wt%, optical purity 78.2% ee, 12.5g, was 100 mmol) and potassium carbonate (16.6 g, 120 mmol) put and stirred at room temperature for one hour.
Formula 49]

When reactor was then cooled at -10 ° C. coolant was introduced slowly sulfuryl fluoride (14.2 g, 139 mmol). The internal temperature of at this time was -10 ~ 5 ℃. Was stirred for 3 hours at an internal temperature of -5 ~ 0 ° C. After the introduction of the sulfuryl fluoride is completed. Thereafter, the temperature was raised to room temperature over 30 minutes. The resulting reaction solution 19 was analyzed by F-NMR, the fluorinated cyclic sulfate of interest represented by the following formula 74.2% yield, 74.2 mmol.
Formula 50]

reaction solution was cooled to 0 ° C., to remove the solid which had precipitated by suction filtration. The filtrate was washed with toluene 30 ml. And concentrated on a rotary evaporator and the combined filtrate and washes. The resulting residue extracted toluene was added to 100ml of water 50 ml, and the two layers separated. The aqueous layer was extracted again with toluene 20 ml. Extraction solution result of the concentration and azeotropic dehydration together to obtain a crude product of the fluorine-containing cyclic sulfate 13.0 g, content 87.8wt%, 65.5mmol, in 65.5% yield. Of the desired product 1 H-NMR (deuterated solvent: CD 3 CN, reference material: tetramethylsilane), δppm: 4.89 (dq, 2H), 5.25 (m, 1H), 6.19 (dt, 1H ), 19 F-NMR (deuterated solvent: CD3 CN, standard: setting the hexafluorobenzene -162.2ppm), - 131.9 (ddd, 1F), - 130.6 (ddd, 1F).
[0112]
　Example 9
　stainless steel autoclave reactor in acetonitrile (850 ml), represented by the following formula (R)-3,3-difluoro-1,2-propanediol (chemical purity: 95.2wt%, optical purity 89 .7% ee, 100.1g, was stirred one hour at room temperature in a 850Mmol) and potassium carbonate (141g, 1020mmol).
Formula 51]

When reactor was then cooled at -10 ° C. coolant was introduced slowly sulfuryl fluoride (104.1g, 1020mmol). Internal temperature at this time was -7 ~ -1 ° C.. Was stirred for 3 hours at an internal temperature of -5 ~ 0 ° C. After the introduction of the sulfuryl fluoride is completed. Thereafter, the temperature was raised to room temperature over 1 hour. The resulting reaction solution 19 was analyzed by F-NMR, the fluorinated cyclic sulfate of interest represented by the following formula Yield: 75.1%, was obtained 638.4Mmol.
Formula 52]

obtained reaction solution was cooled to 0 ° C., to remove the solid which had precipitated by suction filtration. The filtrate was washed with toluene 250 ml. And concentrated on a rotary evaporator and the combined filtrate and washes. The resulting residue extracted toluene was added to 480ml of water 240 ml, and the two layers separated. The aqueous layer was extracted again with toluene 120 ml. Extraction solutions were combined and concentrated to a result of the removal by azeotropic dehydration of moisture remaining with toluene 60 ml, 121.0 g of crude product of the fluorine-containing cyclic sulfate purposes, content: 94.9wt%, 659 .3Mmol, was obtained 77.6% yield.
[0113]
　Example 10
　thermowell, Dimroth condenser, cooling the interior equipped with a septum sodium hydride and THF (55 ml) three-necked flask 300ml substituted with nitrogen (4.4 g, 110 mmol) in ice water put did. Then diethyl malonate (8.0 g, 50 mmol) and the mixture was slowly added over 40 minutes of THF (56 ml). This time the temperature was 3 ~ 5 ° C.. Addition was stirred for 30 minutes while cooled in ice water when finished. Then fluorine-containing cyclic sulfate represented by the following formula obtained in Example 8 (9.9g, 50mmol) and THF (56 ml) and the internal standard substance benzotrifluoride (2.92 g, 20 mmol) for 30 minutes It was added slowly over.
Formula 53]

This time the temperature was 3 ~ 5 ° C.. Addition was stirred for 1 hour while cooling with ice water when finished. It was then stirred for 2.5 hours and heated to near the internal temperature 66 ° C. in an oil bath. Heating and cooled to room temperature when finished, and the mixture was stirred overnight at room temperature. The resulting sulfuric acid the reaction solution was cooled (0.77 g, 7.9 mmol) was added slowly to the mixture of water (167 ml). Internal temperature at this time was 3 ~ 5 ° C.. The solution was then separated into two layers, the resulting aqueous layer was extracted with diisopropyl ether (twice with 170 ml). It was combined all organic layer obtained was concentrated on a rotary evaporator. The residue obtained by concentration by subjecting to column chromatography to obtain a fluorine-containing cyclopropane diesters of interest represented by the following formula Yield 9.7 g, content 30.3 mmol, 62% yield.
[Of 54]

of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 1.29 (td, 6H), 1.54 (m, 1H), 1.75 (m, 1H), 2.35 (m, IH), 4.23 (m, 4H), 5.72 (td, IH), 19 F-NMR (deuterated solvent: setting a hexafluorobenzene -162.2Ppm: heavy chloroform, standard substance), -117.8 (ddd, 1F), - 111.6 (ddd, 1F).
[0114]
　[Example 11]
　thermowell, a Dimroth condenser, septum, sodium hydride and dimethoxyethane (80 ml) four-necked flask 500ml with an internal equipped with a mechanical stirrer was purged with nitrogen (10.08 g, 252 mmol) put was cooled with ice water. Then diethyl malonate (8.0 g, 50 mmol) and a mixture of dimethoxyethane (80 ml) was added slowly over 25 minutes. This time the temperature was 3 ~ 5 ° C.. Addition was stirred for 30 minutes while cooled in ice water when finished. Then fluorine-containing cyclic sulfate represented by the following formula (chemical purity: 90.77wt%, optical purity: 77.3% ee, 23.02g, 120mmol ) benzotrifluoride an internal standard substance and dimethoxyethane (80 ml) Lido (5.84 g, 40 mmol) was added slowly over a mixture of 50 min.
Formula 55]

This time the temperature was 3 ~ 5 ° C.. Addition was stirred for 1 hour while cooling with ice water when finished. It was then stirred for 2 hours and heated to near the internal temperature 80 ° C. in an oil bath. Heating and cooled to room temperature when finished, and the mixture was stirred overnight at room temperature. The resulting reaction solution was concentrated on a rotary evaporator, the solvent was about 170ml removed. Then diisopropyl ether was added 240 ml. The solution cooled sulfuric acid (2.35 g, 24 mmol) was slowly added to the mixture of water (300 ml). Internal temperature at this time was 3 ~ 5 ° C.. The solution was then separated into two layers, the resulting aqueous layer was extracted with diisopropyl ether (twice with 200ml). It was combined all organic layer obtained was concentrated on a rotary evaporator. The residue obtained by concentration by subjecting to column chromatography to obtain a fluorine-containing cyclopropane diesters of interest represented by the following formula Yield 25.68 g, content 85.83Mmol, in 72% yield.
[Of 56]

[0115]
　Example 12
　thermowell, a Dimroth condenser, septum, an internal equipped with a mechanical stirrer four-neck flask 200ml was replaced with nitrogen THF and (50 ml) n-heptane (10ml) and sodium hydride (2 .17g, 54.2mmol) was heated in an oil bath at 80 ° C. put. When the internal temperature reached 68 ° C., the inner while keeping the temperature diethyl malonate (4.34 g, 27.1 mmol) and fluorinated cyclic sulfate represented by the following formula (chemical purity: 94.3wt%, 5. 200 g, was added dropwise over the mixture 5 hours 27.1 mmol).
Formula 57]

After the completion of dropwise addition, the mixture was stirred while 1.5 hours of the internal temperature 68 ° C.. After returning to room temperature, added methyl tert- butyl ether 58 g, was added dropwise to this solution 1 wt% aqueous sulfuric acid 29 g. The solution was then separated into two layers, an organic layer 19 was analyzed by F-NMR, found that fluorinated cyclopropane diesters of interest represented by the following formula is included 85.83mmol (4.72g) It was. It was 74% yield.
[Of 58]

[0116]
　Example 13
　thermowell, a septum, a Dimroth condenser, THF internal equipped with a mechanical stirrer four-neck flask 200ml substituted with nitrogen (45 ml) and diethyl malonate (3.31 g, 20.7 mmol) It was cooled in an ice-water put. Then metallic sodium (0.58 g, 25.3 mmol) were charged, and stirred for 2 hours at an internal temperature of 6 ~ 9 ° C., then stirred at room temperature for 2 hours. Internal (78.2% ee, 3.01g, 14.9mmol chemical purity:: 86 wt%, optical purity) and THF and (7 ml) then When the reaction solution was cooled with ice water a fluorinated cyclic sulfate represented by the following formula benzotrifluoride (1.49 g, 10.2 mmol) is standard mixture was added slowly over 10 minutes.
Formula 59]

