The present invention, (2S, 5S) / (2R, 5R) -5- hydroxypiperidine-2-carboxylic acid, and a method for producing synthetic intermediates thereof. (2S, 5S) / (2R, 5R) -5- hydroxypiperidine-2-carboxylic acid prepared by the process of the present invention is useful as a synthetic intermediate for drugs or the like for inhibiting β-lactamase.
BACKGROUND
[0002]
　(2S, 5S) / (2R , 5R) -5- hydroxypiperidine-2-carboxylic acid, against bacteria resistant to β-lactam antibiotics, drugs, etc. that inhibit β-lactamase is a major cause of the resistance are useful intermediates in the synthesis.
　(2S, 5S) / (2R , 5R) as a method for producing a 5-hydroxy-piperidine-2-carboxylic acid, the production method of the glutamic acid or pyroglutamic acid as a starting material is known. Specifically, in Patent Document 1, a pyroglutamic acid as the starting material, as an intermediate for N- protected oxo azacycloalkyl carboxylic acids, through the homologation-cyclization step, the 5-hydroxypiperidine-2-carboxylic acid it has been described that the protection body is manufactured.
　Further, in Non-Patent Document 1, glutamine as a starting material, via homologation-cyclization step, protected 5-hydroxypiperidine-2-carboxylic acid is described to be manufactured.
　Non-Patent Document 2, a protective glutamic acid as a starting material, via homologation-cyclization step, protected 5-hydroxypiperidine-2-carboxylic acid is described to be produced as a mixture of stereoisomers .
　Non-Patent Document 3, a protective pyroglutamic acid as a starting material, via homologation-cyclization step, protected 5-hydroxypiperidine-2-carboxylic acid is described to be manufactured.
　Patent Document 2, a protective pyroglutamic acid as a starting material, through a step of performing homologation-cyclization in a single step, 5-protection of hydroxypiperidine-2-carboxylic acid is described to be manufactured .
CITATION
Patent Document
[0003]
Patent Document 1: WO2010 / 126820
Patent Document 2: WO2006 / 125974
Non-patent literature
[0004]
Non-Patent Document 1: PD Bailey et al, Chem Commun 1996, 349....
Non-Patent Document 2: PD Bailey et al, Tetrahedron Lett 1988, 29, 2231...
Non-Patent Document 3: MA Letavic et al,. Bioorg. Med. Chem. Lett. 2002, 12, 1387.
Summary of the Invention
Problems that the Invention is to Solve
[0005]
　Described in Patent Document 1 (2S, 5S) / ( 2R, 5R) -5- method for producing hydroxy-piperidine-2-carboxylic acid, must be used very expensive iridium catalyst, suitable for industrialization Absent.
　The manufacturing method described in Non-Patent Document 1, it is necessary to use an expensive rhodium catalyst, further, since the industrial There is the step of using diazomethane use is difficult, industrialization is difficult.
　The method according to Non-Patent Document 2 also, industrialization since the industrial There is the step of using a difficult diazomethane used is difficult, furthermore, the resulting compound is a problem that becomes a mixture of stereoisomers.
　The method according to Non-Patent Document 3 and Patent Document 2 also, industrially difficult to use, industrial because of the step of using an expensive TMS diazomethane is difficult, furthermore, expensive in manufacturing method described in Patent Document 2 it is necessary to use a rhodium catalyst. Industrialization from the fact that both have to be very reactive at low temperatures of the manufacturing method described in Non-Patent Document 3 and Patent Document 2 is difficult.
　In view of the above problems, a (2S, 5S) / (2R , 5R) -5- hydroxypiperidine-2-carboxylic acid and a manufacturing method of achiral body and chiral form of its synthesis intermediates, and to provide an industrially practical possible preparation methods.
Means for Solving the Problems
[0006]
　The present inventors have result of intensive investigations to solve the above problem, by using certain synthetic intermediate, (2S, 5S) / (2R, 5R) -5- optics hydroxypiperidine-2-carboxylic acid It found that the active substance can be efficiently synthesized, and completed the present invention.
[0007]
　That is, the present invention is as follows.
<1>
i) Step 4:
　the following formula (7)
[Formula 1]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is a 1 to 10 carbon atoms alkyl group, an aryl group having 6 to 12 carbon atoms, deprotecting the hydroxyl group at the C 1-4 alkyl group or a compound represented by indicating.) an aralkyloxy group having 7 to 20 carbon atoms, carbon,
　following equation (8)
[formula 2]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group, an aryl group having 6 to 12 carbon atoms of 1 to 10 carbon atoms, a C1- 4 alkyl group, or process, for synthesizing shown.) and a compound represented by the aralkyloxy group having 7 to 20 carbon atoms
　, characterized in that it comprises the following formula (10)
[formula 3]

is represented by that (2S, 5S) / (2R , 5R) -5- method for producing hydroxy-piperidine-2-carboxylic acid.
[0008]
<2>
　In addition, (ii) Step 5:
(a) the compound (8), an ester group is hydrolyzed, one of the carboxyl groups is lactonized by reaction with a hydroxyl group, further, the carboxyl group decarboxylation let,
　or,
(b) the compound (8), an ester group is hydrolyzed, one of the carboxyl groups and stereoisomeric mixture of the 2-position monocarboxylic acid by decarboxylation, then the stereo isomer mixture the isomerizing lactonization,
by,
　the following equation (9)
[formula 4]

(wherein, a represents an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms or 1 to 4 carbon atoms, alkyloxy group, step, to synthesize compounds represented by indicating.) an aralkyloxy group having 7 to 20 carbon atoms
　, characterized in that it comprises a according to <1> (2S, 5S) / (2R, 5R) - Method for producing a 5-hydroxy-piperidine-2-carboxylic acid.
[0009]
<3>
　In addition, (iii) Step 6:
　cleaved the amide bond in the compound (9), by hydrolyzing the lactone in the compound
(9), (2S, 5S) / (2R, 5R) -5 - a step of synthesizing a hydroxy-piperidine-2-carboxylic acid,
　characterized in that it comprises a, according to <1> or <2> (2S, 5S) / (2R, 5R) -5- hydroxy-2- manufacturing method of a carboxylic acid.
[0010]
<4>
　In the step 5 (a) or the step 5 (b), the decarboxylation reaction of the carboxyl group, in the presence of an organic base,
　characterized in that, in <2> or <3> according (2S, 5S) / (2R , 5R) -5- method for producing hydroxy-piperidine-2-carboxylic acid.
[0011]
<5>
　Step 1:
　the following formula (1)
[Chemical Formula 5]

(wherein, X is Cl, Br or indicates I, R, 1 is hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl group the hydroxyl group in the compound represented by the indicating.), it is protected with protecting group,
　the following formula (2)
[chemical formula 6]

(wherein, X represents a Cl, Br or I,, R 1 is a hydrogen atom or substituted represents an alkyl group having carbon atoms which may 1 ~ 4, P is to synthesize a compound represented by a protecting group.),
　then reducing the ester group in the compound (2),
　the following formula (3)
[chemical formula 7]

(wherein, X is Cl, Br or indicates I, P represents a protecting group.) step for synthesizing the compound represented by
　characterized in that it comprises a
　formula ( 7)
[of 8]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, carbon 6 aryl group to 12, an alkyloxy group having 1 to 4 carbon atoms or shows.) An aralkyloxy group having 7 to 20 carbon atoms,
a manufacturing method of a compound represented by the.
[0012]
<6>
(i) Step 2:
　with a sulfonic acid ester of a hydroxyl group in the compound (3),
　the following formula (4)
[Formula 9]

(wherein, X represents a Cl, Br or I,, R 2 is an aryl group having 6 to 12 carbon atoms, an alkyl group having 1 to 10 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.) represented by synthesizing the compound,
　the compound (4),
　the following equation ( 5)
[formula 10]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, having 1 to 4 carbon atoms alkyl group, or by reacting a compound represented by the show.) the aralkyloxy group having 7 to 20 carbon atoms,
　following formula (6)
[formula 11]

(wherein, X is Cl, Br or I, are shown, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is alkyl having 1 to 10 carbon atoms A step of synthesizing an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, or a compound represented by the show.) The aralkyloxy group having 7 to 20 carbon atoms, and,
(ii) step 3:
　the compound (6) cyclizes
　Formula (7)
[of 12]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is-alkyl group, having 6 from 1 to 10 carbon atoms 12 aryl group,.) represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, having 1 to 4 carbon atoms
step, to synthesize compounds represented by
　characterized in that it comprises a, in <5> process for the preparation of a compound according (7).
[0013]
<7>
　In the step 2, the reaction between the compound (4) and the compound (5), in the presence of a iodide salt,
　wherein the production of a compound according to <6> (7) Method.
[0014]
<8>
　In the step 3, the cyclization reaction of the compound (6), carried out in the presence of a quaternary ammonium salt,
　wherein the compound according to <6> or <7> (7) Production method.
[0015]
<9>
　The compound (7), <5> - is produced by the method according to any one of <8>,
　wherein the, according to any one of <1> to <4> of (2S, 5S) / (2R , 5R) -5- method for producing hydroxy-piperidine-2-carboxylic acid.
[0016]
<10>
(i) Step 4:
　the following formula (7)
[of 13]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is a carbon number of 1 to 10 alkyl group, an aryl group having 6 to 12 carbon atoms, deprotecting the hydroxyl group at the C 1-4 alkyl group or a compound represented by indicating.) an aralkyloxy group having 7 to 20 carbon atoms, carbon,
　formula (8)
[formula 14]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group, an aryl group having 6 to 12 carbon atoms of 1 to 10 carbon atoms, 1 to 4 carbon atoms alkyloxy group 1-4 or an aralkyl group having 7 to 20 carbon atoms. step, to synthesize compounds represented by)
　and having a, in the compound represented by the formula (8) Production method.
[0017]
<11>
(i) Step 4:
　the following formula (7)
[Formula 15]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is a carbon number of 1 to 10 alkyl group, an aryl group having 6 to 12 carbon atoms, deprotecting the hydroxyl group at the C 1-4 alkyl group or a compound represented by indicating.) an aralkyloxy group having 7 to 20 carbon atoms, carbon,
　formula (8)
[formula 16]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group, an aryl group having 6 to 12 carbon atoms of 1 to 10 carbon atoms, 1 to 4 carbon atoms synthesising alkyloxy group 1-4, or a compound represented by) an aralkyl group having a carbon number of 7 - 20,.
(ii) step 5:
(a) in the compound (8), an ester group hydrolyzing one of the carboxyl groups is lactonized by reaction with a hydroxyl group, further To the carboxyl group is decarboxylated,
　or
in (b) the compound (8), an ester group is hydrolyzed, by one of the carboxyl groups decarboxylated and 2 of stereoisomeric mixture of monocarboxylic acids, then, isomerizing lactone the stereo isomer mixtures,
by,
　the following equation (9)
[formula 17]

Table (In the formula, A represents an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms or an alkyloxy group having 1 to 4 carbon atoms,. Showing an aralkyloxy group having 7 to 20 carbon atoms,) with process of synthesizing a compound
　characterized by having a method for producing a compound represented by the formula (9).
[0018]
<12>
　a compound represented by the following formula (9a).
[Formula 18]

(wherein, A 'represents an alkyl group having an aryl group or a C1-C10 having 6 to 12 carbon atoms.)
[0019]
<13>
　or a salt thereof represented by the following formula (11a) or (11b).
[Formula 19]

(wherein, A 'represents an alkyl group having an aryl group or a C1-C10 having 6 to 12 carbon atoms.)
[Formula 20]

(In the formulas, A' represents a carbon number of 6 to 12 aryl It denotes a group or an alkyl group having 1 to 10 carbon atoms.)
[0020]
<14>
　a compound represented by the following formula (8) or a salt thereof dicarboxylic acid.
[Formula 21]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy having 1 to 4 carbon atoms group, or an aralkyl group having 7 to 20 carbon atoms.)
[0021]
<15>
　a compound represented by the following formula (7).
Formula 22]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group, an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms, carbon alkyloxy group having 1 to 4 or an aralkyl group having 7 to 20 carbon atoms.)
[0022]
<16>
　a compound represented by the following formula (6a).
[Chem 23]

(wherein, X is Cl, showed a Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or C 7 ~ 20 shows the aralkyl group.)
[0023]
<17>
　a compound represented by the following formula (4a).
Formula 24]

(wherein, X is Cl, showed a Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, R 2 represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, an aryl group, 1 to 10 carbon atoms of 6 to 12 carbon atoms.)
[0024]
<18>
　a compound represented by the following formula (3a).
Formula 25]

(wherein, X represents a Cl, Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group. )
[0025]
<19>
　a compound represented by the following formula (2a).
[Chemical Formula 26]

(wherein, X is Cl, Br or indicates I, R, 1 represents a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl, P '' is a tetrahydropyranyl group or shows ethoxyethyl group.)
The invention's effect
[0026]
　According to the present invention, to provide (2S, 5S) / (2R, 5R) -5- hydroxypiperidine-2-carboxylic acid, excellent in safety and operability industrially practical possible preparation method it can. Further, according to the present invention, it is possible to provide a (2S, 5S) / (2R, 5R) -5- novel synthetic intermediates for the preparation of hydroxy-piperidine-2-carboxylic acid. (2S, 5S) / (2R, 5R) -5- hydroxypiperidine-2-carboxylic acid produced by the production method of the present invention can be utilized as starting materials in the manufacture of a medicament such as to inhibit β-lactamase .
BRIEF DESCRIPTION OF THE DRAWINGS
[0027]
Is a diagram showing an embodiment of FIG 1] (2S, 5S) / (2R, 5R) -5- synthetic scheme hydroxypiperidine-2-carboxylic acid. In the figure, X is shown Cl, Br or I,. P is a protecting group. A represents an alkyl group, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, 1 to 10 carbon atoms. R 1 represents a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl group. R 2 represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, an aryl group, 1 to 10 carbon atoms of 6 to 12 carbon atoms. R 3 is an alkyl group having 1 to 4 carbon atoms.
DESCRIPTION OF THE INVENTION
[0028]
　It will be described in detail the present invention.
　In the present specification, it may be referred to as a "compound (1)" "compound represented by the formula (1)". For even compounds represented by other formulas are the same.
　As used herein, Cl is chlorine, Br is bromine, I is iodine atom, Et represents an ethyl group.
[0029]
[1] Production method
　The present invention, by using certain synthetic intermediates represented by the following formula (8) or (9), (2S, 5S ) / (2R, 5R) -5- hydroxypiperidine - characterized in that to prepare optically active forms of 2-carboxylic acid.
Formula 27]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy having 1 to 4 carbon atoms group, or an aralkyl group having 7 to 20 carbon atoms.)
[formula 28]

(wherein, a represents an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms having 1 to 4 carbon atoms, an alkyloxy group, an aralkyl group having 7 to 20 carbon atoms.)
[0030]
　Compound (8) can be synthesized using conventional organic chemistry techniques, it is preferably synthesized by the following steps 4.
　Step 4, compound (7) as a starting material, a process for preparing a compound represented by the formula (8) (Compound (8)) a.
　Step 4:
　the following formula (7)
[of 29]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms, carbon atoms an aryl group of 6 to 12, an alkyloxy group having 1 to 4 carbon atoms, or show.) the aralkyloxy group having 7 to 20 carbon atoms
by deprotection of the hydroxyl group in the compound represented by,
　the following formula (8)
[ of 30]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms , or to synthesize the compound represented by an aralkyl group having 7 to 20 carbon atoms.).
[0031]
　The conditions for the deprotection, it is possible to adopt a condition generally used for the deprotection of the protecting group, typically an acid or a combination of an acid catalyst and an alcohol used.
　The acid used for deprotection, typically hydrochloric, sulfuric, or organic acids such as phosphoric acid, methanesulfonic acid, p- toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, organic acids such as acetic acid are used, preferably hydrochloric acid, is p- toluenesulfonic acid is used.
　As the acid catalyst, usually hydrochloric, or an inorganic acid such as sulfuric acid, methanesulfonic acid, and organic acids such as p- toluenesulfonic acid used is preferably hydrochloric acid, p- toluenesulfonic acid.
　The alcohol, typically methanol, ethanol, n- propanol, 2-propanol, n- butanol or the like is used, preferably methanol is used.
　For example, in the case of P is tetrahydropyranyl group or ethoxyethyl group of the formula (7), preferably the action of hydrochloric acid in methanol solvent as a catalyst, can be easily deprotected by this method.
[0032]
　Among the compounds represented by formula (8), a compound represented by the following formula (8a)
[of 31]

(wherein, Ac is. Of an acetyl group)
crystallization Since it is crystalline, after deprotection it is easy to isolate purified, it can be synthesized with high purity of the compound (8a). By combining with the high purity of the compound (8a), of high purity (2S, 5S) / (2R , 5R) it is possible to synthesize the 5-hydroxy-piperidine-2-carboxylic acid, compound (8a ) is particularly preferred as synthesis intermediates. The crystallization solvent, such as toluene or may be a mixed solvent of toluene and heptane.
　Incidentally, in the compound (8), R 3 , and A, R in the corresponding groups in the compounds (5) 3 is synonymous with, and A.
[0033]
　Compound (9) can be synthesized using conventional organic chemistry techniques, it is preferably synthesized by 5 steps.
　Step 5, compound (8) as a starting material, a process for preparing a compound represented by the formula (9) (Compound (9)) and. The step 5, the following steps 5 (a) or step 5 (b) are preferred.
[0034]
　Step 5 (a):
　In the compound (8), an ester group is hydrolyzed, one of the carboxyl groups is lactonized by reaction with a hydroxyl group, further, by a carboxyl group decarboxylation,
　the following equation (9 )
[of 32]

(wherein, a represents an alkyl group, an aryl group having 6 to 12 carbon atoms in the alkyl group, an aryl group having 6 to 12 carbon atoms, carbon atoms of 1 to 10 1 to 10 carbon atoms or carbon, alkyloxy group having 1 to 4 to synthesize the compound represented by the show.) the aralkyloxy group having 7 to 20 carbon atoms.
[0035]
　In step 5 (a), first, hydrolyzing the ester group of the compound (8). The hydrolysis of the ester group base is used.
　The reaction solvent, water, methanol, ethanol and the like are used.
　As the base, sodium hydroxide, can be used potassium hydroxide and the like, among them, sodium hydroxide is preferred.
　The amount of the base to be used, relative to compound (8) is usually 2 times mole to 10 moles, preferably 2 moles to 5 moles.
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 50 ° C., preferably from 0 ℃ ~ 10 ℃.
　The reaction time is not particularly limited, usually 1 hour to 24 hours, preferably 5 hours to 10 hours.
[0036]
　Next, after the ester group of the compound (8) was hydrolyzed (ester decomposition), to one of the carboxyl groups are lactonized by reaction with a hydroxyl group.
　To perform the decarboxylation after lactonization, firstly, a dicarboxylic acid obtained by ester cleavage, by reacting a dehydrating agent, to induce the 5-position hydroxyl group and a carboxyl group of the cis configuration in the lactone.
　The dehydrating agent, for example acetic anhydride, acetyl chloride, common dehydrating agent such as thionyl chloride can be used.
　The reaction solvent is not particularly limited as long as it does not inhibit the reaction, preferably acetic acid or a mixed solvent of acetic acid and toluene is used.
[0037]
　The amount of the dehydrating agent is an ester group to hydrolysis to compound (8) is usually 1-fold mole to 20 moles, preferably 1-fold mole to 5 moles.
[0038]
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 80 ° C., preferably from 30 ℃ ~ 60 ℃.
　The reaction time is not particularly limited, usually 1 hour to 12 hours, preferably 2 hours to 5 hours.
[0039]
　After one of the carboxyl groups is lactonized, further to the other carboxyl group decarboxylation.
　The other remaining carboxyl groups in which decarboxylation, by conformational fixation by lactonization, protonation after decarboxylation proceeds stereoselectively, hydroxyl group and a carboxyl group is a cis configuration 5- acyl - 2-oxa-5-azabicyclo [2.2.2] compounds of octan-3-one structure (9) is obtained.
　Decarboxylation can proceed even only heated (simple heating), reaction by adding an organic base such as triethylamine or pyridine is accelerated, preferred since it becomes possible reaction at low temperatures.
　The reaction temperature for carrying out the decarboxylation simple heating is usually 100 ° C. ~ 130 ° C., the reaction temperature in the case of adding the organic base is usually 60 ℃ ~ 90 ℃.
　The reaction solvent is not particularly limited as long as it does not inhibit the reaction, preferably acetic acid or a mixed solvent of acetic acid and toluene is used.
[0040]
　The amount of the organic base is a compound obtained by lactonization against (8) is usually 0.1 times mol to 2 moles, preferably 0.2 moles to 1 moles.
　The reaction time is not particularly limited, usually 1 hour to 12 hours, preferably 2 hours to 5 hours.
[0041]
　Step 5 (b):
　In the compound (8), an ester group is hydrolyzed, one of the carboxyl groups and stereoisomeric mixture of the 2-position monocarboxylic acid by decarboxylation and then the stereo isomer mixture by isomerizing lactonization,
　the following equation (9)
[of 33]

(in the formula, a represents an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms or an alkyloxy having 1 to 4 carbon atoms, group, to synthesize a compound represented by the show.) the aralkyloxy group having 7 to 20 carbon atoms.
[0042]
　In step 5 (b), for the hydrolysis of the ester group of compound (8) can be carried out under the same conditions as step 5 (a).
　After compound an ester group of (8) was hydrolyzed, and 2-position stereoisomeric mixture of monocarboxylic acids by decarboxylation one carboxyl group.
　In step 5 (b), since the First decarboxylation, the dicarboxylic acid obtained by ester cleavage, first decarboxylated to 2-position stereoisomeric mixture of monocarboxylic acids.
　Decarboxylation proceeds even only heated (simple heating) but the reaction by adding an organic base such as triethylamine or pyridine is accelerated, it is possible to react at a low temperature.
　The reaction temperature for carrying out the decarboxylation simple heating is usually 100 ° C. ~ 130 ° C., the reaction temperature in the case of adding the organic base is usually 60 ℃ ~ 90 ℃.
　The reaction solvent is not particularly limited as long as it does not inhibit the reaction, preferably a mixed solvent of acetic acid or acetic acid and methanol are used.
[0043]
　The amount of the organic base, an ester group to hydrolysis to compound (8) is usually 0.1 times mol to 2 moles, preferably 0.2 moles to 1 moles.
　The reaction time is not particularly limited, usually 1 hour to 12 hours, preferably 2 hours to 5 hours.
[0044]
　Then, isomerizing lactone the stereoisomeric mixtures. The 2-position stereoisomeric mixture of monocarboxylic acids when isomerizing lactonization second place that the carboxyl group of 5-position hydroxyl group and cis configuration immediately form a lactone with a dehydrating agent, 2-position carboxyl group is 5-position those hydroxyl groups and trans arrangement to form a lactone while isomerized to cis configuration. As a result, finally a stereoisomer of all 2-position monocarboxylic acids, hydroxyl group and carboxyl group of cis configuration 5-acyl-2-oxa-5-azabicyclo [2.2.2] octan-3-one compounds of structure (9) is obtained. In this case, dehydration and as those capable of performing isomerization at the same time (dehydration and isomerization lactonization agent), acetic anhydride, a combination of acetic anhydride and an amine, trifluoroacetic anhydride, a combination of trifluoroacetic anhydride and an amine, chloro combination of a carbonic ester and the amine can be mentioned, with preference acetic anhydride, or a combination of acetic anhydride and an amine.
[0045]
　The amount of the dehydration and isomerization lactonization agent with respect to the 2-position stereoisomeric mixture of a monocarboxylic acid, is usually 1-fold mole to 20 moles, preferably 1-fold mole to 5 moles.
　The amine when combining amine, pyridine, triethylamine and the like are used, particularly preferably triethylamine. The amount of the amine used for 2-position stereoisomeric mixture of monocarboxylic acids, usually 0.1 times mol to 3 moles, preferably 0.2 moles to 1 moles.
　The reaction temperature is not particularly limited, usually 20 ° C. ~ 130 ° C., preferably from 60 ℃ ~ 90 ℃.
　The reaction time is not particularly limited, usually 1 hour to 12 hours, preferably 2 hours to 5 hours.
[0046]
　In step 5 (a) and step 5 (b), can also be done from dicarboxylic acids derived by ester cleavage compound to (9) without the middle isolated and purified.
　In that case, for example, di-sodium salt of the dicarboxylic acid was dissolved in acetic acid, to form intramolecular lactones by the addition of acetic anhydride, followed by decarboxylation by heating with addition of triethylamine, the compound (9) It can be synthesized.
　Further, for example, the disodium salt of the dicarboxylic acid was dissolved in acetic acid, heated by the addition of triethylamine, and decarboxylated and 2 of stereoisomeric mixture of a monocarboxylic acid and then the compound by heating with acetic anhydride (9) can be synthesized. In this case, sodium acetate by-produced can be removed by precipitation by adding a poor solvent such as toluene and filtered.
　In step 5 (a) or step 5 (b), for A of the synthesized compounds (9) in the case of benzyl group, because it is crystalline, it is possible to isolate purified by crystallization, high purity compound (9) can be synthesized. By combining with the high purity of the compound (9), of high purity (2S, 5S) / (2R, 5R) it is possible to synthesize the 5-hydroxy-piperidine-2-carboxylic acid, compound (9 ) is particularly preferred as synthesis intermediates. The crystallization solvent, for example, a mixed solvent of toluene and heptane can be used.
　Incidentally, in the compound (9), A has the same meaning as A in the later-described compound (5).
[0047]
　Here, is a starting material compound (7) can be synthesized using conventional organic chemistry techniques, it is preferably synthesized by the following steps 1-3.
　Step 1:
　compound represented by formula (1) (Compound (1)) as a raw material, a step for preparing a compound represented by the formula (3) (Compound (3)) a.
　Formula (1)
[formula 34]

(wherein, X is Cl, Br or indicates I,, R 1 table in a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl group.) the hydroxyl groups in the compound, and protected by a protecting group,
　the following formula (2)
[reduction 35]

(wherein, X is Cl, Br or indicates I,, R 1 may be hydrogen or substituted an alkyl group having a carbon number of 1 ~ 4, P is synthesizing the compound represented by a protecting group.),
　by reduction of the ester group in then compound (2),
　the following formula (3)
[of 36]