This time the temperature was about 6 ° C.. Dripping is stirred for 1 hour while cooling with ice water when finished, then the temperature was raised to room temperature. Then metallic sodium (0.47 g, 20.3 mmol) put, after stirring 20 minutes at room temperature, and stirred for 1.5 hours and heated to near the internal temperature 67 ° C. in an oil bath. Heating and cooled to room temperature when finished, and allowed to stand overnight at room temperature. After standing, a result of analyzing the reaction liquid, it was confirmed that the fluorine-cyclopropane diesters of interest represented by the following formula 12.1 mmol, are generated in 81% yield.
Formula 60]

After standing, the resulting sulfuric acid the reaction solution was cooled (0.76 g, 7.8 mmol) was added slowly to the mixture of water (57 ml). The solution was then separated into two layers, the resulting aqueous layer was extracted with diisopropyl ether (three times with 30 ml). It was combined all organic layer obtained was concentrated on a rotary evaporator. By concentrated to give a fluorine-containing cyclopropane diester object Yield 4.0 g, content 6.71 mmol, 45% yield.
[0117]
　Example 14
　fluorinated cyclopropane diester represented by the following formula was synthesized in Example 6 three-necked flask 300ml equipped with a thermowell and stopcock (purity: 90wt%, 4.5g, 17. 1mmol), was added ethanol (8.6 ml) and water (8.6 ml) was cooled with ice water.
Formula 61]

then 25% aqueous solution of tetramethylammonium hydroxide (9.4 g, 25.7 mmol) was added slowly. This time the internal temperature was 2 ~ 5 ℃. After completion of the addition, the mixture was stirred for 30 minutes while cooling with ice water. The reaction mixture temperature was carried out mixing and two-layer separation by adding ethyl acetate 50ml and 3M aqueous hydrochloric acid 10ml Once raised to around 15 ℃ of. The aqueous layer was extracted with ethyl acetate (20ml × 3). The obtained organic layer were combined, washed with water 10 ml. After washing, the organic layer was dried over sodium sulfate, and filtered. The crude product of the fluorine-containing cyclopropane monoester represented the filtrate by the following formula by concentrating on a rotary evaporator to obtain 3.4 g.
Formula 62]

diastereomeric excess of the resulting crude material is 56% de, diastereomers were included Total 13.7 mmol. Of the desired product 1 H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.27 (t, 3H), 1.70 (ddd, 1H), 1.52 (ddd, 1H) , 2.29 (m, IH), 4.21 (q, 2H), 5.77 (td, IH), 19 F-NMR (deuterated solvent: deuterated methanol, reference material: -162.2Ppm hexafluorobenzene and settings) -115.4 (ddd, 1F), - 110.0 (ddd, 1F).
[0118]
　Example 15
　Isopropanol 1 to fluorinated cyclopropane shown in two-necked flask 20ml equipped with a thermowell and stopcock by the following formula obtained in Example 14 monoesters 1.47 g (5.67 mmol) .5Ml, and heated at (S) -1- phenylethylamine (0.76 g, 6.23 mmol) was added an oil bath temperature of 50 ° C..
Formula 63]

was then slowly cooled at room temperature while stirred with n- heptane 9 ml. The internal temperature was filtered crystals precipitated After cooled to about room temperature. The resulting crystals were obtained 1.04g of the desired amine salts by drying until the weight of crystals in a rotary evaporator does not change. Isopropanol 0.9ml was added to the obtained crystals 0.9 g, it was heated in an oil bath at temperature 50 ° C.. Then cooled to a temperature slowly near room at room temperature with stirring by adding n- heptane 5.4 ml. Then cooled with ice water and filtered. The resulting crystals were obtained 0.38g of the desired product represented by the following formula by dry until the weight of crystals in a rotary evaporator does not change.
Formula 64]

of the object 1 H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.25 (t, 3H), 1.31 (ddd, 1H), 1.42 ( ddd, 1H), 1.62 (d , 3H), 2.13 (m, 1H), 4.17 (m, 2H), 4.44 (q, 1H), 5.66 (td, 1H), ~ 7.49 7.36 (m, 5H), 19 F-NMR (deuterated solvent: deuterated methanol, standard: setting the hexafluorobenzene -162.2ppm), - 114.7 (ddd, 1F), - 108.6 (ddd, 1F). The diastereomer excess was 99% de or more.
[0119]
　Example 16
　Determination of the optical purity: obtained crystals (100 mg, 0.304 mmol) in Example 15 to 3M HCl aqueous (5ml, 13.9mmol), was added methyl -tert- butyl ether (10 ml), crystals and mixed until all dissolved, and separated into two layers. The resulting organic layer sulfate (0.1 g, 1.0 mmol), triethyl orthoformate (3.4 g, 22.7 mmol), ethanol (15ml) and the mixture was stirred for 12 hours at 70 ° C.. After the reaction, the solution was concentrated and the resulting residue to water 1ml and methyl -tert- butyl ether 5ml was added and separated separated-two layers. The resulting organic layer was concentrated again, the results obtained residue was analyzed by HPLC, and was ee 99.1%. Analysis Conditions of HPLC column: CHIRALCEL OZ-3, eluent: n-heptane / isopropanol = 99.5 / 0.5, flow rate: 1 ml / min, detector: UV 210 nm, column temperature: 25 ° C., retention time: (S) - the body: 8.4min, (R) - the body: 9.6min.
[0120]
　Example 17
　thermowell and fluorinated cyclopropane diester double neck flask 300ml equipped with a stopcock represented by the following formula was synthesized in Example 10 (purity: 73.6wt%, 9.7g, 30 .3mmol), and cooled ethanol (15ml) and to the vicinity of an inner temperature of 2 ℃ by addition of water (15ml).
Formula 65]

then 25% aqueous solution of tetramethylammonium hydroxide (16.6 g, 45.5 mmol) was added slowly. This time the temperature was 2 ~ 15 ° C.. After completion of the addition, the mixture was stirred for 30 minutes while cooling with ice water. The reaction mixture temperature was carried out mixing and two-layer separation by adding ethyl acetate 100ml and 3M aqueous hydrochloric acid 20ml Once raised to around 15 ℃ of. The aqueous layer was extracted with ethyl acetate (40ml × 3). All the organic layers obtained one Summary and washed with water 20 ml. After washing, the organic layer was dried over sodium sulfate, and filtered. After stirring for 1 hour at room temperature with addition of active charcoal 0.6g To the resulting filtrate was filtered. Crude product of intended product represented resulting filtrate in the following formula by concentrating on a rotary evaporator to obtain 8.6 g.
Formula 66]

diastereomeric excess is 56% de, total yield diastereomer was almost quantitative. Of the desired product 1 H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.27 (t, 3H), 1.70 (ddd, 1H), 1.52 (ddd, 1H) , 2.29 (m, IH), 4.21 (q, 2H), 5.77 (td, IH), 19 F-NMR (deuterated solvent: deuterated methanol, reference material: -162.2Ppm hexafluorobenzene setting a), - 115.4 (ddd, 1F ), - 110.0 (ddd, 1F).
[0121]
　Example 18
　represented by the following formula necked flask 300ml equipped with a thermowell and stopcock (R) - fluorinated cyclopropane diester (purity: 78.5wt%, 5.58g, 18.5mmol ) and it was cooled to near the internal temperature 4 ~ 5 ° C. in addition ethanol (9.2 ml) and water (9.2 ml).
Formula 67]

then 40% aqueous sodium hydroxide (3.5 g, 35.2 mmol) was added slowly. This time the temperature was 4 ~ 8 ° C.. After stirring for 1 hour while cooling with ice water, it was carried out mixing and two-layer separation by adding ethyl acetate 50ml and 3M aqueous hydrochloric acid 10 ml. The aqueous layer was extracted with ethyl acetate (20ml × 3). All the organic layers obtained one Summary and washed with water 20 ml. After washing, the organic layer was dried over sodium sulfate, and filtered. After stirring for 30 minutes at room temperature with addition of active charcoal 0.2g To the resulting filtrate was filtered. The resulting filtrate was concentrated on a rotary evaporator, followed by azeotropic dehydration with toluene in concentrated residue. The crude product of the last purpose of the following formula by removing all organic solvents to obtain 4.68 g.
Formula 68]

the diastereomer excess of the resulting crude material was 72% de, diastereomers were included Total 13.6 mmol.
[0122]
　[Example 19]
　thermowell and stopcock and isopropanol 8.6ml fluorine-containing cyclopropane monoesters 8.6g represented by the following formula obtained in Example 17 three-necked flask 100ml with n- heptane 43ml It was added.
Formula 69]