(wherein, X represents a Cl, Br or I,, P represents a protecting group.) to synthesize a compound represented by.
[0048]
　Compound (1) is the starting material of Step 1.
　X in the formula (1) may, Cl, Br or I,, preferably, X is Cl. R 1 is a hydrogen atom or an optionally substituted good C 1 -C 4 alkyl group, preferably, R 1 is an alkyl group substituted by 1 carbon atoms which may be 1-4. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, a tert- butyl group. Examples of the substituent of the alkyl group, a halogen atom, an alkoxy group or the like.
　Compound (1) is a known method, for example, Tetrahedron: Asymmetry, 12 (12), can be easily produced according to the method described in 1713 (2001) and the like. Also, X is Cl or Br in the formula (1), and, R 1 compound is a methyl group or an ethyl group (1) may be a commercially available product.
[0049]
　First, the hydroxyl group in the compound (1), is protected with protecting group, to synthesize a compound (2).
　Preferably an ether-type protecting group as a protecting group. The reason for using an ether-based protecting group, because it is convenient to withstand the subsequent processes basic conditions. Incidentally, in the compound (2), oxygen bonded to the protecting group P is derived from a hydroxyl group.
　As the protecting group, tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, tert- butyl group, or a tert- butyldimethylsilyl group. Each protecting dihydropyran and an acid catalyst, methoxymethyl chloride and diisopropylethylamine, ethyl vinyl ether and an acid catalyst, isobutylene and an acid catalyst, the hydroxyl group by reaction with a combination of tert- butyldimethylsilyl chloride and imidazole reactant Accordingly, it is possible to introduce a protecting group. Preferred protecting groups are tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group. Among them, tetrahydropyranyl group is preferred as a protecting group because of its high safety.
[0050]
　When using the tetrahydropyranyl group as the protective group, for example, in a reaction solvent, the compound (1), and dihydropyran, methanesulfonic acid, and an acid catalyst such as p- toluenesulfonic acid or pyridinium p- toluenesulfonate to obtain the compound (2) by acting.
　The reaction solvent is not particularly limited as long as the reaction proceeds, toluene, heptane, dichloromethane, ethyl acetate or the like. Further, it is possible to allow the reaction to proceed even without solvent.
[0051]
　The amount of dihydropyran, relative to compound (1) is usually 1-fold mole to 10 moles, preferably 1-fold mole to 1.5 moles.
　The amount of the acid catalyst is, relative to compound (1) is usually 0.001 moles to 0.1 moles, preferably 0.002 times mole to 0.02 times mole.
[0052]
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 80 ° C., preferably from 20 ℃ ~ 60 ℃.
　The reaction time is not particularly limited, 0.5 hour to 10 hr, preferably 1 hour to 3 hours.
[0053]
　Further, in the compound (2), X is a Cl, Br or I,, preferably, X is Cl.
　In the compound (2), R 1 is a hydrogen atom or an optionally substituted good C 1 -C 4 alkyl group, preferably, R 1 is substituted 1 carbon atoms which may be 1-4 alkyl a group. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, a tert- butyl group. Examples of the substituent of the alkyl group, a halogen atom, an alkoxy group or the like.
　In the compound (2), P is a protecting group, preferably a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, and particularly preferably tetrahydropyranyl group it is.
[0054]
　Then, by reducing the ester group in the compound (2), to synthesize a compound (3).
　The reduction of the ester group to an alcohol compound (2), it is preferable to use a hydride reducing agent. For example, using lithium aluminum hydride, or aluminum-based hydride reducing agent such as diisobutyl aluminum hydride or sodium bis-methoxyethoxy aluminum hydride, sodium borohydride, lithium borohydride, a boron hydride reducing agent such as calcium borohydride or borane be able to. Above all, due to the high reactivity of the ester reduction, it is preferable to use an aluminum-based hydride reducing agent or lithium borohydride.
[0055]
　For example, in a reaction solvent, the compound (2), by the action of aluminum-based hydride reducing agent, it is possible to synthesize a compound (3).
　The reaction solvent is not particularly limited as long as the reaction proceeds, tetrahydrofuran, toluene and the like. Further, it is possible to allow the reaction to proceed even without solvent.
[0056]
　The amount of hydride reducing agent as hydride, the compound (2) is usually 2 times mole to 10 moles, preferably 2 moles to 3 moles.
[0057]
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 80 ° C., preferably from 0 ℃ ~ 20 ℃.
　The reaction time is not particularly limited, 0.5 hour to 10 hr, preferably 1 hour to 3 hours.
　Incidentally, in the compound (3), X, and P have the same meanings as X, and P in the compound (2).
[0058]
　Step 2:
　Compound (3) as a raw material, a step for preparing a compound represented by the formula (6) (Compound (6)) a.
[0059]
　The hydroxyl group in the compound (3) sulfonic acid esterification,
　the following formula (4)
[of 37]

(wherein, X is Cl, Br or indicates I, R, 2 is an aryl group having 6 to 12 carbon atoms, carbon an alkyl group having 1 to 10 or an aralkyl group having 7 to 20 carbon atoms.) to synthesize a compound represented by,,
　the compound (4),
　the following formula (5)
[formula 38]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or C 7 ~ 20 shows the aralkyl group. the compound represented by the) were reacted,
　following formula (6)
[formula 39]

(wherein, X represents a Cl, Br or I,, P represents a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is Ali alkyl group, having 6 to 12 carbon atoms having 1 to 10 carbon atoms Group, to synthesize a compound represented by.) Represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, having 1 to 4 carbon atoms.
[0060]
　First, Compound (3) hydroxyl and sulfonic acid esterification of the, to synthesize a compound (4).
　The sulfonic acid esterification of the hydroxyl groups of compound (3), general alkylsulfonyl chloride and a base, a combination of aryl sulfonyl chloride and a base can be employed. For example, a combination of methanesulfonyl chloride and p- toluenesulfonyl chloride and triethylamine may be employed.
　For example, in a reaction solvent, the compound (3), an alkyl sulfonyl chloride or aryl sulfonyl chloride, the base can be compound (4) synthesized by the action of.
　The reaction solvent is not particularly limited as long as the reaction proceeds, toluene, methylene chloride, tetrahydrofuran, ethyl acetate or the like. Further, it is possible to allow the reaction to proceed even without solvent.
　As the base, pyridine, or organic bases such as triethylamine, sodium hydrogen carbonate, or an inorganic base such as sodium hydroxide.
[0061]
　The amount of the alkylsulfonyl chloride or arylsulfonyl chloride, the compound (3) is usually 1-fold mole to 2 moles, preferably 1-fold mole to 1.2 moles.
　The amount of the base to be used, relative to compound (3) is usually 1-fold mole to 2 moles, preferably 1-fold mole to 1.5 moles.
[0062]
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 50 ° C., preferably from 0 ℃ ~ 20 ℃.
　The reaction time is not particularly limited, 0.5 hour to 5 hr, preferably 1 hour to 2 hours.
　Incidentally, in the compound (4), X, and P have the same meanings as X, and P in the compound (2).
　Further, in the compound (4), R 2 represents an aryl group having 6 to 12 carbon atoms, an aralkyl group an alkyl group or a C 7-20, 1 to 10 carbon atoms, R 2 is preferably a carbon number 6-7 aryl group, an alkyl group or an aralkyl group having 7 to 11 carbon atoms, having 1 to 3 carbon atoms, more preferably a methyl group. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group, a biphenyl group and the like. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. Examples of the aralkyl group include benzyl group, phenethyl group and the like.
[0063]
　Next, the compound (4), compound (5) are reacted, to synthesize a compound (6).
　In the compound (5), R 3 represents an alkyl group having 1 to 4 carbon atoms, preferably an alkyl group having 1 to 2 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, a tert- butyl group.
　Further, in the compound (5), A is an alkyl group, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, from 1 to 10 carbon atoms , preferably, an aryl group having 6 to 10 carbon atoms, an alkyl group having 1 to 3 carbon atoms, an alkyl group or an aralkyloxy group having 7 to 11 carbon atoms, having 1 to 4 carbon atoms, more preferably a methyl group it is. Examples of the aryl group include a phenyl group, a naphthyl group, a biphenyl group and the like. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. The alkyl group, a methyloxy group, ethyloxy group, n- propyl group, an isopropyl group, n- butyloxy, iso-butyloxy group, a tert- butyloxy and the like. The aralkyloxy group, a benzyloxy group, a phenethyloxy group.
　Compound (5) can be a commercially available product. Compound (5) is, for example, available from Tateyama Kasei Corporation.
[0064]
　Carrying out the reaction of the compound (4) with the compound (5), it is necessary bases to generate the α-position anion compound (5). Therefore, for example, sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, sodium tert- butoxide, potassium tert- butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, etc. strong base or, cesium carbonate, potassium carbonate, it is preferred to conduct the reaction in the presence of a weak base such as sodium carbonate. Among them, sodium hydride, sodium tert- butoxide, potassium tert- butoxide, sodium ethoxide, cesium carbonate, it is preferred to conduct the reaction in the presence of a base such as potassium carbonate.
[0065]
　The amount of the base used, usually, the substrate (compound (5)) with respect to is 0.8 moles or more, preferably, 0.8 fold mole to 1.2 moles in the case of a strong base, weak base the case of a 0.8-fold molar to 3-fold molar.
[0066]
　The reaction solvent is not particularly limited as long as the substrate is dissolved, preferably, dimethyl sulfoxide, N, N- dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methylpyrrolidone and, methanol, ethanol, propanol, alcohol solvents butanol, tetrahydrofuran, diethyl ether, methyl -tert- butyl ether, ether solvents such as methyl cyclopropyl ether, and with them, toluene, hexane, Ya hydrocarbon solvents such as heptane , dichloromethane, chloroform, a mixed solvent of a halogenated hydrocarbon solvent 1,2-dichloroethane and the like are used. More preferably, dimethyl sulfoxide, N, N- dimethylformamide, N- methylpyrrolidone, tetrahydrofuran, and a mixed solvent thereof and toluene, a mixed solvent of ethanol and toluene is used.
[0067]
　The reaction temperature is not particularly limited, usually from 0 ° C. ~ 130 ° C., preferably from 20 ℃ ~ 80 ℃.
[0068]
　The reaction time is not particularly limited, usually 1 hour to 24 hours, preferably 1 hour to 5 hours.
[0069]
　In this step, the reaction is accelerated, in order to improve the selectivity, it is desirable to add an iodine salt. The iodine salt is preferably one represented by MI (M is an alkali metal), among others, potassium iodide, sodium iodide and the like are preferable. These amount added substrate (Compound (4)) is 0.02 moles to 1 moles relative, preferably 0.2-fold mol to 0.4 moles.
　To the compound (4), the amount of the compound (5) is a 1-fold mole to 2 moles relative to the compound (4), preferably 1-fold mole to 1.2 moles.
[0070]
　Incidentally, in the compound (6), X, and P, and X, and P in the compound (2), R 3 , and A, R in the compound (5) 3 is synonymous with, and A.
[0071]
　Step 3:
　Compound (6) as a raw material, a step for preparing a compound represented by the formula (7) (Compound (7)) and.
[0072]
　　The compound (6) cyclizes
　formula (7)
[of 40]

(wherein, P is a protecting group, R 3 represents an alkyl group of 1 to 4 carbon atoms, A is a C1- 10 alkyl group, an aryl group having 6 to 12 carbon atoms,.) represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, having 1 to 4 carbon atoms
to synthesize the compound represented by.
[0073]
　The present step 3 is needed bases. Examples of the base include sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, sodium tert- butoxide, potassium tert- butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, strong bases and such as potassium, cesium carbonate, potassium carbonate, weak base such as sodium carbonate is used, preferably, sodium hydride, sodium tert- butoxide, potassium tert- butoxide, cesium carbonate, potassium carbonate is used.
[0074]
　The amount of base used is normally a substrate (compound (6)) is 1-fold mol or more with respect, preferably, 1-fold mole to 2 moles in case of a strong base, in the case of weak base 1 fold mole to it is a three-fold molar.
　The reaction solvent is a substrate (compound (6)) is not particularly limited as long as it dissolves, preferably, dimethyl sulfoxide, N, N- dimethylformamide, N, N- dimethylacetamide, such as N- methylpyrrolidone and aprotic polar solvents, tetrahydrofuran, diethyl ether, methyl -tert- butyl ether, and ether solvents such as methyl cyclopropyl ether and these, toluene, hexane, or a hydrocarbon solvent such as heptane, dichloromethane, chloroform, 1, 2 mixed solvent of a halogenated hydrocarbon solvent dichloroethane is used, or more preferably, N, N- dimethylformamide, N- methylpyrrolidone, tetrahydrofuran, and a mixed solvent thereof and the toluene used.
[0075]
　The reaction temperature is not particularly limited, it is usually 0 ° C. ~ 130 ° C., preferably, 10 ° C. ~ 50 ° C. For a strong base, 80 ° C. ~ 130 ° C. In the case of a weak base.
　The reaction time is not particularly limited, usually 1 hour to 24 hours, preferably 1 hour to 6 hours.
[0076]
　In this step, the reaction is accelerated, in order to improve the selectivity, it is desirable to carry out in the presence of a quaternary ammonium salt such as tetrabutylammonium bromide. These usage substrate (compound (6)) is 0.02 moles to 1 moles relative, preferably 0.2-fold mol to 0.4 moles.
[0077]
　Moreover, the way the process 2 and process 3, it is also possible to continuously performed without isolating and purifying the compound (6) can be carried out by the the end of the reaction of step 2 if, the base is added .
　Incidentally, in the compound (7), P is a P in the compound (2), R 3 , and A, R in the compound (5) 3 is synonymous with, and A.
[0078]
　In the present invention, (2S, 5S) / (2R, 5R) -5- hydroxypiperidine-2-carboxylic acid is preferably synthesized by the following step 6.
[0079]
　Step 6 Compound (9) as a starting material, a step for preparing a compound represented by the formula (10) (Compound (10)) the.
[0080]
　Wherein the lactone in compound (9) was hydrolyzed to cleave the amide bond in the compound (9),
　the following equation (10)
[formula 41]

represented by (2S, 5S) / (2R, 5R) synthesizing 5-hydroxy-piperidine-2-carboxylic acid.
[0081]
　Cleavage of the amide bond in the lactone hydrolysis compound (9) in the compound (9) may be allowed to proceed simultaneously.
　Cleavage of the amide bond can be employed commonly conditions used. For example A is in the case of alkyl or aryl group, can be easily cleaved by the action of hydrochloric acid in a reaction solvent, a strong acid such as hydrobromic acid as a catalyst.
　The reaction solvent, water or water-containing dioxane, water-containing dimethoxyethane, aqueous solvents such as aqueous acetone is used.
　The amount of the strong acid, relative to the compound (9) is usually 1-fold mole to 10 moles, preferably 1-fold mole to 2 moles.
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 100 ° C., preferably from 80 ℃ ~ 100 ℃.
　The reaction time is not particularly limited, usually 1 hour to 12 hours, preferably 3 hours to 6 hours.
　The hydrolysis of the lactone, according to the method commonly employed in hydrolysis, acid or base is used, such as hydrochloric acid or sodium hydroxide.
　The reaction solvent, water, methanol, ethanol and the like are used.
[0082]
　The amount of acid or base, compound cleave amide bond to (9), is usually 1-fold mole to 10 moles, preferably 1-fold mole to 2 moles.
[0083]
　The reaction temperature is not particularly limited, usually 0 ° C. ~ 100 ° C., preferably from 60 ℃ ~ 100 ℃.
　The reaction time is not particularly limited, usually 1 hour to 12 hours, preferably 8 hours to 12 hours.
[0084]
　In step 6, compound (9) is represented by the formula (9a) Compound
Formula 42]