The solution was cooled with ice water, then (R)-1-phenylethylamine (4.4 g, 34.6 mmol) was added. Thereafter, the mixture was stirred for 30 minutes at around room temperature. The solution was confirmed to become homogeneous and heated in an oil bath to the vicinity of an internal temperature 67 ° C. while stirring at a stirring element. Then remove the oil bath and start cooling of the solution at room temperature with stirring. Seed crystals were added 10mg When the inside temperature reached to 53 ° C.. The internal temperature started to crystals precipitated at 40 ~ 50 ° C.. The temperature of the solution is subjected to cooling with ice water When turned 28 ° C., and cooled to an internal temperature of 0 ~ 5 ° C., and filtered. Filtered crystals were washed with a solution 26ml was mixed 1:10 isopropanol and n- heptane. The washed crystals were obtained 6.37g of a fluorine-containing cyclopropane monoester salt of target by drying until no change in weight of the crystal on a rotary evaporator. The resulting crystals 6.27g added isopropanol 6.3ml to near the internal temperature 70 ° C. while stirring at a stirrer was heated in an oil bath. Crystals dissolved, it was confirmed that uniform. Next, n- heptane was added 19 ml. As a result, crystals were precipitated. Cooling was started with stirring and remove the oil bath After further n- heptane was added 19 ml. When the inside temperature reached to around 43 ° C. was added n- heptane 13 ml. The temperature of the solution is subjected to cooling with ice water When turned 28 ° C., and cooled to an internal temperature of 0 ~ 5 ° C., and filtered. The resulting crystals were obtained 5.66g of the desired product represented by the following formula by drying until no change in weight of the crystal on a rotary evaporator.
Formula 70]

of the object 1H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.25 (t, 3H), 1.31 (ddd, 1H), 1.41 (ddd, 1H), 1.62 (d, 3H), 2.12 ( m, 1H), 4.15 (q, 2H), 4.44 (q, 1H), 5.66 (td, 1H), 7.37 ~ 7.47 ( m, 5H), 19 F-NMR (deuterated solvent: deuterated methanol, standard: setting the -162.2ppm hexafluorobenzene), - 114.6 (ddd, 1F ), - 108.7 (ddd, 1F) , the diastereomer excess was 99% de or more. Results of the measurement of the optical purity EXAMPLE 16 reference was ee 99.3%.
[0123]
　Example 20
　fluorinated cyclopropane diester double neck flask 300ml equipped with a thermowell and stopcock represented by the following formula was synthesized in Example 2 (racemic mixture, purity: 58.8wt%, 8. 85 g, 22.0 mmol), and cooled ethanol (11 ml) and to the vicinity of an inner temperature of 2 ℃ by addition of water (11 ml).
Formula 71]

then 25% aqueous solution of tetramethylammonium hydroxide (17.1 g, 26.4 mmol) was added slowly. This time the temperature was 2 ~ 10 ° C.. After stirring for 1 hour while cooling with ice water, it was carried out mixing and two-layer separation by adding ethyl acetate 50ml and 3M aqueous hydrochloric acid 10 ml. The aqueous layer was extracted with ethyl acetate (20ml × 3). All the organic layers obtained one Summary and washed with water 20 ml. After washing, the organic layer was dried over sodium sulfate, and filtered. After stirring for 2 hours at room temperature with addition of active charcoal 0.2g To the resulting filtrate was filtered. Crude product of intended product represented resulting filtrate in the following formula by concentrating on a rotary evaporator to give 6.35 g.
Formula 72]

diastereomeric excess is 86% de, total yield diastereomer was almost quantitative. Of the desired product 1 H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.27 (t, 3H), 1.70 (ddd, 1H), 1.52 (ddd, 1H) , 2.29 (m, IH), 4.21 (q, 2H), 5.77 (td, IH), 19 F-NMR (deuterated solvent: deuterated methanol, reference material: -162.2Ppm hexafluorobenzene setting a), - 115.4 (ddd, 1F ), - 110.0 (ddd, 1F).
[0124]
　[Example 21]
　Dimroth condenser, a fluorine-containing cyclopropane represented by the following formula obtained in Example 20 three-necked flask 100ml equipped with a thermowell and stopcock monoester 6.35 g, diisopropyl ether 6.4ml and he was charged with n- hexane 12.8ml.
Formula 73]

Then (R)-1-phenylethylamine (3.26 g, 26.9 mmol) was added and heated to near the internal temperature 69 ° C. in an oil bath. Then remove the oil bath and start cooling of the solution at room temperature with stirring. Crystals at an internal temperature of 69 ° C. vicinity compound represented by the following formula as a seed crystal was added approximately 20 mg.
Formula 74]

again seeded around the temperature of 35 ° C. was added approximately 20 mg. Temperature was cooled with ice water Once reduced to around room temperature. The seed crystals were added about 20mg near an internal temperature 8 ° C.. Then, the mixture was stirred overnight at low temperature constant temperature water bath with a magnetic stirrer set to 0 ℃ (Tokyo Rika Equipment Co., Ltd. PSL type). The solution was filtered and crystals precipitated while cooling to 0 ~ 5 ° C., dried to change the weight of the crystals on a rotary evaporator is eliminated. Diisopropyl ether 12.8ml then added to the obtained crystals and heated to near the internal temperature 67 ° C. in an oil bath. Crystals remove the oil bath After ensuring that dissolved and slowly cooled at room temperature. Internal temperature of the seed crystals was added about 10mg at around 67 ° C.. Thereafter, while stirring the results of seed crystals added about 10mg near an internal temperature 20 ° C., crystals were deposited. The solution was filtered and cooled with ice water. The obtained crystals to give the desired product represented by the following formula by drying until no change in weight of the crystal on a rotary evaporator 0.99 g, 19% yield.
[Of 75]

diastereomeric excess rate was 96.9% de. Results of the measurement of the optical purity EXAMPLE 16 reference was 25.6% ee.
[0125]
　Example 22
　represented by the following formula necked flask 500ml equipped with a thermowell and stopcock (R) - fluorinated cyclopropane diester (purity: 63.2wt%, 128.5g, 343.8mmol ) and cooled to -5 ° C. the internal temperature was added ethanol (69 ml).
Formula 76]

Then 2-hydroxyethyl trimethylammonium hydroxide 48% aqueous solution (130.2g, 515.7mmol) was added slowly. This time the temperature was -5 ~ -2 ° C.. After the internal temperature was stirred for 8 hours while the -2 ° C., was performed by mixing two layers separated by adding methyl tert- butyl ether 258g and 3.2M aqueous hydrochloric acid 261 g. Separated aqueous layer was extracted with methyl tert- butyl ether (103g × 2). The resulting combined into one all of the organic layers were washed with water 138 ml, and concentrated on a rotary evaporator, followed by azeotropic dehydration with toluene in concentrated residue (120g × 2). The crude product of the last purpose of the following formula by removing all organic solvents to obtain 100.3 g. The resulting diastereomeric excess of the crude material was 65.3% de.
[Of 77]

[0126]
　Example 23
　isopropanol was added 27g and methylcyclohexane 133g fluorine-containing cyclopropane monoester 50.2g of three-necked flask 500ml equipped with a thermowell and stopcock represented by the following formula obtained in Example 22 .
Formula 78]

The solution was cooled with ice water, then (R)-1-phenylethylamine (22.0g, 181.5mmol) was added. The solution was heated in an oil bath then to an internal temperature of 70 ° C. with stirring was confirmed to become homogeneous. Then remove the oil bath and start cooling of the solution at room temperature with stirring. The internal temperature was filtered after continued for an additional 1 hour of stirring after becoming 20 ° C.. Filtered crystals were washed with a mixture of isopropanol 5g and methylcyclohexane 27 g. Washed crystals was obtained a fluorine-containing cyclopropane monoester salt of target by drying until no change in weight of the crystal on a rotary evaporator 36.7 g, 65% yield. The resulting crystals total amount of isopropanol was added 27g and cyclo-methylhexanoic 132g to near the internal temperature 70 ° C. with stirring and heated in an oil bath. Crystals after confirming that become dissolved uniformly, and start cooling with stirring and remove the oil bath. Crystals precipitated in the vicinity of the internal temperature 44 ° C., was filtered after the additional 1 hour stirring at an internal temperature of 20 ° C.. The obtained crystals to give the desired product represented by the following formula by drying until no change in weight of the crystal on a rotary evaporator 29.5 g, 51% yield.
[Of 79]

the diastereomer excess of the desired product was 99% de or more. Results of the measurement of the optical purity EXAMPLE 16 reference was 99.7% ee.
[0127]
　Example 24
　was added diisopropyl ether 31mL fluorine-containing cyclopropane monoester 25.1g of three-necked flask 500ml equipped with a thermowell and stopcock represented by the following formula obtained in Example 22. The solution was cooled with ice water, then (S) -1- phenylethylamine (10.9g, 90.3mmol) was added.
Formula 80]

was heated in an oil bath and then to an internal temperature of 65 ° C. while stirring the solution was confirmed to become homogeneous. Then remove the oil bath and start cooling of the solution at room temperature with stirring. When the internal temperature was filtered after continued for an additional 1 hour of stirring after becoming 20 ° C., to obtain a fluorine-containing cyclopropane monoester salts of interest represented by the following formula 15.1 g, in 53% yield.
[Of 81]

the diastereomer excess of the target compound was 95.0% de. Results of the measurement of the optical purity EXAMPLE 16 reference was ee 93.2%. Of the desired product 1 H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.23 (t, 3H), 1.30 (ddd, 1H), 1.40 (ddd, 1H) , 1.61 (d, 3H), 2.11 (m, 1H), 4.15 (m, 2H), 4.42 (q, 1H), 5.66 (td, 1H), 7.30 ~ 7.46 (m, 5H), 19 F-NMR (deuterated solvent: deuterated methanol, standard: setting the -162.2ppm hexafluorobenzene), - 114.7 (ddd, 1F ), - 108.6 ( ddd, 1F).
[0128]
　Example 25
　represented by the following formula in a three-neck flask equipped with a thermowell and stopcock (R) - fluorinated cyclopropane diester (purity: 73.8wt%, 3.2g, 10.0mmol) and was cooled internal temperature of -5 ° C. was added ethanol (2 ml).
[Of 82]