(wherein, A 'represents an alkyl group or an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms.)
for, for example by heating with the addition of hydrochloric acid, hydrolysis of the hydrolyzable and acetyl groups of the lactone may be performed simultaneously.
　In this case, the resulting (2S, 5S) / (2R , 5R) -5- hydroxypiperidine-2-carboxylic acid because it is a hydrochloride salt, in accordance with the method commonly employed for the purification of amino acids, ion exchange can or the like to dehydrochlorination in the resin. Further, lithium hydroxide to neutralize hydrochloric acid, and lithium chloride with lithium carbonate, or the triethylamine hydrochloride with triethylamine, by adding an alcohol or acetone, etc. After concentration, lithium chloride and triethylamine hydrochloride it can be removed.
[0085]
　Incidentally, in the compound (9a), A 'is an aryl group of the alkyl group carbon atoms or 6 to 10 from 1 to 10 carbon atoms, preferably an alkyl group or an aryl group having 6 carbon atoms having 1 to 3 carbon atoms is there. Examples of the aryl group include a phenyl group. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like.
[0086]
　Furthermore, (2S, 5S) / for (2R, 5R) -5- hydroxypiperidine-2-carboxylic acid is crystalline, can be purified by recrystallization. The recrystallization solvent, e.g., water - ethanol mixture system, methanol - acetone mixed system or the like can be used.
[0087]
　In the present invention, in step 1-5, the compound (1) X is Cl in ~ (9), R 1 and R 3 is an ethyl group, R 2 is a methyl group or a p- toluyl group, A is a methyl group or a phenyl group, P is a tetrahydropyranyl group or a methoxymethyl group, ethoxyethyl group, is preferably a tert- butyldimethylsilyl group or tert- butyl group.
　In the present invention, optically active 4-halo-3-hydroxybutanoic acid ester (Compound (1)) sulfonic acid ester of optically active 4-halo-3-protected hydroxy-butanol derived from (Compound (4)) If, acylamino malonic acid diester (compound (5)) and was coupled 2-optically active 2-acylamino with [4-halo-3-protected hydroxy-butyl] - malonic acid diester (compound (6)) and obtained,
　cyclized this give deprotected to optically active 1-acyl-5-hydroxypiperidine-2,2-dicarboxylic acid diester (compound (8)),
then, after hydrolysis of the ester, ( a) 5-position hydroxyl group and to the 2-position from one carboxylic acid that remain to form a lactone of the dicarboxylic acid is decarboxylated, or, (b) solid in the decarboxylation to 2-position monocarboxylic acids A sex-mixture, by isomerizing lactonization to give 5-acyl-2-oxa-5-azabicyclo [2.2.2] octan-3-one (Compound (7)) and,
　finally, deprotection and by hydrolyzing (2S, 5S) / (2R , 5R) it is preferable to produce the 5-hydroxy-piperidine-2-carboxylic acid. Thus the optically active substance can be efficiently synthesized.
[0088]
[2] The novel compounds
　The present invention relates to novel compounds shown below. These novel compounds are useful as a synthetic intermediate for drugs or the like for inhibiting β-lactamase.
　The novel compounds of this invention can be produced by the production method of the present invention. Further, hereby, since the structure was revealed using conventional organic chemistry techniques, it can also be synthesized.
[0089]
(A) compound represented by the following formula (2a).
Formula 43]

(wherein, X is Cl, Br or indicates I, R, 1 represents a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl, P '' is a tetrahydropyranyl group or shows ethoxyethyl group.)
　X is, Cl, Br or I,, X is preferably is Cl.
　R 1 is a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl group, R 1 is preferably an alkyl group substituted-1 carbon atoms and optionally 4. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, a tert- butyl group. Examples of the substituent of the alkyl group, a halogen atom, an alkoxy group or the like.
　P '' is a tetrahydropyranyl group or, an ethoxyethyl group.
　Among the compounds (2a), particularly preferred are compounds represented by the following formula.
[Of 44]

[0090]
(B) a compound represented by the following formula (3a).
Formula 45]

(wherein, X represents a Cl, Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group. )
　P 'is a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, tert- butyl group or tert- butyldimethylsilyl group.
　Incidentally, in the compound (3a), X has the same meaning as X in the compound (2a).
[0091]
　Among the compounds (3a), particularly preferred are compounds represented by the following formula.
[Of 46]

[0092]
(C) a compound represented by the following formula (4a).
Formula 47]

(wherein, X is Cl, showed a Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, R 2 represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, an aryl group, 1 to 10 carbon atoms of 6 to 12 carbon atoms.)
[0093]
　R 2 is an aralkyl group the alkyl group or a C 7-20, aryl group, 1 to 10 carbon atoms of 6 to 12 carbon atoms, R 2 is preferably an aryl group having 6 to 7 carbon atoms, carbon atoms alkyl group of 1 to 3, or an aralkyl group having 7 to 11 carbon atoms, more preferably a methyl group. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group, a biphenyl group and the like. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. Examples of the aralkyl group include benzyl group, phenethyl group and the like.
　Incidentally, in the compound (4a), X is as X in the compound (2a), P 'is P in the compound (3a)' is synonymous with.
[0094]
　Among the compounds (4a), particularly preferred are compounds represented by the following formula.
[Of 48]

[0095]
(D) a compound represented by the following formula (6a).
Formula 49]

(wherein, X is Cl, showed a Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or C 7 ~ 20 shows the aralkyl group.)
[0096]
　R 3 is an alkyl group having 1 to 4 carbon atoms, R 3 is preferably an alkyl group having 1 to 2 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, a tert- butyl group.
　A is an alkyl group, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, from 1 to 10 carbon atoms, A is preferably a carbon number alkyl group of 1 to 3, an aryl group having 6 to 10 carbon atoms, an alkyl group or an aralkyloxy group having 7 to 11 carbon atoms, having 1 to 4 carbon atoms, more preferably methyl group and phenyl group. Examples of the aryl group include a phenyl group, a naphthyl group, a biphenyl group and the like. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. The alkyl group, a methyloxy group, ethyloxy group, n- propyl group, an isopropyl group, n- butyloxy, iso-butyloxy group, a tert- butyloxy and the like. The aralkyloxy group, a benzyloxy group, a phenethyloxy group.
　Incidentally, in the compound (6a), X is as X in the compound (2a), P 'is P in the compound (3a)' is synonymous with.
[0097]
　Among the compounds (6a), particularly preferred are compounds represented by the following formula.
Formula 50]

(wherein, Ac represents an acetyl group, Bz represents a benzoyl group.)
[0098]
(E) a compound represented by the following formula (7).
Formula 51]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group, an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms, carbon alkyloxy group having 1 to 4 or an aralkyl group having 7 to 20 carbon atoms.)
[0099]
　P is a protecting group, P is preferably a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, tert- butyl group or tert- butyldimethylsilyl group.
　Incidentally, in the compound (7), R 3 and A, R in the compound (6a) 3 is synonymous with and A.
[0100]
　Among the compounds (7), particularly preferred are compounds represented by the following formula.
Formula 52]

(wherein, Ac represents an acetyl group, Bz represents a benzoyl group.)
[0101]
(F) a compound represented by the following formula (8) or a salt thereof dicarboxylic acid.
Formula 53]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy having 1 to 4 carbon atoms group or. an aralkyl group having 7 to 20 carbon atoms),
　Note that in the compound (8), R 3 and a, R in the compound (6a) 3 is synonymous with and a.
[0102]
　Among the compound (8), particularly preferred are compounds represented by the following formula.
Formula 54]

(wherein, Ac represents an acetyl group, Bz is. Shows a benzoyl group)
　Of these, compounds (8a) is capable of isolation purification by crystallization because they are crystalline, synthetic intermediate the preferred as the body.
[0103]
(G) a compound represented by the following formula (9a).
Formula 55]

(In the formulas, A 'represents. An alkyl group or an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms)
　A' is an alkyl group or a C 6-12 having 1 to 10 carbon atoms an aryl group, a 'is preferably an alkyl group or an aryl group having 6 carbon atoms having 1 to 3 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. The aryl group is a phenyl group, a naphthyl group and the like.
[0104]
　Among the compounds (9a), particularly preferred are compounds represented by the following formula.
Formula 56]

(wherein, Ac represents an acetyl group, Bz represents a benzoyl group.)
[0105]
(H) or a salt thereof represented by the following formula (11a) or (11b).
Formula 57]

(wherein, A 'represents an alkyl group or an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms.)
[0106]
Formula 58]

(wherein, A 'represents an alkyl group or an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms.)
　In addition, in the compound (11a) and (11b), A', the compound the same meaning as a 'in (9a).
[0107]
　Among the compounds (11a) or (11b), particularly preferred are compounds represented by the following formula.
[Of 59]

Example
[0108]
　Hereinafter, further detailed explanation of the present invention embodiment, the present invention is not intended to be limited by these.
[0109]
[Example 1] (3S)-4-chloro-3- (tetrahydropyran-2-yloxy) - production of butan-1-ol (X = Cl, compounds of P = tetrahydropyranyl group in the formula (3))
　in 50mL reactor, (3S)-4-chloro-3-hydroxybutanoic acid ethyl ester (X = Cl, R in formula (1) 1 a compound of = ethyl group) 1.50 g (9 mmol), dihydropyran 1.51g (18 mmol), 29 [mu] L methanesulfonic acid (0.45 mmol), was charged toluene 15 mL, at room temperature, after stirring for 0.5 h, the reaction was quenched by the addition of triethylamine 250 [mu] L (1.8 mmol). After the mixture was washed with water, dried, concentrated to an oily crude (3S) and 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl in the butanoic acid ethyl ester (Formula (2), P = tetrahydro pyranyl group, R 1 to give compound) 3.14 g of = ethyl.
[0110]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２３（３Ｈ，ｍ），１．４４－１．８５（６Ｈ，ｍ），２．５８－２．８０（２Ｈ，ｍ），３．４７－３．９５（４Ｈ，ｍ），４．１７（２Ｈ，ｍ），４．２０－４．３７（１Ｈ，ｍ），４．７３－４．８０（１Ｈ，ｍ）．
[0111]
　Then, the resultant crude (3S)-4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl, P = tetrahydropyranyl group in butanoic acid ethyl ester (Formula (2), R 1 = compounds of ethyl group) in dry tetrahydrofuran (hereinafter "THF") was dissolved in 15 mL, 2 hours after stirring at 5 ° C. was added lithium aluminum hydride 0.34 g (9 mmol), ethyl acetate 1mL, then water is added 1mL decomposition to terminate the reaction the excess reducing agent is. The mixture was filtered through Celite, and purified by silica gel column chromatography, (3S)-4-chloro-3- (tetrahydropyran-2-yloxy) oil - X in butan-1-ol (formula (3) = give Cl, P = compound of tetrahydropyranyl group) 1.43 g (73% 2 steps overall yield).
[0112]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．４５－２．０８（８Ｈ，ｍ），３．３５－４．１３（８Ｈ，ｍ），４．６８－４．７６（１Ｈ，ｍ）．
[0113]
[Example 2] (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl in butyl ester (formula (4), P = tetrahydropyranyl, R 2 = methyl preparation of the compounds of the group)
　in 50mL reactor, obtained in example 1 - in (3S)-4-chloro-3- (tetrahydropyran-2-yloxy) butan-1-ol (formula (3) X = Cl, P = compound of tetrahydropyranyl group) 1.43g (6.8mmol), triethylamine 1.05 mL (7.5 mmol), of toluene 14 mL, at 5 ° C., methanesulfonyl chloride 0.56 mL (7.18 mmol) and the mixture was stirred for 1 hour at 5 ° C.. After the reaction was washed with water, dried, and concentrated to an oily crude (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl in butyl ester (formula (4), P = tetrahydropyranyl group, R 2 to give the = compound of methyl group) 2.13 g (97% yield).
[0114]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．４８－１．６０（４Ｈ，ｍ），１．７２－１．８５（２Ｈ，ｍ），１．９７－２．２０（２Ｈ，ｍ），３．０２（３Ｈ，ｓ），３．５０－４．１２（５Ｈ，ｍ），４．３０－４．４５（２Ｈ，ｍ），４．６８（１Ｈ，ｍ）．
[0115]
[Example 3] (3S) Methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - butyl ester (X = Cl in the formula (4), P = tetrahydropyranyl, R 2 = methyl compounds) of manufacturing
　a 1L reactor, (3S)-4-chloro-3-hydroxybutanoic acid ethyl ester (formula (1) X = Cl, R in 1 compound of = ethyl) 30g (180.18mmol), dihydropyran 18.16g (216.22mmol), pyridinium -p- toluenesulfonate 0.44 g (1.80 mmol), was charged toluene 240 mL, at 45 ° C., and stirred for 10 h, (3S) -4- chloro - 3- (tetrahydropyran-2-yloxy) - X = Cl in the butanoic acid ethyl ester (formula (2), P = tetrahydropyranyl Group, R 1 to obtain a toluene solution of = compound ethyl group).
　Then the reaction mixture was added sodium bis-methoxyethoxy aluminum hydride (70% toluene solution) 70 mL of (252.25Mmol) at 5 ° C. ~ 10 ° C., and stirred for 7 hours at 5 ℃ ~ 10 ℃. Water 22.7mL to the reaction solution, magnesium sulfate 31.59G, water 22.7mL sequentially added at 5 ° C. ~ 10 ° C., and stirred for 1 hour at 5 ° C. ~ 10 ° C., allowed to stand overnight at 5 ° C. after it was filtered solids. Then wash the filtrate with brine, dried and concentrated, (3S)-4-chloro-3- (tetrahydropyran-2-yloxy) - X in butan-1-ol (formula (3) = Cl, to give a toluene solution 247.39g of P = compound of tetrahydropyranyl group). (91% 2 steps overall yield)
　Then the solution ((3S)-4-chloro-3- (tetrahydropyran-2-yloxy) - butan-1-ol (X = Cl in the formula (3), the compound of P = tetrahydropyranyl group) 32.59G including (156.33mmol)) to 237.3G, triethylamine 17.37g and (171.96mmol) was added methanesulfonyl chloride 18.79g of (164.15mmol) was added at 5 ℃ ~ 12 ℃, 5 ℃ ~ 10 ℃ at the mixture was stirred for 1 hour. After the reaction was washed with water, dried, and concentrated to give crude (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl in butyl ester (formula (4), P = tetrahydropyranyl group, R 2 to give compound of = methyl group) 51.72G the (pure content 43.92G) (3 step overall yield 89%).
[0116]
[Example 4-1] (3S) - methanesulfonic acid 4-chloro-3-methoxymethyloxy - butyl ester (formula (4) X = Cl, P = methoxymethyl group, R 2 the compounds of = methyl group) manufacturing
　in 50mL reactor, (3S)-4-chloro-3-hydroxybutanoic acid ethyl ester (X = Cl, R in formula (1) 1 a compound of = ethyl group) 1.50 g (9.01 mmol), diisopropyl ethylamine 2.02mL (11.71mmol), of toluene 15 mL, at room temperature, methoxymethyl chloride 1.18g of (11.71mmol) was added and stirred at room temperature. After completion of the reaction, washing the reaction solution, dried, and concentrated to give crude (3S)-4-chloro-3-methoxymethyloxy - butanoic acid ethyl ester (Compound (2) (X = Cl, P = methoxymethyl , R 1 to give compound) 2.54 g of = ethyl.
[0117]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２６（３Ｈ，ｔ，Ｊ＝７．６Ｈｚ），２．６０－２．７５（２Ｈ，ｍ），３．３８（３Ｈ，ｓ），３．６７（２Ｈ，ｄ，Ｊ＝５．２Ｈｚ），４．１５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），４．２３（１Ｈ，ｍ），４．７１（２Ｈ，ｄｄ，Ｊ＝６．８，２２Ｈｚ）．
[0118]
　Then this crude (3S)-4-chloro-3-methoxymethyloxy - (X = Cl in the formula (2), P = methoxymethyl radical, R butanoic acid ethyl ester 1 compound of = ethyl group) in 2.54g was dissolved in toluene 14 mL, was added sodium bis-methoxyethoxy aluminum hydride (70% toluene solution) 2.75 mL of (9.91 mmol) at 5 ℃ ~ 10 ℃, and stirred 1 hour at 5 ℃ ~ 10 ℃. Water 1.8mL To this reaction solution, sodium sulfate 0.56 g, successively added at 5 ° C. ~ 10 ° C. The 0.68g of magnesium sulfate, stirred for 1 hour at 5 ° C. ~ 10 ° C., and filtered solids. Then wash the filtrate with brine, dried and concentrated, (3S)-4-chloro-3-methoxymethyloxy - butan-1-X = Cl in ol (formula (3), P = methoxy to obtain a toluene solution of methyl compound of group).
[0119]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．７８－１．９５（２Ｈ，ｍ），３．４３（３Ｈ，ｓ），３．５８－３．６７（２Ｈ，ｍ），３．９８（１Ｈ，ｍ），４．７４（２Ｈ，ｄｄ，Ｊ＝７．２，２４Ｈｚ）．
[0120]
　Then to this solution was added triethylamine 1.57mL the (11.29mmol) was added methanesulfonyl chloride 0.83mL the (10.72mmol) was added at 5 ° C. ~ 10 ° C., and stirred for 1 hour at 5 ℃ ~ 10 ℃. The reaction was washed with water, dried, and concentrated, (3S) - methanesulfonic acid 4-chloro-3-methoxymethyloxy - butyl ester (X = Cl in the formula (4), P = methoxymethyl group, R 2 =-methyl compound of group) 1.39 g (3 step overall yield 62%).
[0121]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．９８－２．１５（２Ｈ，ｍ），３．０１（３Ｈ，ｓ），３．４０（３Ｈ，ｓ），３．５９－３．６８（２Ｈ，ｍ），３．９２（１Ｈ，ｍ），４．３６（１Ｈ，ｍ），４．７１（２Ｈ，ｄｄ，Ｊ＝８，１３．６Ｈｚ）．　
[0122]
[Example 4-2] (3S) Methanesulfonic acid 4-chloro-3- (1-ethoxyethyl-oxy) - butyl ester (X = Cl in the formula (4), P = ethoxyethyl group, R 2 = methyl compounds) of manufacturing
　a 1L reactor, (3S)-4-chloro-3-hydroxybutanoic acid ethyl ester (formula (1) in X = Cl, R 1 compound of = ethyl group) 5.02 g (30.13Mmol ), ethyl vinyl ether 2.39g (33.14mmol), pyridinium -p- toluenesulfonate 0.08 g (0.30 mmol) of toluene 25 mL, at 40 ° C., and stirred for 3 h, (3S)-4- chloro-3- (1-ethoxyethyloxy) - butanoic acid ethyl ester (formula (X = Cl, P = ethoxyethyl radical, R in 2) 1 compound of = ethyl group) To obtain a toluene solution.
[0123]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１８－１．３６（９Ｈ，ｍ），２．５８－２．７７（２Ｈ，ｍ），３．２３－３．７５（４Ｈ，ｍ），４．１０－４．３５（３Ｈ，ｍ），４．８２（１Ｈ，ｍ）．
[0124]
　Then the reaction mixture was added sodium bis-methoxyethoxy aluminum hydride (70% toluene solution) 70 mL of (252.25Mmol) at 5 ° C. ~ 10 ° C., and stirred for 1 hour at 5 ℃ ~ 10 ℃. Water 3.25mL to the reaction solution, magnesium sulfate 9.53 g, water 3.25mL sequentially added at 5 ° C. ~ 10 ° C., and stirred for 4 hours at 5 ° C. ~ 10 ° C., and filtered solids. Then wash the filtrate with brine, dried and concentrated, (3S)-4-chloro-3- (1-ethoxyethyloxy) - X = Cl in butan-1-ol (formula (3) , to obtain a toluene solution 5.81 g (pure content 5.44 g) of the compound of P = ethoxyethyl group). (92% 2 steps overall yield)
[0125]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１７－１．２９（３Ｈ，ｍ），１．３０－１．３７（３Ｈ，ｍ），１．６１－１．７２（０．６Ｈ，ｍ），１．８０－２．００（２Ｈ，ｍ），３．０２（０．４Ｈ，ｍ），３．５０－３．９０（６Ｈ，ｍ），３．９２－４．０８（１Ｈ，ｍ），４．７９－４．８６（１Ｈ，ｍ）．
[0126]
　Then the solution ((3S)-4-chloro-3- (1-ethoxyethyloxy) - butan-1-ol (X = Cl in the formula (3), the compound of P = an ethoxyethyl group) 4.16 g (21 .17Mmol) to the containing) 4.44 g, toluene 20 mL, triethylamine 2.35g and (23.29mmol) was added methanesulfonyl chloride 2.55g of (22.23mmol) was added at 5 ℃ ~ 15 ℃, 5 ℃ ~ 10 ℃ in the mixture was stirred for 0.5 hours. The reaction was washed with water, dried, and concentrated to give crude (3S) - methanesulfonic acid 4-chloro-3- (1-ethoxyethyloxy) - X = Cl, P = ethoxy in butyl ester (formula (4) ethyl group, R 2 to give a toluene solution 10.83g of = compound of methyl group) (pure content 5.33 g) (92% yield).
[0127]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２０（３Ｈ，ｔ，Ｊ＝５．９Ｈｚ），１．３２（３Ｈ，ｄ，Ｊ＝７．４Ｈｚ），１．９２－２．１９（２Ｈ，ｍ），２．９９（３Ｈ，ｓ），３．４３－３．７１（４Ｈ，ｍ），３．８８（０．５Ｈ，ｍ），４．０２（０．５Ｈ，ｍ），４．２６－４．４０（２Ｈ，ｍ），４．７８（１Ｈ，ｍ）．
[0128]
[Example 4-3] (3S) - methanesulfonic acid 4-chloro -3-tert-butyldimethylsilyloxy - X = Cl in butyl ester (formula (4), P = tert- butyldimethylsilyl group, R 2 = compound of methyl group) of production
　in 50mL reactor, X = Cl, R in (3S)-4-chloro-3-hydroxybutanoic acid ethyl ester (formula (1) 1 a compound of = ethyl group) 5.00 g ( 30.01mmol), imidazole 3.06g (45.02mmol), were charged dichloromethane 25 mL, under cooling with ice, tert- butyldimethylsilyl chloride 5.88g (39.01mmol) methoxymethyl chloride 1.18g (11.71mmol) the mixture was stirred at room temperature. After completion of the reaction, washing the reaction solution, a saturated layer washed with water, dried, and concentrated to give crude (3S)-4-chloro -3-tert-butyldimethylsilyloxy - butanoic acid ethyl ester (Compound (2) (X = Cl, P = tert-butyldimethylsilyl group, R 1 to give the compounds of the = ethyl group) 8.01 g. (95% yield)
[0129]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ０．０５（３Ｈ，ｓ），０．１１（３Ｈ，ｓ），０．８８（９Ｈ，ｓ），１．２６（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），２．４９－２．７３（２Ｈ，ｍ），３．５２（２Ｈ，ｓ），４．１４（２Ｈ，ｍ），４．３１（１Ｈ，ｍ）．
[0130]
　Then this crude (3S)-4-chloro -3-tert-butyldimethylsilyloxy - X = Cl in the butanoic acid ethyl ester (Formula (2), P = tert-butyldimethylsilyl group, R 1 a = ethyl compound) a 8.01g were dissolved in toluene 25 mL, was added sodium bis-methoxyethoxy aluminum hydride (70% toluene solution) 9.5 mL of (34.24Mmol) at 5 ℃ ~ 15 ℃, 2 at 5 ℃ ~ 10 ℃. 5 hours and the mixture was stirred. Acetate 2.05mL to the reaction solution, water 5.55mL sequentially added at 5 ° C. ~ 10 ° C., and stirred for 0.5 hours at room temperature, and filtered solids. Then wash the filtrate with brine, dried and concentrated, (3S)-4-chloro -3-tert-butyldimethylsilyloxy - X = Cl in butan-1-ol (formula (3), P = tert compound of butyldimethylsilyl group) to give a toluene solution 4.66g of (pure content 4.28 g). (63% yield)
[0131]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ０．１４（６Ｈ，ｓ），０．９２（９Ｈ，ｓ），１．８０－２．０１（３Ｈ，ｍ），３．５２（２Ｈ，ｍ），３．８１（２Ｈ，ｍ），４．１０（１Ｈ，ｍ）．
[0132]
　Then to this solution, toluene 23 mL, triethylamine 2.17mL the (21.46mmol) was added methanesulfonyl chloride 2.35g of (20.49mmol) was added at 5 ℃ ~ 10 ℃, 1 hour stirring at 5 ° C. ~ 10 ° C. did. The reaction washed with water, dried, and concentrated, (3S) - methanesulfonic acid 4-chloro -3-tert-butyldimethylsilyloxy - X = Cl in butyl ester (formula (4), P = tert-butyl butyldimethylsilyl group, R 2 to give a toluene solution 6.09g of = compound of methyl group) (pure content 5.46 g) (96% yield).
[0133]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ０．１０（６Ｈ，ｓ），０．８９（９Ｈ，ｓ），１．９０－１．９９（１Ｈ，ｍ），２．０６－２．１７（１Ｈ，ｍ），３．０２（３Ｈ，ｓ），３．４７（２Ｈ，ｍ），４．０３（１Ｈ，ｍ），４．２８－４．４０（２Ｈ，ｍ）．
[0134]
[Example 4-4] (3S) - methanesulfonic acid 4-chloro -3-tert butyloxy - in butyl ester (formula (4) X = Cl, P = tert- butyl group, R 2 the compounds of = methyl group preparation of)
　the 100mL reactor, (3S)-4-chloro-3-hydroxybutanoic acid ethyl ester (formula (1) X = Cl, R in 1 compound of = ethyl group) 7.51g (45.11mmol), g of n- hexane 18 mL, under ice-cooling, concentrated sulfuric acid 0.47 g (4.51 mmol), isobutylene 6.17g of (110.07mmol) was added and stirred for 18 hours at 30-35 ° C.. Saturated layer washed with water, dried and the reaction mixture was then concentrated and purified by silica gel chromatography, (3S)-4-chloro -3-tert butyloxy - butanoic acid ethyl ester (Compound (2) (X = Cl, P = tert-butyl group, R 1 to give compound) 4.92 g of = ethyl group. (49% yield)