Then 2-hydroxyethyl trimethylammonium hydroxide 48% aqueous solution (5.1 g, 20.0 mmol) was added slowly. This time the internal temperature was -8 ~ -10 ℃. After the internal temperature was stirred for 4 hours while the -4 ° C., was performed by mixing two layers separated by adding methyl tert- butyl ether 7.5g and 3.2M aqueous hydrochloric acid 7.5g. Separated aqueous layer was extracted with methyl tert- butyl ether (3.0g × 2). The resulting combined into one all of the organic layers were washed with water 4.0 ml, and concentrated on a rotary evaporator, followed by azeotropic dehydration with toluene in concentrated residue (3.5g × 2). The resulting crude material was added isopropanol 1.6g and methylcyclohexane 7.7g to. The solution was cooled with ice water, then (R) -1- (1- naphthyl) ethylamine (1.8 g, 10.5 mmol) was added. The solution was heated in an oil bath then to an internal temperature of 70 ° C. with stirring was confirmed to become homogeneous. Then remove the oil bath and start cooling of the solution at room temperature with stirring. The internal temperature was filtered after continued for an additional 1 hour of stirring after becoming 3 ° C.. The resulting crystals were washed with a mixture of isopropanol 0.3g and methylcyclohexane 1.5 g. The resulting crystals total amount of isopropanol was added 1.6g of methyl cyclohexane 7.7g to an internal temperature of 70 ° C. with stirring and heated in an oil bath. Crystals after confirming that become dissolved uniformly, and start cooling with stirring and remove the oil bath. Filtration after a 1 hour stirring was carried out at an inner temperature of -5 degrees it was performed. The obtained crystals to give a fluorine-containing cyclopropane monoester salts of interest represented by the following formula by drying until no change in weight of the crystal on a rotary evaporator 0.61 g, in 16% yield.
[Of 83]

of the object 1H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.25 (t, 3H), 1.32 (m, 1H), 1.42 (dd, 1H), 1.75 (d, 3H), 2.14 ( m, 1H), 4.18 (m, 2H), 5.38 (q, 1H), 5.67 (td, 1H), 7.62 (m, 4H) , 7.96 (t, 2H), 8.15 (d, IH), 19 F-NMR (deuterated solvent: deuterated methanol, standard: setting the hexafluorobenzene -162.2ppm), - 117.0 ( ddd, 1F), - 111.0 ( ddd, 1F). The diastereomeric excess was 98.6% de. Results of the measurement of the optical purity EXAMPLE 16 reference was ee 92.3%.
[0129]
　Example 26
　thermowell, a Dimroth condenser, septum, 60 wt% sodium hydride THF (131 ml) and n- heptane and (26 ml) four-necked flask 300ml substituted internal equipped with a mechanical stirrer with nitrogen (7.5 g, 188 mmol) was heated in an oil bath at 80 ° C. put. When the internal temperature reached 66 ° C., the inner while keeping the temperature of dimethyl malonate (12.4g, 93.9mmol) and fluorinated cyclic sulfate represented by the following formula (chemical purity: 94.6wt%, 17. 3g, was added dropwise over the mixture 5 hours 93.9mmol).
Formula 84]

After the completion of dropwise addition, the internal temperature was stirred for 3 hours while the 66 ° C.. After returning to room temperature, it was added methyl tert- butyl ether 140mL after the addition of acetic acid (5.6 g). Then separating the solution bilayer, it was concentrated removed organic layer, 19 6 was analyzed by F-NMR, the fluorinated cyclopropane diesters of interest represented by the following formula crude weight 9.5 g, the content. 3 g, 30.5 mmol, was obtained in 32% yield.
Formula 85]

of the object 1 H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 1.58 (m, 1H), 1.78 (m, 1H), 2.37 ( m, IH), 3.77 (s, 3H), 3.79 (s, 3H), 5.74 (td, IH), 19 F-NMR (deuterated solvent: chloroform-d, standard: hexafluorobenzene -162.2ppm and configuration), - 118.0 (ddd, 1F ), - 112.0 (ddd, 1F).
[0130]
　Example 27
　shown in a three-neck flask equipped with a thermowell and stopcock by the following formula obtained in Example 26 (R) - fluorinated cyclopropane diester (purity: 66.6wt%, 9.5g was cooled 6.3g as content, the internal temperature was added 30.5 mmol) and methanol (6 ml) to -8 ° C..
Formula 86]

Then 2-hydroxyethyl trimethylammonium hydroxide 48% aqueous solution (11.5 g, 45.7 mmol) was added slowly. This time the temperature was -8 ~ -1 ° C.. After the internal temperature was stirred in this state for 2 hours, it was performed by mixing two layers separated by adding methyl tert- butyl ether 30g and 2.8M aqueous hydrochloric acid 22.3 g. Separated aqueous layer was extracted with methyl tert- butyl ether (15g × 2). The resulting combined into one all of the organic layers were washed with water 12 ml, and concentrated on a rotary evaporator, followed by azeotropic dehydration with toluene in concentrated residue (15g × 2). The crude product of the last purpose of the following formula by removing all organic solvents to obtain 8.84 g.
[Of 87]

Of isopropanol was added 10.6mL and methylcyclohexane 30.5mL this crude material total amount. Then (R)-1-phenylethylamine (4.1 g, 33.5 mmol) was added. The solution was heated in an oil bath then to an internal temperature 74 ° C. with stirring was confirmed to become homogeneous. Then remove the oil bath and start cooling of the solution at room temperature with stirring. Internal temperature was filtered after continued for an additional 1 hour of stirring after becoming 26 ° C.. Crystals fluorinated cyclopropane monoester salt of target by drying until no change in weight of the crystal on a rotary evaporator to obtain 6.5 g. The resulting crystals total amount of isopropanol was added 11.6mL and methylcyclohexane 30.5mL to an internal temperature of 75 ° C. with stirring and heated in an oil bath. Crystals after confirming that become dissolved uniformly, and start cooling with stirring and remove the oil bath. Internal temperature crystals precipitated in the vicinity of 60 ° C., was filtered after the additional 1 hour stirring at an internal temperature of 24 ° C.. The obtained crystals to give the desired product represented by the following formula by drying until no change in weight of the crystal on a rotary evaporator 4.7 g, 49% yield.
[Of 88]

the diastereomer excess of the desired product was 83% de. Performs methyl esterification by adding a process trimethyl orthoformate and methanol in the reference as described in Example 16, the results of measuring the optical purity was ee 99%. 1 H-NMR (deuterated solvent: deuterated methanol, reference: tetramethylsilane), δppm: 1.31 (m, 1H), 1.42 (m, 1H), 1.62 (d, 3H), 2. 11 (m, IH), 3.70 (s, 3H), 4.43 (q, IH), 5.65 (td, IH), 7.42 (m, 5H), 19F-NMR (deuterated solvent: deuterated methanol, standard: setting the hexafluorobenzene -162.2ppm), - 114.9 (ddd, 1F), - 108.9 (ddd, 1F).
[0131]
　[Reference Example 1]
　International Publication 2014-078220 discloses was prepared to 3,3-difluoro-lactic acid amide reference. Water 190mL (1.2mL / mmol), 3,3- difluoro lactic amide 20g (160mmol, 1.0eq) and stirred for 20 hours at 100 ° C. by addition of sulfuric acid 78g (800mmol, 5.0eq). The completion of the reaction solution was extracted with 2-methyltetrahydrofuran, and concentrated under reduced pressure The recovered organic layer to obtain 3,3-difluoro-lactic acid 16g of (130 mmol). The yield was 81%. Ethanol 5.5 g (120 mmol, 1.5 eq) in 3,3-difluoro lactate 10 g (79 mmol, 1.0 eq), triethyl orthoformate 17.8 g (120 mmol, 1.5 eq) and sulfuric acid 1.2 g (12 mmol, 0 .15Eq) added and the mixture was stirred overnight at room temperature. The reaction-terminated liquid of simple distillation (jacket: 50 ~ 110 ° C., vacuum degree: 5 ~ 50 torr) gave 3,3-difluoro ethyl lactate 10.6g of (69 mmol). The yield was 87%. Of 3,3-difluoro ethyl lactate 1 H-NMR and 19 to F-NMR are shown below. 1 H-NMR (reference material: tetramethylsilane, solvent: heavy chloroform), δ ppm; 1.34 (t , 3H), 4.29 ~ 4.43 (m, 3H), 5.97 (dt, 1H ), the proton of the hydroxyl group can not be assigned. 19 F-NMR (reference material: hexafluorobenzene the -162.2ppm and setting, solvent; deuterated chloroform), δ ppm; -131.0 (ddd , 1F), - 129.6 (ddd, 1F).
[0132]
　[Reference Example 2]
　Dimroth condenser, thermowell, stopcock, inner put the ethanol 3.6L four-necked flask 3,3-difluoro ethyl lactate 606g of 5L equipped with a mechanical stirrer (3.93mol) It cooled to temperature 10 ° C. of about. Then slowly charged over 4 h sodium borohydride 223g (5.90mol). This time the temperature was 10 ~ 30 ° C.. Charged is stirred for 2 hours at an internal temperature of the 20 ~ 30 ° C. After completion, the mixture was stirred at room temperature overnight. The reaction mixture was analyzed by gas chromatography to confirm that the raw materials. Then it was concentrated reaction solution using a rotary evaporator. Weight of the concentrate residue was added 1515ml of 4N HCl aqueous residue Once concentrated to 1681G. The internal temperature at this time heat to rose to 58 ℃. Thereafter, the mixture was stirred at room temperature overnight. The solution was filtered and the precipitate was cooled with ice water. The filtrate 19 was analyzed by F-NMR, it was confirmed that 1,1-difluoro-2,3-propanediol object exists almost quantitatively. The filtrate was concentrated on a rotary evaporator. Weight of concentrated residue is stopped once concentrated Once turned 2050 g, it was performed filtered. The filtrate was washed with toluene 600 ml. The combined resultant filtrate and washings were concentrated on a rotary evaporator. Weight of concentrated residue is filtered again Once turned 673.5G. The filtrate was washed with toluene 100 ml. The combined resultant filtrate and washings were concentrated again on a rotary evaporator. Weight of the concentrate residue was performed by flash distillation in a distillation apparatus When turned 515.6G. Jacket 60 ~ 120 ° C., result of the distilled at 0.001MPa pressure, 394.9G the 3,3-difluoro-1,2-propanediol represented by the following formula, purity: 83.7wt%, the desired product 3.002Mol, it was obtained in 76.4% yield.
[Of 89]

of the target compound1 H-NMR (deuterated solvent: heavy acetonitrile, reference material: tetramethylsilane), [delta] ppm: 3.61 (m, 2H), 3.72 (m, IH), 5.79 (td, IH), 19 F -NMR (deuterated solvent: heavy acetonitrile, standard: setting the hexafluorobenzene -162.2ppm), - 130.9 (ddd, 1F), - 128.2 (ddd, 1F)
[0133]
　[Reference Example 3]
　water to 3,3-difluoro-1,2-propanediol obtained in Reference Example 2 was carried out dehydration with toluene because it contains 16.3wt%. Dean-Stark apparatus, thermowell, was carried out azeotropic dehydration put fractions 30g of toluene 100ml obtained in Reference Example 2 obtained on the three-necked flask 300ml fitted with a stopcock at the jacket 125 ~ 130 ° C.. Azeotropic of moisture has been completed when it is no longer possible to confirm. Yield 21.9g remaining residual liquid in the flask by separating two layers was obtained in 87% yield. Results of measurement of moisture Karl Fischer moisture meter, the water content was 0.47 wt%.
[0134]
　[Reference Example 4]
　as medium preculture, distilled water 1000 ml, polypeptone 10 g, yeast extract 5g, the liquid medium was prepared having the composition of sodium chloride 10 g, aliquoted 5ml test tube (φ1.6cm × 15cm) min It was steam-sterilized for 15 minutes at 121 ° C.. The liquid medium is aseptically inoculated with the recombinant Escherichia coli of mass expressing Chiralscreen (R) alcohol dehydrogenase OH E039 Ltd. Daicel at time platinum, 30 ° C., subjected to overnight incubation at 160Spm, to obtain a pre-culture of optical density (OD600) 8.2 at a wavelength of 600 nm. As the medium of the present culture, distilled water 2500ml yeast extract, sodium glutamate, glucose, lactose, inorganic salts, to prepare a liquid medium consisting of antifoaming agents, culture tank capacity 5L ((Ltd.) Maruhishi Bio Engineering Ltd., MDN imposition on the type 5L (S)), was sterilized by steam for 30 minutes at 121 ° C.. The pre-culture broth culture vessel was aseptically 5ml inoculation, 30 ° C., aeration 0.5 vvm, stirring cultured for 40 hours to prepare a suspension of optical density (OD600) 24. The pH of the culture is 20% aqueous sodium carbonate was adjusted to about pH7.0 with 42.5% phosphoric acid aqueous solution. After completion of the culture, change the aeration 0Vvm, 3-chloro-1,1-difluoro-2-propanone hydration of 80% wt / wt with respect to culture solution 6.25% wt / v (156.25g ) was added, 20 ° C. while the reproduction of coenzyme by formate dehydrogenase was carried out 24 hours a reduction reaction at pH 6.2. Conversion after the reaction is 96%, the optical purity was ee 83.0% (R). Vacuum distillation (pressure 19.2KPa, steam temperature 57 ~ 61 ° C.) from the culture solution after the reaction was 443g recover an aqueous solution of (R)-1-chloro-3,3-difluoro isopropyl alcohol 80g by. Of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), [delta] ppm: 3.72 (m, 2H), 4.03 (m, IH), 5.86 (td, IH), 19 F- NMR (deuterated solvent: chloroform, standard substance: setting a hexafluorobenzene -162.2ppm), - 132.2 (ddd, 1F), - 130.6 (ddd, 1F)
[0135]
　[Reference Example 5]
　Example 4 was recovered in (R)-1-chloro-3,3-difluoro isopropyl aqueous alcohol content of the alcohol part of the aqueous solution such that the 30g extraction, with ice cooling, 48 % aqueous solution of sodium hydroxide 1.0 was added dropwise equivalents. Dropwise while checking the internal temperature was carried out to maintain the 0 ~ 3 ° C.. After the addition, the mixture was stirred for 120 minutes at 1 ° C., it was carried out ring closure reaction. After the reaction, a steam temperature of 50 ~ 70 ° C. by distillation (atmospheric pressure), the generated (S) -2- difluoromethyl ethylene oxide and 17g collected in 83.1% ee was analyzed optical purity analysis conditions described below there were. Of the desired product 1 H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 2.8-2.9 (m, 2H), 3.27 (m, 1H), 5.56 ( td, IH), 19 F-NMR (deuterated solvent: chloroform, standard substance: set the -162.2ppm hexafluorobenzene), - 125.2 (ddd, 1F ), - 122.5 (ddd, 1F)
[0136]
　[Reference Example 6]
　against 2-difluoromethyl-ethylene oxide obtained in Reference Example 5, 2-naphthalene thiol 1.1 eq, triethylamine 1.1 added eq, induces the sulfide, and the analyzed sample. Fast column of liquid chromatography using a Daicel Co. CHIRALCEL OD-H (4.6mm × 25cm , particle size 5 [mu] m), mobile phase n- hexane / IPA = 95/5, flow rate 0.7 ml, column temperature 15 ° C., was calculated optical purity by the area of the peak obtained by the detection wavelength 230 nm. The retention time of each enantiomer, R body 24.2min, S body was 27.4Min.
[0137]
　Reference Example 7
　Reference Example 5 to give (S) -2- difluoromethyl ethylene oxide 17g of 20% sulfuric acid aqueous solution was added 0.2 eq was stirred for 8 hours at 50 ° C.. After the reaction, to adjust the pH of the solution to 5 with sodium hydroxide, after removing the inorganic salts by filtration, vacuum distillation by performing (pressure 1.5 kPa, steam temperature 80 ~ 81 ℃), 17g of ( was obtained S)-3,3-difluoro-1,2-propanediol. Moreover, it was 83.1% ee was analyzed optical purity analysis conditions described below. Of the desired product 1 H-NMR (deuterated solvent: heavy acetonitrile, reference material: tetramethylsilane), δppm: 3.61 (m, 2H), 3.72 (m, 1H), 5.79 (td, 1H) , 19 F-NMR (deuterated solvent: heavy acetonitrile, standard: setting the hexafluorobenzene -162.2ppm), - 130.9 (ddd, 1F), - 128.2 (ddd, 1F)
[0138]
　[Reference Example 8]
　relative obtained in Reference Example 7 (S) -3,3- difluoro-1,2-propanediol, acetate 2.5 equivalents anhydrous pyridine 2.5 by reacting equivalent, to diacetoxy body induced, and the analysis sample. A column of gas chromatography using an Agilent Technologies Corp. Cyclosil-B (0.25mm × 30m × 0.25μm), the carrier gas is nitrogen, the pressure is 163KPa, column temperature 50 ℃ (5min), 50 ~ 150 ℃ (5 ℃ / min) , 150 ℃ (15min), was calculated optical purity by the area of the peaks obtained in the analysis conditions of the vaporization chamber detector (FID) temperature 230 ° C.. The retention time of each enantiomer, R body 16.3min, S body was 17.2Min. Stereochemistry was determined based on known information.
[0139]
　[Reference Example 9]
　as medium preculture, distilled water 1000 ml, polypeptone 10 g, yeast extract 5g, the liquid medium was prepared having the composition of sodium chloride 10 g, aliquoted 5ml test tube (φ1.6cm × 15cm) min It was steam-sterilized for 15 minutes at 121 ° C.. The liquid medium is aseptically inoculated with the recombinant Escherichia coli of mass expressing Chiralscreen (R) alcohol dehydrogenase OH E094 Ltd. Daicel at time platinum, 30 ° C., subjected to overnight incubation at 160Spm, to obtain a pre-culture of optical density (OD600) 6.4 at a wavelength of 600 nm. As the medium of the present culture, distilled water 2500ml yeast extract, sodium glutamate, glucose, lactose, inorganic salts, to prepare a liquid medium consisting of antifoaming agents, culture tank capacity 5L ((Ltd.) Maruhishi Bio Engineering Ltd., MDN imposition on the type 5L (S)), was sterilized by steam for 30 minutes at 121 ° C.. The pre-culture broth culture vessel was aseptically 5ml inoculation, 30 ° C., aeration 0.5 vvm, stirring cultured for 40 hours to prepare a suspension of optical density (OD600) 22. The pH of the culture is 20% aqueous sodium carbonate was adjusted to about pH7.0 with 42.5% phosphoric acid aqueous solution. After completion of the culture, change the aeration 0Vvm, 3-chloro-1,1-difluoro-2-propanone hydration of 90% wt / wt with respect to culture solution 6.25% wt / v (156.25g ) was added, 30 ° C. while the reproduction of coenzyme by glucose dehydrogenase, was carried out 24 hours a reduction reaction at pH 6.0. Conversion of 99% optical purity after the reaction was ee 89.2% (S). Vacuum distillation (pressure 19.2KPa, steam temperature 57 ~ 61 ° C.) from the culture solution after the reaction was 526g recover an aqueous solution of (S) -1- chloro-3,3-difluoro isopropyl alcohol 85g by. Of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), [delta] ppm: 3.72 (m, 2H), 4.03 (m, IH), 5.86 (td, IH), 19 F- NMR (deuterated solvent: chloroform, standard substance: setting a hexafluorobenzene -162.2ppm), - 132.2 (ddd, 1F), - 130.6 (ddd, 1F)
[0140]
　[Reference Example 10]
　with ice-cooling (S) -1- chloro-3,3-difluoro isopropyl alcohol solution of 85g collected in Reference Example 9, was added dropwise 48% aqueous sodium hydroxide 1.0 eq. Dropwise while checking the internal temperature was carried out to maintain the 0 ~ 3 ° C.. After the addition, the mixture was stirred for 120 minutes at 1 ° C., it was carried out ring closure reaction. After the reaction, a steam temperature of 50 ~ 70 ° C. by distillation (atmospheric pressure), the generated (R)-2-difluoromethyl-ethylene oxide and 49g recovered, analysis of the optical purity analysis conditions of Reference Example 6 89.1% It was ee. Of the desired product 1 H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 2.8-2.9 (m, 2H), 3.27 (m, 1H), 5.56 ( td, IH), 19 F-NMR (deuterated solvent: chloroform, standard substance: set the -162.2ppm hexafluorobenzene), - 125.2 (ddd, 1F ), - 122.5 (ddd, 1F)
[0141]
　[Reference Example 11]
　49g of prepared in Reference Example 10 (R) -2- 20% aqueous sulfuric acid solution difluoromethyl ethylene oxide is contained was added 0.2 eq, was 7 hours at 60 ° C.. After the reaction, to adjust the pH of the solution to 5 with sodium hydroxide, after removing the inorganic salts by filtration, vacuum distillation by performing (pressure 1.5 kPa, steam temperature 80 ~ 81 ° C.), the 46 g ( was obtained R)-3,3-difluoro-1,2-propanediol. Moreover, it was 89.2% ee was analyzed optical purity analysis conditions of Reference Example 8. Of the desired product 1 H-NMR (deuterated solvent: heavy acetonitrile, reference material: tetramethylsilane), δppm: 3.61 (m, 2H), 3.72 (m, 1H), 5.79 (td, 1H) , 19 F-NMR (deuterated solvent: heavy acetonitrile, standard: setting the hexafluorobenzene -162.2ppm), - 130.9 (ddd, 1F), - 128.2 (ddd, 1F)
[0142]
　[Reference Example 12]
　The compound 5.66g represented by the following formula as prepared in Example 19 (17.2 mmol), stirring is carried out for the addition of isopropyl ether (78 ml) at room temperature, there 1M phosphoric acid solution (43 ml) It was added dropwise.
Formula 90]