[0135]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２０（９Ｈ，ｓ），１．２８（３Ｈ，ｔ，Ｊ＝８Ｈｚ），２．５１－２．７６（２Ｈ，ｍ），３．４８－３．６０（２Ｈ，ｍ），４．１５（３Ｈ，ｍ）．
[0136]
　Then this crude (3S)-4-chloro -3-tert butyloxy - (X = Cl in the formula (2), P = tert-butyl radical, R butanoic acid ethyl ester 1 compound of = ethyl group) 4.92 g the (22.11Mmol) was dissolved in toluene 25 mL, was added sodium bis-methoxyethoxy aluminum hydride (70% toluene solution) 8mL (28.74mmol) at 5 ℃ ~ 15 ℃, and stirred for 2 hours at 5 ° C. ~ 10 ° C. . Ethanol 0.77mL To this reaction solution, 3.41 g of citric acid, water 20mL sequentially added at 5 ℃ ~ 10 ℃, 5 ℃ ~ stirred 10 ° C. at 0.5 hours, separated and the organic phase saturated saline washed with water, dried, concentrated, and purified by silica gel chromatography, (3S)-4-chloro -3-tert-butyloxy - butan-1-X = Cl in ol (formula (3), P = tert - to give the compound) 3.29 g of butyl. (82% yield)
[0137]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２５（９Ｈ，ｓ），１．８０－１．８８（１Ｈ，ｍ），１．９４－２．０３（１Ｈ，ｍ），２．５８（１Ｈ，ｂｒｍ），３．４４－３．５６（２Ｈ，ｍ），３．７５（１Ｈ，ｍ），３．８３（１Ｈ，ｍ），３．９６（１Ｈ，ｍ）．
[0138]
　Then the resulting (3S)-4-chloro -3-tert-butyloxy - butan-1-ol (X = Cl, compounds of P = tert-butyl group in the formula (3)) 2.25g (12.47mmol) in toluene 23 mL, triethylamine 2.24mL the (16.21mmol) was added methanesulfonyl chloride 1.01mL the (13.09 mmol) was added at 5 ° C. ~ 10 ° C., and stirred for 2 hours at 5 ℃ ~ 10 ℃. The reaction was washed with water, dried, and concentrated, (3S) - methanesulfonic acid 4-chloro -3-tert butyloxy - X = Cl in butyl ester (formula (4), P = tert-butyl radical, R 2 = obtain a toluene solution 4.23g of methyl compounds of group) (pure content 3.19 g) (99% yield).
[0139]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２３（９Ｈ，ｓ），１．８８－１．９６（１Ｈ，ｍ），２．１２－２．２１（１Ｈ，ｍ），３．０２（３Ｈ，ｓ），３．３９－３．５７（２Ｈ，ｍ），３．８６（１Ｈ，ｍ），４．３５（２Ｈ，ｍ）．
[0140]
[Example 4-5] (3S) -p- toluenesulfonic acid 4-chloro-3-methoxymethyloxy - butyl ester (X = Cl in the formula (4), P = methoxymethyl group, R 2 = p-toluyl preparation of the compounds of the group)
　is obtained analogously to example 4 (3S)-4-chloro-3-methoxymethyloxy - butan-1-ol (formula (3) X = Cl in, P = methoxymethyl the compound) 2.22 g (pure content 2.00 g 11.86 mmol), toluene 9 mL, pyridine 1.00g and (13.10mmol) was added, at room temperature p- toluenesulfonyl chloride 2.40 g (12.50 mmol), 4-dimethylaminopyridine 29mg of (0.24 mmol) was added and stirred for 16 h at 40 ° C.. The reaction was washed with water, dried, concentrated and purified by silica gel chromatography, (3S)-p-toluenesulfonic acid 4-chloro-3-methoxymethyloxy - X in butyl ester (formula (4) = Cl, P = methoxymethyl group, R 2 to give = p-compound of toluyl group) 1.75 g (46% yield).
[0141]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．８８－２．０３（２Ｈ，ｍ），２．４６（３Ｈ，ｓ），３．３５（３Ｈ，ｓ），３．５３－３．６６（２Ｈ，ｍ），３．８７（１Ｈ，ｍ），４．０９－４．２０（４Ｈ，ｍ），４．６１（２Ｈ，ｍ），７．３５（２Ｈ，ｄ、Ｊ＝８．４Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ）．
[0142]
[Example 4-6] (3S)-p-toluenesulfonic acid 4-chloro-3- (1-ethoxyethyl-oxy) - butyl ester (X = Cl in the formula (4), P = ethoxyethyl group, R 2 = production of p- compound of toluyl group)
　was obtained in the same manner as in example 4-2 (3S)-4-chloro-3- (1-ethoxyethyloxy) - butan-1-ol (formula (3) X = Cl, the P = compound of ethoxyethyl group) 1.31 g (pure content 6.23 mmol), toluene 6.1 mL, triethylamine 0.69g (6.85mmol), p- toluenesulfonyl chloride 1.19 g (6 in .23mmol), 4- dimethylaminopyridine 0.76g of (6.23 mmol) was added, followed by stirring for 33 hours at 40 ° C.. The reaction was washed with water, dried, concentrated and purified by silica gel chromatography, (3S)-p-toluenesulfonic acid 4-chloro-3- (1-ethoxyethyl-oxy) - butyl ester (formula (4 ) in X = Cl, P = ethoxyethyl group, R 2 to give the = p-compound of toluyl group) 0.95 g (pure content 0.44 g) (20% yield).
[0143]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１２－１．３８（６Ｈ，ｍ），１．８０－２．１０（２Ｈ，ｍ），２．４３（３Ｈ，ｓ），３．４０－３．８５（４Ｈ，ｍ），３．９３－４．２３（３Ｈ，ｍ），４．８０（１Ｈ，ｍ），７．３６（２Ｈ，ｍ），７．８０（２Ｈ，ｍ）．
[0144]
[Example 5] (3S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran-2-yloxy) - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = tetrahydropyranyl group, R 3 = ethyl, a = compound of methyl group) of production
　in 20mL reactor, acetaminophen malonic acid diethyl ester (formula (5) R in the 3 = ethyl group, compounds where a = methyl group) 0.10 g (0.46 mmol), was charged toluene 1 mL, 1.5 hours stirring at 25 ° C. was added 20% sodium ethoxide 180 [mu] L (0.46 mmol). Thereto, the crude obtained in Example 2 (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl, P = tetrahydropyranyl in butyl ester (formula (4) group, R 2 = compound of methyl group) 0.15 g (pure content 0.13 g, toluene 0.5mL solution and potassium iodide 0.08g of 0.46mmol) (0.46mmol), in ethanol 1 mL 25 ° C. the mixture was heated under reflux overnight. Ethyl acetate was added to the reaction solution, washed with water, dried, concentrated and purified by silica gel column chromatography, (3S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran -2 - yloxy) - butyl] X = Cl in malonic acid diethyl ester (formula (6), P = tetrahydropyranyl group, R 3 = ethyl, compound of a = methyl group) 0.12 g (63% yield) Obtained.
[0145]
[Example 6] (3S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran-2-yloxy) - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = tetrahydropyranyl group, R 3 = ethyl, a = compound of methyl group) of production
　in 50mL reactor, acetaminophen malonic acid diethyl ester (formula (5) R in the 3 = ethyl group, compounds where a = methyl group) 0.68g (3.15mmol), N, N- dimethylformamide were charged 3.4 mL, and stirred 1 hour at added 30 ° C. sodium -tert- butoxide 0.29 g (3.00 mmol). Thereto, the crude obtained in Example 3 (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl, P = tetrahydropyranyl in butyl ester (formula (4) group, R 2 = compound of methyl group) 1.01 g (pure content 0.86 g, 3.00 mmol) in toluene 4mL solution and potassium iodide 0.10g of (0.6 mmol) was added at 30 ° C. of the 60 ° C. and the mixture was stirred for 7.5 hours Te. The reaction was washed with water, dried, and concentrated to give crude (3S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran-2-yloxy) - butyl] malonic acid diethyl ester (Formula ( X = Cl in the 6), P = tetrahydropyranyl group, R 3 to give = ethyl, a = compound of methyl group) 1.22 g (pure content 1.01 g) (83% yield).
[0146]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２５（６Ｈ，ｍ），１．１５－１．８３（８Ｈ，ｍ），２．０３（３Ｈ，ｓ），２．３０－２．５０（２Ｈ，ｍ），３．４７－３．９５（５Ｈ，ｍ），４．２０－４．３０（４Ｈ，ｍ），４．６１　ａｎｄ　４．７２（１Ｈ，ｍ），６．８０（１Ｈ，ｂｒｓ）．
[0147]
[Example 7-1] (3S) -2-acetylamino-2- (4-chloro-3-methoxymethyloxy - butyl) X = Cl, P = methoxymethyl group in malonic acid diethyl ester (Formula (6) , R 3 = ethyl, a = compound of methyl group) of production
　in 30mL reactor, R in acetaminophen malonic acid diethyl ester (formula (5) 3 = ethyl, compound of a = methyl group) 0.49 g ( 2.27 mmol), were charged dimethyl sulfoxide 2.5 mL, and stirred 2 hours at added 30 ° C. sodium -tert- butoxide 0.23 g (2.38 mmol). Thereto, the crude obtained in Example 4 (3S) - methanesulfonic acid 4-chloro-3-methoxymethyloxy - butyl ester (X = Cl in the formula (4), P = methoxymethyl group, R 2 = methyl toluene 2.5mL solution and potassium iodide 0.08g of the compound of group) 0.56 g (2.27 mmol) of (0.45 mmol) at 30 ° C., and stirred for 5 hours at 80 ° C.. The reaction was taken out 200 [mu] L, washed by adding ethyl acetate, dried, and concentrated (3S) -2-acetylamino-2- (4-chloro-3-methoxymethyloxy - butyl) malonic acid diethyl ester (Formula in (6) X = Cl, P = methoxymethyl group, R 3 to give = ethyl group, compounds where a = methyl group) 25 mg (94% yield).
[0148]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２３（６Ｈ，ｔ，Ｊ＝５．２Ｈｚ），１．３３－１．５０（２Ｈ，ｍ），２．０１（３Ｈ，ｓ），２．３０－２．４６（２Ｈ，ｍ），３．３６（３Ｈ，ｓ），３．５５（２Ｈ，ｄ，Ｊ＝５．２Ｈｚ），３．６７（１Ｈ，ｍ），４．２１（４Ｈ，ｑ，Ｊ＝７．３Ｈｚ），４．６４（２Ｈ，ｄｄ，Ｊ＝７．２，１８Ｈｚ）、６．７７（１Ｈ，ｂｒｓ）．
[0149]
[Example 7-2] (3S) -2-acetylamino-2- (4-chloro-3- (1-ethoxyethyl-oxy) - butyl) X = Cl in malonic acid diethyl ester (Formula (6), P = an ethoxyethyl group, R 3 = ethyl, a = compound of methyl group) of production
　in 50mL reactor, R in acetaminophen malonic acid diethyl ester (formula (5) 3 = ethyl, compound of a = methyl group) 4.95g (22.82mmol), N, N- dimethylformamide were charged 22 mL, and stirred for 1.5 hours added 40 ° C. sodium -tert- butoxide 2.15g (22.40mmol). Thereto, the crude obtained in Example 4-2 (3S) - methanesulfonic acid 4-chloro-3- (1-ethoxyethyloxy) - X = Cl, P = ethoxyethyl in butyl ester (formula (4) group, R 2 = toluene solution 10.83g methyl compounds of group) (pure content 5.33g 19.41mmol), toluene 4 mL, and potassium iodide 0.69g of (4.16 mmol) was added at 40 ° C., 80 ℃ in the mixture was stirred for 2 hours. Of toluene was added to the reaction solution, washed with water, dried, and concentrated (3S) -2-acetylamino-2- (4-chloro-3- (1-ethoxyethyl-oxy) - butyl) malonic acid diethyl ester ( X = Cl in the formula (6), P = ethoxyethyl group, R 3 to give = ethyl, a = compound of methyl group) 7.64 g of (pure content 7.14 g 93% yield).
[0150]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１５－１．３２（１２Ｈ，ｍ），１．３０－１．６０（２Ｈ，ｍ），２．０３（３Ｈ，ｓ），２．３０－２．５２（２Ｈ，ｍ），３．４７－３．８３（５Ｈ，ｍ），４．２３（４Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．７３　ａｎｄ　４．８１（１Ｈ，ｍ）、６．７８（１Ｈ，ｂｒｓ）．
[0151]
[Example 7-3] (3S) -2-acetylamino-2- (4-chloro -3-tert-butyldimethylsilyloxy - butyl) X = Cl in malonic acid diethyl ester (Formula (6), P = tert- butyldimethylsilyl group, R 3 = ethyl, a = compound of methyl group) of production
　in 50mL reactor, in acetaminophen malonic acid diethyl ester (formula (5) R 3 = ethyl, a = methyl group compound) 1.15g (5.29mmol), N, N- dimethylformamide 6.8mL was charged, was added sodium -tert- butoxide 0.50 g (5.19 mmol) and stirred for 1 hour at 40 ° C.. Thereto, the crude obtained in Example 4-3 (3S) - methanesulfonic acid 4-chloro -3-tert-butyldimethylsilyloxy - X = Cl in butyl ester (formula (4), P = tert-butyl butyldimethylsilyl group, R 2 = toluene solution 1.70g of methyl compounds of group) (pure content 1.52 g 4.81 mmol), was added toluene 1 mL, and potassium iodide 0.16g of (0.96 mmol) at 40 ° C. , and the mixture was stirred for 4 hours at 80 ℃. Of toluene was added to the reaction solution, washed with water, dried, and concentrated to give (3S) -2-acetylamino-2- (4-chloro -3-tert-butyldimethylsilyloxy - butyl) malonic acid diethyl ester (Formula (6) in the X = Cl, P = tert-butyldimethylsilyl group, R 3 to give = ethyl, a = compound of methyl group) 2.10 g of (pure content 1.77 g 84% yield).
[0152]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ０．０９（６Ｈ，ｓ），０．９０（９Ｈ，ｓ），１．２４（６Ｈ，ｔ，Ｊ＝７．５Ｈｚ），１．２９－１．５５（２Ｈ，ｍ），２．０２（３Ｈ，ｓ），２．３０－２．５０（２Ｈ，ｍ），３．４２（２Ｈ，ｍ），３．８３（１Ｈ，ｍ），４．２５（４Ｈ，ｍ），６．７５（１Ｈ，ｂｒｓ）．
[0153]
[Example 7-4] (3S) -2-acetylamino-2- (4-chloro -3-tert butyloxy - butyl) X = Cl in malonic acid diethyl ester (Formula (6), P = tert- butyl group, R 3 = ethyl, a = compound of methyl group) of production
　in 50mL reactor, R in acetaminophen malonic acid diethyl ester (formula (5) 3 = ethyl, compound of a = methyl group) 0.87 g (4.00mmol), N, N- dimethylformamide were charged 4.3 mL, was added sodium -tert- butoxide 0.38 g (3.92 mmol) and stirred for 1 hour at 40 ° C.. This crude obtained in Example 4-4 (3S) - methanesulfonic acid 4-chloro -3-tert butyloxy - X = Cl in butyl ester (formula (4), P = tert-butyl radical, R 2 = toluene solution 1.25g of methyl compounds of group) (pure content 0.94 g 3.64 mmol), was added toluene 2 mL, and potassium iodide 0.12g of (0.73 mmol) at 40 ° C., at 80 ° C. and the mixture was stirred for 2 hours. Of toluene was added to the reaction solution, washed with water, dried, concentrated and purified by silica gel chromatography (3S) -2-acetylamino-2- (4-chloro -3-tert butyloxy - butyl) malonate (X = Cl in the formula (6), P = tert-butyl radical, R acid diethyl ester 3 = ethyl group, compounds where a = methyl group) to give 1.06g of (pure content 0.95 g 69% yield) .
[0154]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１９（９Ｈ，ｓ），１．２５（６Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．３０－１．３８（１Ｈ，ｍ），１．４９－１．５９（１Ｈ，ｍ），２．０３（３Ｈ，ｓ），２．３０－２．４７（２Ｈ，ｍ），３．３３－３．４９（２Ｈ，ｍ），３．６５（１Ｈ，ｍ），４．２７（４Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．７８（１Ｈ，ｂｒｓ）．
[0155]
[Example 7-5] (3S) -2-acetylamino-2- (4-chloro-3-methoxymethyloxy - butyl) X = Cl, P = methoxymethyl group in malonic acid diethyl ester (Formula (6) , R 3 = ethyl, a = compound of methyl group) of production