leave the 30 minutes stirring, was carried out a two-layer separation by 20 minutes stand. The aqueous layer was removed, and stirred again for 30 minutes by addition of water (50 mL), it was allowed to stand for 20 minutes. The organic layer was removed, the compound represented by the following formula by performing concentrated on a rotary evaporator to yield 3.29 g (15.8 mmol).
[Of 91]

Toluene at room temperature to the compound 3.29g (15.8mmol) (32ml), triethylamine (3.20g, 31.6mmol), was added t- butanol (3.51g, 47.4mmol). The solution was heated with 70 ° C. was added dropwise thereto slowly diphenyl phosphate azide (6.52g, 23.7mol). As 80 ° C. The internal temperature after the dropwise addition, the reaction was carried out for 15 hours. After the reaction, was concentrated in the rotary evaporator, and stirred with the residue in isopropyl ether and (50ml) and water were separated into two layers. Remove the organic layer, similarly stirred with water (35 ml), was performed a two-layer separation. The organic layer was separated, was concentrated on a rotary evaporator to obtain a crude product. Potassium hydroxide (1.14 g, 20.4 mmol) was dissolved in methanol (10 ml), was added at room temperature to the crude material obtained above. The solution hydrolysis has progressed by 5 hours at 40 ° C.. The solution was cooled in an ice bath, it was added slowly 1M phosphoric acid solution (20ml). Further adding isopropyl ether (50 ml), it was separated into two layers after stirring at room temperature for 30 minutes. The organic layer was removed, and the organic layer was again stirred at room temperature for 30 minutes by addition of water (20ml) was taken out, by performing concentrated in a rotary evaporator, the compound 2.37 g (9.4 mmol) obtained of the following formula It was.
Formula 92]

wherein, Boc represents a tert- butoxycarbonyl group. ]
[0143]
　[Comparative Example 1]
　thermowell, dichloromethane (14 ml) in 100ml three-necked glass reactor equipped with a dropping funnel and three-way cock, 3,3-difluoro-1,2-propanediol represented by the following formula ((water content : 0.47%), 1.0g, 8.9mmol ,), and stirred for 20 minutes at room temperature was added imidazole (1.5g, 22.3mmol).
Formula 93]

The reaction mixture was cooled in a dry ice and a mixture of acetonitrile (-45 ° C.), sulfuryl chloride using the dropping funnel (1.2 g, 8.9 mmol) and the mixture 2 h dichloromethane (3 ml) It was added dropwise over 30 minutes. The temperature of the reaction solution at this time was -38 ~ -34.7 ℃. Addition was stirred at around the temperature of -35 ° C. for two hours when done. Then stirred overnight at room temperature. The resulting reaction solution 19 was analyzed by F-NMR, giving a complex mixture, the desired product represented by the following formula was obtained.
[Of 94]

[0144]
　[Comparative Example 2]
　Difluoro propene oxide that double neck flask 20ml equipped with a thermowell and stopcock represented by the following formula (racemic mixture, purity: 44%, 8.97g, 42.2mmol) were charged, ice water It was cooled to near the internal temperature 1 ℃ in.
Formula 95]

then 48% aqueous hydrobromic acid (7.47 g, 44.3 mmol) was added slowly. The temperature at this time was 0 ~ 10 ℃. Dropping the temperature is raised slowly to room temperature When you are finished, the mixture was stirred overnight. Was extracted and separated into two layers then added methyl -tert- butyl ether (15ml) to the reaction solution. The results obtained organic layer was concentrated by flash distillation apparatus to obtain a crude product 9.2g of the bromohydrin of interest represented by the following formula as a concentrated residue.
Formula 96]

desired product content in a crude product is 80 wt%, was obtained almost quantitatively. Of the desired product 1 H-NMR (deuterated solvent: heavy acetonitrile, reference material: tetramethylsilane), δppm: 3.05 (m, 2H), 3.60 (m, 1H), 5.76 (td, 1H) , 19 F-NMR (deuterated solvent: heavy acetonitrile, standard: setting the hexafluorobenzene -162.2ppm), - 130.3 (ddd, 1F), - 127.6 (ddd, 1F)
[0145]
　[Comparative Example
　3] bromohydrin body represented by the following formula obtained in a recovery flask with Comparative Example 2 50 ml (purity: 80wt%, 4.3g, 20mmol) , para-toluenesulfonyl chloride (5.7g, 30mmol), methyl It was cooled in an ice-water added -tert- butyl ether (20ml).
Formula 97]

then triethylamine (3.0 g, 30 mmol) was stirred for 30 minutes in addition. Then, the mixture was stirred overnight at the temperature is raised slowly to room temperature. The reaction mixture was washed four times with water 20 ml, and the solvent was removed on a rotary evaporator. Then added toluene was removed by azeotropic dehydration of moisture, and filtered solids Once dried again sodium sulfate solution to remove water. To obtain a crude product of the last purpose of the following formula After removal of the toluene on a rotary evaporator 12.8 g, 34.9 mmol, in 87% yield.
Formula 98]

of the object 1 H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 2.47 (s, 3H), 3.56 (m, 2H), 4.73 ( m, IH), 6.00 (dt, IH), 7.37 (d, 2H), 7.83 (d, 2H), 19 F-NMR (deuterated solvent: chloroform-d, standard: hexafluorobenzene -162.2ppm and configuration), - 132.4 (ddd, 1F ), - 130.1 (ddd, 1F)
[0146]
　[Comparative Example 4]
　thermowell, septum, sodium hydride in a three-necked flask 50ml equipped with a three-way cock (0.2 g, 5 mmol) internal put was replaced with nitrogen. It was then cooled to around an inner temperature 2 ℃ with ice water put DMF (20 ml). It was then added slowly diethyl malonate (0.8g, 5mmol). This time the temperature was 2 ~ 4 ° C.. Crude product 1.8g of then represented by the following formula obtained in Comparative Example 3 Compound (5 mmol) was added slowly.
Formula 99]

addition was stirred overnight raised to room temperature the reaction mixture slowly when finished. Then, the result of analysis of the reaction solution, malonic acid adduct of interest represented by the following formula was obtained.
[Of 100]

[0147]
　[Comparative Example 5]
　chlorohydrin represented by the following formula in 30ml two-neck flask equipped with a thermowell and stopcock (racemic mixture, purity: 75wt%, 3.5g, 20mmol) , methyl -tert- butyl ether (20ml) and added para-toluenesulfonyl chloride (4.2 g, 22 mmol) was cooled to near an inner temperature 2 ℃ with ice water.
Formula 101]

then triethylamine (2.4 g, 24 mmol) was added slowly. This time the temperature was 2 ~ 3 ° C.. Addition the mixture was stirred overnight slowly raising the temperature to room temperature when you are finished. The resulting reaction mixture was washed four times with water 20 ml, the organic layer obtained by separating two layers and the organic solvent was removed on a rotary evaporator. It was azeotropically remove water by adding toluene to the concentrate. The desired product of the solution to remove water and filtered represented by the following formula by concentrating on a rotary evaporator 4.6 g, 15 mmol, in 75% yield.
Formula 102]

of the target compound 1 H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 2.45 (s, 3H), 3.75 (m, 2H), 4.73 ( m, IH), 5.99 (dt, IH), 7.36 (d, 2H), 7.82 (d, 2H), 19 F-NMR (deuterated solvent: chloroform-d, standard: hexafluorobenzene -162.2ppm and configuration), - 132.3 (ddd, 1F ), - 130.1 (ddd, 1F)
[0148]
　[Comparative Example 6]
　thermowell, septum, sodium hydride in a three-necked flask 50ml equipped with a three-way cock (0.2 g, 5 mmol) internal put was replaced with nitrogen. It was then cooled to around an inner temperature 2 ℃ with ice water put DMF (20 ml). Then diethyl malonate (0.83 g, 5.2 mmol) was added slowly. This time the temperature was 2 ~ 7 ° C.. Then the following formula obtained in Comparative Example 5 Compound (1.4 g, 5 mmol) was added slowly.
Formula 103]

addition was stirred overnight raised to room temperature the reaction mixture slowly when finished. Then, the result of analysis of the reaction solution, malonic acid adduct represented by the following formula was obtained.
Formula 104]

[0149]
　[Comparative Example 7]
　thermowell, illustrated in 100ml three-necked flask equipped with a Dimroth condenser and stopcock by the following formula was synthesized in Reference Example 2 3,3-difluoro-1,2-propanediol (purity: 83.7wt%, 5.0g, 38mmol), cooled to around an inner temperature 2 ℃ with ice water added methyl -tert- butyl ether (38 ml) and para-toluenesulfonyl chloride (21.7g, 114mmol).
Formula 105]

then triethylamine (15.4 g, 152 mmol) was added slowly. Addition is heated for 2 hours to near the internal temperature 47 ° C. in an oil bath When finished, then stirred overnight at room temperature. To the resulting reaction solution was added 20ml of water were mixed, was performed two-layer separation. To the resulting organic layer was added water 10ml and methyl -tert- butyl ether 10ml were mixed and again separated two layers. The resulting organic layer was washed with saturated with water 10ml aqueous sodium chloride solution 5 ml × 2 was separated into two layers. The resulting organic layer was concentrated and the solvent on a rotary evaporator, and then carried out azeotropic dehydration with toluene. Methyl -tert- butyl ether 50ml and 30ml of toluene was added to the concentrated residue so paratoluenesulfonic acid remained, mixture and again washed two layers with water 10ml water 10ml and sodium bicarbonate 3.2 g (38 mmol) separated. The obtained organic layer to give 16.9g of crude product of the target product represented by the following formula by removing the solvent on a rotary evaporator.
Formula 106]

19 was analyzed by F-NMR, the content of the target compound proceeded almost quantitatively reacted with 38 mol. The resulting crude material 3g obtain 2.56g of the desired product was purified by subjecting to column chromatography. Of the object 1H-NMR (deuterated solvent: chloroform, standard substance: tetramethylsilane), δppm: 2.47 (s, 6H), 4.17 (ddd, 1H), 4.26 (ddd, 1H), 4.69 (m, IH), 5.90 (dt, IH), 7.36 (d, 4H), 7.71 (d, 2H), 7.77 (d, 2H), 19 F-NMR (deuterated solvent: heavy chloroform, standard substance: set the -162.2ppm hexafluorobenzene), - 132.2 (ddd, 1F ), - 128.7 (ddd, 1F)
[0150]
　[Comparative Example 8]
　thermowell, Dimroth condenser, and the internal replaced by nitrogen put sodium hydride in a three-necked flask 50ml equipped with a stopcock (0.2 g, 5 mmol). It was then cooled to around an inner temperature 3 ° C. with ice water put DMF (20 ml). It was then added slowly diethyl malonate (0.8g, 5mmol). This time the temperature was 3 ~ 4 ° C.. Then represented by the following formula was purified obtained in Comparative Example 7 Compound (2.56 g, 6 mmol) was added slowly a mixture of 5 ml of DMF.
Formula 107]

This time the temperature was 3 ~ 5 ° C.. It was stirred for 4 hours at around an internal temperature 50 ° C. After stirring for 30 minutes while cooling with ice water and heated in an oil bath. Then stirred overnight at room temperature. The results obtained analyzing the reaction liquid, malonic acid adduct of interest represented by the following formula was obtained.
[Of 108]

[0151]
　[Comparative Example 9]
　thermowell, was cooled with ice water and put DBU (2.62 g, 17.2 mmol) in 100ml three-necked flask equipped with a stopcock and a Dimroth condenser and THF to (29.7 ml). Then diethyl malonate (2.76 g, 17.2 mmol) was stirred for 30 minutes while cooled with ice water was added. Thereafter, the fluorine-containing cyclic sulfate represented by the following formula After raising the temperature to near room temperature (racemic mixture, 3.0g, 17.2mmol), THF5.7ml and the internal standard substance in a benzotrifluoride (1.46 g, 10 mmol ) mixture was slowly added a.
Formula 109]

internal temperature at this time was 22 ~ 37 ° C.. Then stirred for two hours at room temperature. Then DBU (3.14 g, 20.7 mmol) was added to the reaction mixture, and the mixture was heated for 1 hour 45 minutes at around an internal temperature 65 ° C. was heated in an oil bath. The reaction mixture was cooled to room temperature, was analyzed by NMR, it cyclopropane compound of interest represented by the following formula was not confirmed.
[Of 110]

[0152]
　[Comparative Example 10]
　thermowell, THF (19 ml) in 100ml three-necked glass reactor equipped with a dropping funnel and three-way cock, 3,3-difluoro-1,2-propanediol represented by the following formula (moisture content 0 .47%, 5.6g, 50mmol), triethylamine (13.7 g, 135 mmol) was added to stirred 20 minutes at room temperature.
Formula 111]

The reaction mixture was cooled at -5 ° C. for refrigerant, and the inner temperature to 0 ° C.. Sulfuryl chloride using the dropping funnel (8.1 g, 60 mmol) the mixture of dichloromethane (11 ml), and the internal temperature was added dropwise over 15 minutes while maintaining at 0 ° C.. Finishing of the dripping, the inner temperature was raised to 20 ° C., the conversion rate was 100% for 1 hour by stirring. The resulting reaction solution 19 was analyzed by F-NMR, giving a complex mixture, the desired product represented by the following formula in it was not obtained.
[Of 112]