　in 50mL reactor, R in acetaminophen malonic acid diethyl ester (formula (5) 3 = ethyl, compound of a = methyl group) 1.04 g ( 4.81 mmol), N, N-dimethylformamide 5.4mL was charged, was added sodium -tert- butoxide 0.45 g (4.72 mmol) and stirred for 1 hour at 40 ° C.. Thereto, the resulting crude (3S)-p-toluenesulfonic acid 4-chloro-3-methoxymethyl-oxy in Example 4-5 - butyl ester (X = Cl in the formula (4), P = methoxymethyl group, R 2 = p-compound of toluyl group) 1.80 g of (pure content 1.41 g 4.37 mmol) in toluene 5.1mL solution and potassium iodide 0.15 g (0.87 mmol) was added at 40 ° C., 80 ° C. at the mixture was stirred for 2 hours. The reaction was washed with toluene, after drying, concentrated to (3S) -2-acetylamino-2 - In (4-chloro-3-methoxymethyl-oxy butyl) malonate diethyl ester (Formula (6) X = Cl, P = methoxymethyl group, R 3 to give = ethyl group, compounds where a = methyl group) 2.08 g of (pure content 1.45 g 90% yield).
[0156]
[Example 8-1] (3S) -2-benzoylamino-2- [4-chloro-3- (tetrahydropyran-2-yloxy) - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = tetrahydropyranyl group, R 3 = ethyl, a = compound of phenyl groups) of production
　in 30mL reactor, benzoylamino malonic acid diethyl ester (formula (5) in R 3 = ethyl, the a = phenyl compound) 0.38g (1.37mmol), N, were charged N- dimethylformamide 1.9 mL, and stirred at room temperature for 1 hour by addition of sodium -tert- butoxide 0.13 g (1.37 mmol). Thereto, the crude obtained in Example 3 (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl, P = tetrahydropyranyl in butyl ester (formula (4) group, R 2 = compound of methyl group) 0.51 g (pure content 0.39 g, 1.37 mmol) in toluene 1.9mL solution and potassium iodide 0.09g of (0.55 mmol) was added at room temperature, 80 ° C. at the mixture was stirred for 1 hour. Taking out a small amount of the reaction solution, washed with toluene, dried, and concentrated to give crude (3S) -2-benzoylamino-2- [4-chloro-3- (tetrahydropyran-2-yloxy) - butyl] malonic acid diethyl ester (formula (6) in the X = Cl, P = tetrahydropyranyl group, R 3 = ethyl, compound of a = phenyl group) was obtained 27 mg.
[0157]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２０（６Ｈ，ｍ），１．３２－１．８０（８Ｈ，ｍ），１．９７－２．２０（１Ｈ，ｍ），２．４０－２．５７（１Ｈ，ｍ），３．１６－３．９２（５Ｈ，ｍ），４．２０（４Ｈ，ｍ）、４．５２　ａｎｄ　４．６５（１Ｈ，ｍ），７．３０（３Ｈ，ｍ）、７．８０（２Ｈ，ｍ）．
[0158]
[Example 8-2] (3S) -2-benzoylamino-2- [4-chloro-3- (methoxymethyloxy - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = methoxymethyl group, R 3 = ethyl, a = compound of phenyl groups) of production
　in 50mL reactor, R in benzoylamino malonic acid diethyl ester (formula (5) 3 = ethyl, compound of a = phenyl group) 1.87 g (6.69 mmol), N, N-dimethylformamide were charged 5.7 mL, was added sodium -tert- butoxide 0.63 g (6.57 mmol) and stirred for 1 hour at 40 ° C.. thereto, in example 3 the resulting crude (3S) - methanesulfonic acid 4-chloro-3- (tetrahydropyran-2-yloxy) - X = Cl in butyl ester (formula (4), P = methoxymethyl group, R 2 addition compounds of = methyl group) 1.50 g of (toluene 6.08 mmol) 6 mL solution and potassium iodide 0.20 g (1.22 mmol) at 40 ° C., 2 at 80 ° C. time was stirred the reaction mixture washed with toluene, after drying, and concentrated to give crude (3S) -2-benzoylamino-2-. [4-chloro-3-methoxymethyloxy - butyl] malonic acid diethyl ester (X = Cl in the formula (6), P = methoxymethyl group, R 3 to give = ethyl, a = compound of phenyl group) 2.83 g of (pure content 2.20 g 84% yield).
[0159]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２６（６Ｈ，ｔ，Ｊ＝７．５Ｈｚ），１．２０－１．８５（８Ｈ，ｍ），２．４５－２．６５（２Ｈ，ｍ），３．４０－３．９２（５Ｈ，ｍ），４．２９（４Ｈ，ｍ）、４．６０　ａｎｄ　４．７１（１Ｈ，ｍ），７．４２－７．５５（４Ｈ，ｍ）、７．８２（２Ｈ，ｍ）．
[0160]
[Example 8-3] (3S) -2-benzoylamino-2- [4-chloro-3- (1-ethoxyethyl-oxy) - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = an ethoxyethyl group, R 3 = ethyl, a = compound of phenyl groups) of production
　in 30mL reactor, R in benzoylamino malonic acid diethyl ester (formula (5) 3 = ethyl, compound of a = phenyl group) 2.31g (8.27mmol), N, N- dimethylformamide were charged 8 mL, was added sodium -tert- butoxide 0.78 g (8.12 mmol) and stirred for 2 hours at 40 ° C.. Thereto, the crude obtained in accordance with Example 4-2 (3S) - methanesulfonic acid 4-chloro-3- (1-ethoxyethyloxy) - X = Cl in butyl ester (formula (4), P = ethoxyethyl group, R 2 = compound of methyl group) 2.06 g (pure content 1.99 g, 7.52 mmol) in toluene 4mL solution and potassium iodide 0.25g of (1.50 mmol) was added at 40 ° C. of 80 ℃ in the mixture was stirred for 4.5 hours. Of toluene was added to the reaction solution, washed with water, dried, concentrated and purified by silica gel chromatography, (3S) -2-benzoylamino-2- [4-chloro-3- (1-ethoxyethyloxy ) - butyl] X = Cl, P = an ethoxyethyl group in malonic acid diethyl ester (formula (6), R 3 = ethyl, to give the compound) 2.31 g of a = phenyl group. (67% yield)
[0161]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１３－１．３５（１２Ｈ，ｍ），１．４０－１．６３（２Ｈ，ｍ），２．４５－２．６５（２Ｈ，ｍ），３．４３－３．８３（５Ｈ，ｍ），４．３０（４Ｈ，ｍ）、４．７２　ａｎｄ　４．８０（１Ｈ，ｍ），７．４３－７．５８（４Ｈ，ｍ）、７．８３（２Ｈ，ｍ）．
[0162]
[Example 8-4] (3S) -2-benzoylamino-2- [4-chloro -3-tert-butyldimethylsilyloxy - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = tert- butyldimethylsilyl group, R 3 = ethyl, a = compound of phenyl groups) of production
　in 30mL reactor, benzoylamino malonic acid diethyl ester (formula (5) in R 3 = ethyl, the a = phenyl compound) 1.48g (5.29mmol), N, N- dimethylformamide 6.8mL was charged, was added sodium -tert- butoxide 0.50 g (5.19 mmol) and stirred for 1 hour at 40 ° C.. Thereto, the crude obtained in Example 4-3 (3S) - methanesulfonic acid 4-chloro -3-tert-butyldimethylsilyloxy - X = Cl in butyl ester (formula (4), P = tert-butyl butyldimethylsilyl group, R 2 = compound of methyl group) 1.70 g (pure content 1.52 g, 4.81 mmol) in toluene 1mL solution and potassium iodide 0.16g of (0.96 mmol) was added at 40 ° C. of 80 ℃ in the mixture was stirred for 4.5 hours. Of toluene was added to the reaction solution, washed with water, dried, and concentrated to give crude (3S) -2-benzoylamino-2- [4-chloro -3-tert-butyldimethylsilyloxy - butyl] malonic acid diethyl ester (X = Cl in the formula (6), P = tert-butyldimethylsilyl group, R 3 to give = ethyl group, compounds where a = phenyl group) and 2.68 g. (Purity: 1.95 g 81% yield)
[0163]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ０．１０（６Ｈ，ｓ），０．９０（９Ｈ，ｓ），１．３０（６Ｈ，ｔ，Ｊ＝８．３Ｈｚ），１．３５－１．６５（２Ｈ，ｍ），２．４８－２．６５（２Ｈ，ｍ），３．４３（２Ｈ，ｍ），３．８５（１Ｈ，ｍ），４．３３（４Ｈ，ｍ），７．４５－７．６０（４Ｈ，ｍ）、７．８４（２Ｈ，ｍ）．
[0164]
[Example 8-5] (3S) -2-benzoylamino-2- [4-chloro -3-tert butyloxy - butyl] X = Cl in malonic acid diethyl ester (Formula (6), P = tert- butyl group, R 3 = ethyl, a = compound of phenyl groups) of production
　in 50mL reactor, benzoylamino malonic acid diethyl ester (formula (5) in R 3 = ethyl, compound of a = phenyl group) 1.12 g (4.00mmol), N, N- dimethylformamide were charged 4.4 mL, was added sodium -tert- butoxide 0.38 g (3.92 mmol) and stirred for 1 hour at 40 ° C.. To this resulting crude (3S) methanesulfonic acid 4-chloro -3-tert-butyloxy in Example 4-4 - X = Cl in butyl ester (formula (4), P = tert-butyl group, R 2 = compound of methyl group) 1.25 g (pure content 0.94 g, 3.64 mmol) in toluene 2mL solution and potassium iodide 0.12g of (0.73 mmol) was added at 40 ° C., and stirred for 2 hours at 80 ° C. did. Of toluene was added to the reaction solution, washed with water, dried, concentrated and purified by silica gel chromatography, (3S) -2-benzoylamino-2- [4-chloro -3-tert butyloxy - butyl] (X = Cl in the formula (6), P = tert-butyl radical, R malonic acid diethyl ester 3 = ethyl group, compounds where a = phenyl group) was obtained 1.24 g. (Purity: 1.10 g 69% yield)
[0165]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１６（９Ｈ，ｓ），１．２５－１．２９（７Ｈ，ｍ），１．３１－１．４２（１Ｈ，ｍ），２．４８－２．５７（２Ｈ，ｍ），３．３４－３．４９（２Ｈ，ｍ），３．６５（１Ｈ，ｍ），４．２８（４Ｈ，ｑ，Ｊ＝６．８Ｈｚ），７．４４－７．５３（４Ｈ，ｍ）、７．８１（２Ｈ，ｍ）．
[0166]
Example 9] (5S)-1-acetyl-5- (tetrahydropyran-2-yloxy) - P In piperidine-2,2-dicarboxylic acid diethyl ester (Formula (7) = tetrahydropyranyl group, R 3 = ethyl, a = preparation of methyl compound of group)
　in 100mL reactor, the crude obtained in example 5 (3S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran-2-yloxy ) - butyl] X = Cl in malonic acid diethyl ester (formula (6), P = tetrahydropyranyl group, R 3 = ethyl, compound of a = methyl group) 5.08 g (pure content 4.35 g, 10. 68 mmol), dimethylformamide 40 mL, was charged with cesium carbonate 10.44g (32.04mmol), followed by stirring for 7 hours at 100 ° C.. Toluene was added to the reaction solution, washed with water, dried, and concentrated to give crude (5S)-1-acetyl-5- (tetrahydropyran-2-yloxy) - piperidine-2,2-dicarboxylic acid diethyl ester (Formula ( P = tetrahydropyranyl group in 7), R 3 = ethyl, to give the a = compound of methyl group) 4.18 g (94% yield).
[0167]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．１５－１．２５（６Ｈ，ｍ），１．３２－１．９５（８Ｈ，ｍ），１．９５－２．１０（１Ｈ，ｍ），２．１０（３Ｈ，ｓ），２．４０－２．５０（１Ｈ，ｍ），３．０２　ａｎｄ　３．２２（１Ｈ，ｍ），３．４３（１Ｈ，ｍ），３．５５－３．７０（１Ｈ，ｍ），３．７２－３．８８（２Ｈ，ｍ），４．１０－４．２５（４Ｈ，ｍ），４．６５（１Ｈ，ｍ）．
[0168]
[Example 10] (5S)-1-acetyl-5- (tetrahydropyran-2-yloxy) - P In piperidine-2,2-dicarboxylic acid diethyl ester (Formula (7) = tetrahydropyranyl group, R 3 = ethyl, a = preparation of methyl compound of group)
　in 100mL reactor, the crude
(3 obtained in example 5 S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran-2 yloxy) - butyl] X = Cl in malonic acid diethyl ester (formula (6), P = tetrahydropyranyl group, R 3 = ethyl, compound of a = methyl group) 5.77 g (pure content 4.95 g, 12 .14mmol), were charged dimethylformamide 58 mL, Spec 3 divided and over a period of 3 hours sodium -tert- butoxide 1.52g of (15.78mmol) at 15 ℃ Inclusive, and the mixture was stirred for 2 hours at 15 ℃. The reaction mixture was added acetic acid 0.22mL neutralize the excess base, toluene was added, washed with water, dried, and concentrated to give crude (5S)-1-acetyl-5- (tetrahydropyran-2-yloxy) - piperidine-2,2-dicarboxylic acid diethyl ester (formula (7) in the P = tetrahydropyranyl group, R 3 = ethyl, compound of a = methyl group) 3.85 g (pure content 2.77 g, yield 62 %) was obtained.
[0169]
[Example 11-1] (5S)-1-acetyl-5- (tetrahydropyran-2-yloxy) - P In piperidine-2,2-dicarboxylic acid diethyl ester (Formula (7) = tetrahydropyranyl radical, R 3 = ethyl, a = preparation of methyl compound of group)
　in 10mL reactor, the crude obtained in example 5 (3S) -2-acetylamino-2- [4-chloro-3- (tetrahydropyran -2 - yloxy) - butyl] X = Cl in malonic acid diethyl ester (formula (6), P = tetrahydropyranyl group, R 3 = ethyl, compound of a = methyl group) 0.53 g (pure content 0.5g, 1.23 mmol), were charged dimethylformamide 2.7 mL, potassium carbonate (1.23 mmol), tetrabutylammonium bromide (hereinafter, "TBAB") (1.227 mol) were charged, and the mixture was stirred for 15 hours at 100 ℃.
　Toluene was added, washed with brine, dried, and concentrated, (5S)-1-acetyl-5- (tetrahydropyran-2-yloxy) - piperidine-2,2-dicarboxylic acid diethyl ester (Formula (7) in P = tetrahydropyranyl group, R 3 to give = ethyl, a = compound of methyl group) 0.61 g (pure content 0.37 g, 80% yield).
[0170]
[Example 11-2] (5S) -1- acetyl-5-methoxymethyloxy - piperidine-2,2-dicarboxylic acid diethyl ester (P = methoxymethyl group in the formula (7), R 3 = ethyl, A = production of methyl compound of group)
　in 50mL reactor, crude obtained analogously to example 7 (3S) -2-acetylamino-2- [4-chloro-3-methoxymethyloxy - butyl] malonic acid diethyl ester (X = Cl in the formula (6), P = methoxymethyl group, R 3 = ethyl, compound of a = methyl group) 1.41 g (pure content 1.12 g, 3.04 mmol), dimethylformamide 5.3mL It was charged with cesium carbonate 2.97 g (9.12 mmol), and stirred for 3 hours at 100 ° C.. Toluene was added to the reaction solution, washed with water, dried, and concentrated to give crude (5S)-1-acetyl-5-methoxymethyloxy - In piperidine-2,2-dicarboxylic acid diethyl ester (Formula (7) P = methoxymethyl group, R 3 to give = ethyl group, compounds where a = methyl group) 0.95 g of (pure content 0.87 g 87% yield).
[0171]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２７－１．３１（６Ｈ，ｍ），１．５０－１．５９（１Ｈ，ｍ），１．８０－１．９０（１Ｈ，ｍ），２．０８－２．１７（１Ｈ，ｍ），２．１７（３Ｈ，ｓ），２．４８－２．５５（１Ｈ，ｍ），３．２８－３．４０（１Ｈ，ｍ），３．４０（３Ｈ，ｓ），３．６３（１Ｈ，ｍ），３．７６（１Ｈ，ｍ），４．１８－４．３０（４Ｈ，ｍ），４．７１（２Ｈ，ｍ）．
[0172]
[Example 11-3] (5S)-1-acetyl-5- (1-ethoxyethyloxy) - piperidine-2,2-dicarboxylic acid diethyl ester (P = an ethoxyethyl group in the formula (7), R 3 = ethyl, a = preparation of methyl compound of group)
　in 100mL reactor, the crude obtained in example 7-2 (3S) -2-acetylamino-2- [4-chloro-3- (1-ethoxyethyl oxy) - butyl] X = Cl in malonic acid diethyl ester (formula (6), P = ethoxyethyl group, R 3 = ethyl, compound of a = methyl group) 7.64 g (pure content 7.14 g, 18. 06mmol), were charged dimethylformamide 17.1 mL, it was added portionwise 60% sodium hydride 853mg of (21.40mmol) over 5 hours at 40 ° C.. Acetic acid 0.43mL and toluene was added to the reaction solution, washed with water, 2% potassium carbonate washed with water, dried, and concentrated to give crude (5S)-1-acetyl-5- (1-ethoxyethyloxy) - piperidine -2 , 2-dicarboxylic acid diethyl ester (formula (7) in the P = ethoxyethyl group, R 3 to give = ethyl, a = compound of methyl group) 5.64 g of (pure content 5.31 g 77% yield).
[0173]
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ 3）δ１．２０－１．３５（１２Ｈ，ｍ），１．３５－１．５０（１Ｈ，ｍ），１．９０（１Ｈ，ｍ），２．０３－２．１２（１Ｈ，ｍ），２．１４（３Ｈ，ｓ），２．４７－２．５５（１Ｈ，ｍ），３．０２－３．１５　ａｎｄ　３．４４－３．８６（５Ｈ，ｍ），４．２０－４．３５（４Ｈ，ｍ），４．８１（１Ｈ，ｍ）．