Industrial Applicability
[0153]
　Fluorinated cyclopropane carboxylic acids of interest in the present invention, a pharmaceutical, can be used as intermediates for agricultural chemicals.
The scope of the claims
[Claim 1]
A fluorine-containing diol compound represented by the general formula [1], alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal the presence of carbonates, alkali metal hydrogen carbonates, and at least one basic compound selected from the group consisting of alkaline earth metal hydrogen carbonates, represented by the general formula [2] by reacting with sulfuryl fluoride method for producing a fluorine-containing cyclic sulfate.
Formula 113]

[wherein, R f represents a linear or branched fluoroalkyl group having 1 to 6 carbon atoms having more than one fluorine atom, and * represents an asymmetric carbon. ]
[Formula 114]

[wherein, R f is the formula [1] represents the same substituents as, * represents an asymmetric carbon. ]
[Claim 2]
R f is difluoromethyl group (CF 2 H) or a trifluoromethyl group (CF 3 is) The method of claim 1.
[Claim 3]
A temperature of between -50 ~ + 50 ° C. when reacting sulfuryl fluoride, the method according to claim 1 or 2.
[Claim 4]
The method according to any one of claims 1 to 3 used in an amount of sulfuryl fluoride is from 0.7 to 4.0 equivalents.
[Claim 5]
To produce a fluorine-containing cyclic sulfate by a method according to any one of claims 1 to 4, then by reacting the ester in the presence of an inorganic base, a malonic acid diester represented by the general formula [3] the method for producing a fluorine-containing cyclopropane diester represented by the general formula [5].
Formula 115]

[wherein, R 1 , R 2 having a carbon number of 1 are each independently 18 linear, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, the carbon number It represents from 6 to 18 aromatic ring group or a substituted aromatic ring group. ]
[Formula 116]

[wherein, R f is the general formula [1 in claim 1] R in the f the same as. R 1 , R 2 R in the formula [3] 1 , R 2 the same as. * Represents an asymmetric carbon. ]
[Claim 6]
Inorganic bases alkali metal, alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides or alkaline earth metal hydroxide, A method according to claim 5.
[Claim 7]
General formula [2] in the fluorine-containing cyclic sulfate general formula represented malonic acid diester represented by [3], is characterized by adding a solvent containing an inorganic base, according to claim 5 or claim the method according to 6.
[8.]
To produce a fluorine-containing cyclopropane diester by the method according to any one of claims 5 to 7, then, an alkali metal hydroxide to the diester, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, the presence of a quaternary ammonium hydroxide represented by the alkaline earth metal hydrogen carbonates or general formula [6], represented by the general formula [7] by carrying out the hydrolysis method for producing a fluorine-containing cyclopropane monoester.
Formula 117]

[wherein, R 3 , R 4 , R 5 , R 6 are each independently, having 1 to 18 linear, branched alkyl or cyclic (in the case of 3 or more carbon atoms) It represents group, a substituted alkyl group, an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms. Also, R 3 , R 4 , R 5 , R 6 out of, or may be two or more forms part of the same aliphatic ring or aliphatic aromatic ring. ]
[Formula 118]

[wherein, R f is the general formula [1 in claim 1] represents the same substituents as, R 2 represents the same substituents as the general formula [3] in claim 5. * Represents an asymmetric carbon. ]
[Claim 9]
Temperature in the hydrolysis reaction is -30 ~ + 40 ℃, The method of claim 8.
[Claim 10]
Fluorine-containing cyclopropane monoesters represented by the general formula [7], the addition of an amine represented by the general formula [8], the general formula [9] in the fluorine-containing cyclopropane monoester and amine represented the salt was formed, further comprising the step of performing recrystallization purification method according to claim 8 or 9.
Formula 119]

[wherein, R 7 , R 8 , R 9 are each independently hydrogen, C 1 -C 18 straight, branched chain alkyl group or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms. ]
[Formula 120]

[wherein, R f is the general formula [1] represents the same substituents as, R 2 represents a same substituent as the general formula [3] in claim 5, R 7 , R 8 , R 9 represents the same substituent as in formula [8]. ]
[Claim 11]
Amine represented by the general formula [8] is an amine represented by the general formula [10] The method of claim 10.
Formula 121]

[wherein, R 7 , R 8 , R 10 are independently a hydrogen atom, C 1 -C 18 straight, branched alkyl or cyclic (in the case of 3 or more carbon atoms) group, a substituted alkyl group or an aromatic ring group having 6 to 18 carbon atoms, a substituted aromatic ring group, Ar 1 represents an aromatic ring group or a substituted aromatic ring group having 6 to 14 carbon atoms. Further, R 10 of, 1-18 linear, branched or cyclic alkyl group, a substituted alkyl group or an aromatic ring group having 6 to 18 carbon atoms (if 3 or more carbon atoms), substituted aromatic for Hajime Tamaki, * represents an asymmetric carbon. ]
[Claim 12]
Comprising the following steps, the production method of salts of the general formula [11] fluorinated cyclopropane monoester represented by the 1-phenylethylamine.
Formula 122]

[wherein, R 2 represents the same substituents as the general formula [3] in claim 5. * Represents an asymmetric carbon. ]
　[Cyclic sulfate step]
　in the fluorine-containing diol compound represented by the formula [12], an alkali metal hydride, alkali metal carbonates, by reacting an alkali metal hydrogen carbonate and sulfuryl fluoride in equation [13] obtaining a fluorinated cyclic sulfate according.
Formula 123]

[Formula 124]

In the formulas, * represents an asymmetric carbon. ] [Cyclopropanation
　step]
　in the fluorine-containing cyclic sulfate obtained in the cyclic sulfate step, the presence of an alkali metal or alkali metal hydride is reacted with malonic acid diester represented by the general formula [3] it is to obtain a fluorine-containing cyclopropane diester represented by the general formula [15].
Formula 125]

[wherein, R 1 , R 2 are each independently a number from 1 to 18 linear carbon atoms, an alkyl group branched or cyclic (in the case of 3 or more carbon atoms), a substituted alkyl group, It represents an aromatic ring group or substituted aromatic ring group having 6 to 18 carbon atoms. ]
[Formula 126]

[wherein, R 1 , R 2Represent the same substituents as the general formula [3] in claim 5, * represents an asymmetric carbon. ]
　[Hydrolysis step]
　The alkali metal hydroxide in the fluorine-containing cyclopropane diester obtained in cyclopropanation step, the presence of a quaternary ammonium hydroxide represented by the alkali metal carbonate or the general formula [6], hydrous obtaining a fluorine-containing cyclopropane monoesters represented by the general formula [16] by performing the decomposition.
Formula 127]

[wherein, R 3 , R 4 , R 5 , R 6 are each independently, having 1 to 18 linear, branched alkyl or cyclic (in the case of 3 or more carbon atoms) group, a substituted aromatic ring group having optionally substituted alkyl group having a substituent on carbon, optional substituents on the carbons of the aromatic ring group or aromatic ring group having 6 to 18 carbon atoms in the alkyl group. The R 3 , R 4 , R 5 , R 6 out of, or may be two or more forms part of the same aliphatic ring or aliphatic aromatic ring. ]
[Formula 128]

[wherein, R 2 is the general formula [3 in claim 5] represents the same substituents as, * represents an asymmetric carbon. ]
　[Recrystallization process]
　The optically active 1-phenylethylamine was added to the fluorine-containing cyclopropane monoester obtained in the hydrolysis step, to form salts with the fluorinated cyclopropane monoester and 1-phenylethylamine of the formula [11], the step of performing the recrystallization purification operation.
Formula 129]

[wherein, R 2 is R in the general formula [3] 2 same as. ]
[Claim 13]
Fluorinated cyclic sulfate of the formula [13].
Formula 130]

In the formulas, * represents an asymmetric carbon. ]
[Claim 14]
Salts with fluorinated cyclopropane monoester with an amine of the formula [17].
Formula 131]

[wherein, R 11 represents a straight-chain or branched-chain on the alkyl group having 1 to 6 carbon atoms, R 12 , R 13 , R 14 are each independently a hydrogen atom, C 1 -C represents a straight or branched chain alkyl group of ~ 6, Ar 2 represents an aromatic ring group or a substituted aromatic ring group having 6 to 10 carbon atoms. Further, R 14 of, for straight-chain or branched alkyl group having 1 to 6 carbon atoms, * the amine represents an asymmetric carbon. ]
[Claim 15]
Salts with fluorinated cyclopropane monoester and 1-phenylethylamine of the formula [18].
Formula 132]

[wherein, Et represents an ethyl group. ]
[Claim 16]
Salts with fluorinated cyclopropane monoester and 1-phenylethylamine of the formula [19].
Formula 133]

[wherein, Et represents an ethyl group. ]