WE claims

[Requested item 1]
(I) Step 4:
　the following formula (7)
[Formula 1]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms , an aryl group having 6 to 12 carbon atoms, and a hydroxyl group deprotected in the compound represented by alkyl group having 1 to 4 carbon atoms, or. of an aralkyl group having 7 to 20 carbon atoms),
　formula ( 8)
[formula 2]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, having 1 to 4 carbon atoms alkyl group, or process, for synthesizing shown.) and a compound represented by the aralkyloxy group having 7 to 20 carbon atoms
　, characterized in that it comprises the following formula (10)
[formula 3]

represented by ( 2S, 5S) / (2R, 5R) -5- method for producing hydroxy-piperidine-2-carboxylic acid.
[Requested item 2]
　Further, (ii) Step 5:
(a) In the compound (8), an ester group is hydrolyzed, one of the carboxyl groups is lactonized by reaction with a hydroxyl group, further, the carboxyl group is decarboxylated,
　or ,
(b) the compound (8), an ester group is hydrolyzed, one of the carboxyl groups and stereoisomeric mixture of the 2-position monocarboxylic acid by decarboxylation, then isomerizing a stereo isomer mixture is lactonized,
by,
　the following equation (9)
[formula 4]

(wherein, a represents an alkyl group, an aryl group having 6 to 12 carbon atoms or an alkyloxy group having 1 to 4 carbon atoms, 1 to 10 carbon atoms , process for synthesizing a compound represented by an aralkyl group having 7 to 20 carbon atoms).
　characterized in that it comprises a, according to claim 1 (2S, 5S) / ( 2R, 5R) - 5 Method for producing a hydroxy-piperidine-2-carboxylic acid.
[Requested item 3]
Furthermore, (iii) Step 6:
　cleaved the amide bond in the compound (9), by hydrolyzing the lactone in the compound (9), (2S, 5S ) / (2R, 5R) -5- hydroxypiperidine a step of synthesizing 2-carboxylic acid,
　characterized in that it comprises a, according to claim 1 or claim 2 (2S, 5S) / ( 2R, 5R) -5- hydroxy-2-carboxylic acid Production method.
[Requested item 4]
　In the step 5 (a) or the step 5 (b), the decarboxylation reaction of the carboxyl group, in the presence of an organic base,
　characterized in that, according to claim 2 or claim 3 ( 2S, 5S) / (2R, 5R) -5- method for producing hydroxy-piperidine-2-carboxylic acid.
[Requested item 5]
　Step 1:
　the following formula (1)
[Chemical Formula 5]

(wherein, X is Cl, Br or indicates I,, R 1 represents a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl group. the hydroxyl group in the compound represented by), and protected with a protecting group,
　the following formula (2)
[chemical formula 6]

(wherein, X is Cl, Br or indicates I,, R 1 is is hydrogen atom or a substituent indicates an alkyl group having 1 to 4 carbon atoms even, P is to synthesize a compound represented by a protecting group.),
　by reduction of the ester group in then compound (2),
　the following equation (3)
[chemical formula 7]

(wherein, X is Cl, Br or indicates I,, P represents a protecting group.) step for synthesizing the compound represented by
　characterized in that it comprises a
　following formula (7)
[ of 8]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, having a carbon number of 6 to 2 aryl group, an alkyloxy group having 1 to 4 carbon atoms, or.) Of an aralkyl group having 7 to 20 carbon atoms,
a manufacturing method of a compound represented by the.
[Requested item 6]
(I) Step 2:
　with a sulfonic acid ester of a hydroxyl group in the compound (3),
　the following formula (4)
[Formula 9]

(wherein, X represents a Cl, Br or I,, R 2 is 6 carbon atoms aryl groups of 1-12, an alkyl group having 1 to 10 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.) represented by synthesizing the compound,
　the compound (4),
　the following formula (5)
[ of 10]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or an aralkyl group having 7 to 20 carbon atoms. the compound represented by the) were reacted,
　following formula (6)
[formula 11]

(wherein, X represents a Cl, Br or I,, P represents a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, charcoal . 6 aryl groups of 1-12, the step of synthesizing the compound represented by) represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms, having 1 to 4 carbon atoms, and,
(ii) Step 3:
　the compound (6) cyclizes
　formula (7)
[Formula 12]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group, an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms, carbon an alkyloxy group having 1 to 4 or shown.) the aralkyloxy group having 7 to 20 carbon atoms,
a process for synthesizing a compound represented by,
　characterized in that it comprises a compound according to claim 5 (7 method of manufacturing).
[Requested item 7]
　In the step 2, the reaction between the compound (4) and the compound (5), in the presence of a iodide salt,
　wherein the method for producing a compound according to claim 6 (7).
[Requested item 8]
　In the step 3, the cyclization reaction of the compound (6), carried out in the presence of a quaternary ammonium salt,
　and wherein the method for producing a compound according to claim 6 or claim 7 (7).
[Requested item 9]
　Said compound (7) is prepared by a method according to any one of claims 5 to claim 8,
　characterized in that, according to any one of claims 1 to 4 (2S , 5S) / (2R, 5R ) -5- method for producing hydroxy-piperidine-2-carboxylic acid.
[Requested item 10]
(I) Step 4:
　the following formula (7)
[of 13]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms , an aryl group having 6 to 12 carbon atoms, and a hydroxyl group deprotected in the compound represented by alkyl group having 1 to 4 carbon atoms, or. of an aralkyl group having 7 to 20 carbon atoms),
　formula ( 8)
[formula 14]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, having 1 to 4 carbon atoms alkyl group or step, to synthesize compounds represented by indicating.) an aralkyloxy group having 7 to 20 carbon atoms,
　and having a method for producing a compound represented by the formula (8).
[Requested item 11]
(I) Step 4:
　the following formula (7)
[Formula 15]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms , an aryl group having 6 to 12 carbon atoms, and a hydroxyl group deprotected in the compound represented by alkyl group having 1 to 4 carbon atoms, or. of an aralkyl group having 7 to 20 carbon atoms),
　formula ( 8)
[formula 16]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, having 1 to 4 carbon atoms a step of synthesizing a compound represented by the alkyl group or an aralkyl group having a carbon number of 7 ~ 20,),.
(ii) step 5:
(a) in the compound (8), an ester group was hydrolyzed , one of the carboxyl groups is lactonized by reaction with a hydroxyl group, further, Cal The cyclohexyl group is decarboxylated,
　or
in (b) the compound (8), an ester group is hydrolyzed, by one of the carboxyl groups decarboxylated and 2 of stereoisomeric mixture of a monocarboxylic acid and then, the stereo isomer mixture is isomerized lactonization,
by,
　the following equation (9)
[formula 17]

Table (In the formula, A represents an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms or an alkyloxy group having 1 to 4 carbon atoms,. Showing an aralkyloxy group having 7 to 20 carbon atoms,) with process of synthesizing a compound
　characterized by having a method for producing a compound represented by the formula (9).
[Requested item 12]
　Compound represented by the following formula (9a).
[Formula 18]

(wherein, A 'represents an alkyl group or an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms.)
[Requested item 13]
　Or a salt thereof represented by the following formula (11a) or (11b).
[Formula 19]

(wherein, A 'represents an alkyl group or an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms.)
[Formula 20]

(In the formulas, A' represents alkyl having 1 to 10 carbon atoms a group or an aryl group having 6 to 12 carbon atoms.)
[Requested item 14]
　Compounds represented by the following formula (8) or a salt thereof dicarboxylic acid.
[Formula 21]

(wherein, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy having 1 to 4 carbon atoms group, or an aralkyl group having 7 to 20 carbon atoms.)
[Requested item 15]
　Compound represented by the following formula (7).
Formula 22]

(wherein, P is a protecting group, R 3 represents an alkyl group having 1 to 4 carbon atoms, A is an alkyl group, an aryl group having 6 to 12 carbon atoms having 1 to 10 carbon atoms, carbon alkyloxy group having 1 to 4 or an aralkyl group having 7 to 20 carbon atoms.)
[Requested item 16]
　Compound represented by the following formula (6a).
[Chem 23]

(wherein, X is Cl, showed a Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms, a is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms or C 7 ~ 20 shows the aralkyl group.)
[Requested item 17]
　Compound represented by the following formula (4a).
Formula 24]

(wherein, X is Cl, showed a Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group, R 2 represents an alkyl group, an aryl group having 6 to 12 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, 1 to 10 carbon atoms.)
[Requested item 18]
　Compound represented by the following formula (3a).
Formula 25]

(wherein, X represents a Cl, Br or I,, P 'represents a tetrahydropyranyl group, a methoxymethyl group, ethoxyethyl group, a tert- butyl group or tert- butyldimethylsilyl group. )
[Requested item 19]
　Compound represented by the following formula (2a).
[Chemical Formula 26]

(wherein, X is Cl, Br or indicates I, R, 1 represents a hydrogen atom or a substituted 1 carbon atoms which may be 1-4 alkyl, P '' is a tetrahydropyranyl group or shows ethoxyethyl group.)