Field of the Invention
[0001] The present invention relates to a method for industrial production of a
(2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone.
Background Art
[0002] There have been reported some methods for production of (2R)-2-
fluoro-2-C-methyl-D-ribono-y-lactQnes. Among others, ring-opening fluorination of
diols to cyclic sulfates is known as a suitable technique for large-scale production of
(2R)-2-fluoro-2-C-rnethyl-D-ribono-y-lactones. As one such fluorination technique,
the present applicant has disclosed a method of reaction of a 1,2-diol with sulfuryl
fluoride in the presence of an organic base (Patent Document 1). In this reaction, a
(2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone precursor can be produced with high
yield and high reproducibility by stereoselective introduction of a fluorine atom. On
the other hand, there has been reported a method of producing a (2R)-2-fluoro-2-C-
methyl-D-ribono-y-lactone precursor as a mixture of diastereomers by aldol reaction
of a 2-fluoropropionic.acid ethyl ester with (R)-(+)-2,2-dimethyl-l,3-dioxolane-4-
carboxyaldehyde in the presence of a base, and then, separating the diastereomers by
substrate-selective enzymatic hydrolysis (see the following scheme where Et
represents an ethyl group and Bz represents a benzoyl group) (Patent Document 2
and Non-Patent Document 1). There has also been a report made on improvement
in the selectivity of production of a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone
precursor by aldol reaction of a 2-fluoropropionic acid amide or thioester, in place of
a 2-fluoropropionic acid ester, with (R)-(+)-2,2-dimethyl-l ,3-dioxolane-4-
carboxyaldehyde in the presence of a base (Patent Document 3).


Prior Art Documents
Patent Documents
[0003.] Patent Document 1: Internationa) Patent Publication No. 2011/152155
Patent Document 2: U.S. Patent Publication No. 2008/0145901
Patent Document 3: U.S. Patent Publication No. 2008/0177079
Non-Patent Documents
[0004.] Non-Patent Document 1: Tetrahedron: Asymmetry (U.K.), 2009, vol. 20,
p. 305-312
Summary of the Invention
Problems to be Solved by the Invention
[0005.] It is an object of the present invention to provide a method for industrial
production of a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone.

[0006.] The method of Patent Document 1 discloses the reaction of a 1,2-diol,
which also corresponds to the raw substrate material of the present invention.
Although the diol compound can be produced by a known process, it is somewhat
difficult to reduce the production cost of the diol compound due to the adoption of a
Wittig reaction process, a stereoselective dihydroxylation process using a metal
reagent etc. The methods of Patent Document 2 and Non-Patent Document 1 can be
reduced in operation, but are low in total yield, as compared to the method of Patent
Document 1. Further, there remains the problem of reproducibility and productivity
due to the separation of diastereomers by enzymatic reaction in the methods of
Patent Document 2 and Non-Patent Document 1 so that it is difficult to meet the
requirements (such as high productivity and high reproducibility) for industrial
applications. The method of Patent Document 3 is not able to attain a sufficient
level of selectivity and yield and is in need of an efficient separation technique.
There has thus been a strong demand to establish a more efficient and simple
diastereomer separation technique, than conventional diastereomer separation
techniques, for the development of a purification process of the target (2R)-2-fluoro-
2-C-methyl-D-ribono-y-lactone compound of the present invention.
[0007.] In the above-mentioned prior art documents, researches are made on the
separation and purification of diastereomers of a (2R)-2-fluorO-2-C-methyl-D-
ribono-y-lactone precursor or 3,5-acylated (2R)-2-fluoro-2-C-methyl-D-ribono-Y-
lactone by enzymatic reaction, recrystallization, column purification etc. However,
no report has been made on the efficient production method of a 3,5-unacylated
(2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone by diastereomer separation and
purification.
Means for Solving the Problems
[0008.] In view of the above circumstances, the present inventors have made
extensive researches and resultantly found that, by subjecting a mixture of
diastereomers of a (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone precursor of the
general formula [2] to deprotection followed by lactonization under acidic
conditions, thereby forming a mixture of diastereomers of a dihydroxylactone of the
general formula [3], and then, subjecting the resulting diastereomer mixture to

recrystallization, it is possible to achieve efficient diastereomer separation and easily
produce the optically active 2-fluoro-2-C-methyl-D.-ribono-y-lactone.
In the general formula [2], R1 represents an .alkyl group or a substituted alkyl group;
A represents an oxygen atom, a nitrogen atom or a sulfur atom; P1 and P2 each
independently represent a hydroxyl protecting group; and * represents an
asymmetric carbon.

In the general formula [3], * represents an asymmetric carbon.
[0009.] The present inventors have also found that it is possible to obtain the
optically active 2-fluoro-2-C-methyl-D-ribono-Y-lactone with high yield, high
reproducibility and high purity by the use of any one or combination of alcohol
solvents, nitrile solvents,, ester solvents, ether solvents, aliphatic hydrocarbon
solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ketone
solvent and water as a recrystallization solvent.
[0010.] The thus-obtained lactone can be converted to a corresponding protected
lactone compound by acylation with high yield.
[0011.] The present invention is particularly characterized by the order of
execution of the recrystallization and the acylation. Even if a mixture of
diastereoisomers of a 3,5-acylated (2R)-2-fluoro-2-C-rnethyl-D-ribono-y-lactone is
subjected to recrystallization, that is, the recrystallization is performed after the
acylation, it is not possible to selectively separate the target stereoisomer product
(see the after-mentioned comparative example 1). It means that the separation of
diastereomers of a lactone having hydroxyl groups at 3- and 5-positions (i.e. 3,5-
unacylated lactone) is clearly different in behavior from that of a 3,5-acylated
lactone. In particular, there is seen a remarkable difference in behavior during the

separation of (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone and (2S)-2-fluoro-2-C-
methyl-D-ribono-y-lactone. These findings go far beyond the disclosures of Patent
Documents 1, 2 and 3 and Non-Patent Document 1.
[0012.] As mentioned above, the present inventors have newly found the very
useful techniques for production of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone. The present inventor is.based on those newly found techniques.
[0013.] Namely, the present invention provides a method for industrial
production of a.(2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone as defined by the
following inventive aspects 1 to 7.
[0014.] . [Inventive Aspect 1]
A production method of a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone
of the general formula [1], comprising:
subjecting a mixture of diastereomers of a lactone precursor of the
general formula [2] to deprotection followed by lactonization under acidic
conditions, thereby forming a mixture of diastereomers of a dihydroxylactone of the
general formula [3];
separating and purifying a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone
of the general formula [4] by recrystallization of the mixture of diastereomers of the
dihydroxylactone; and
acylating the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone,

where R2 represents an acyl group

where R1 represents an alkyl group or a substituted alkyl group; A represents an
oxygen atom, a nitrogen atom or a sulfur atom; P1 and P2 each independently
represent a hydroxyl protecting group; and * represents an asymmetric carbon


where * represents an asymmetric carbon

[0015.] [Inventive Aspect 2]
The production method according to Inventive Aspect 1, wherein the
mixture of diastereoisomers of the dihydroxylactone is recrystallized with the use of
at least one kind of solvent selected from the group consisting of alcohol solvents,
aromatic hydrocarbon solvents, ester solvents, nitrile solvents, ether solvents,
halogenated hydrocarbon solvents, ketone solvents, water and aliphatic hydrocarbon
solvents as a recrystallization solvent.
[0016.] [Inventive Aspect 3]
The production method according to Inventive Aspect 1 or 2, wherein the
mixture of diastereomers of the dihydroxylactone is recrystallized with the use of
isopropanol, toluene, ethyl acetate or n-heptane as a recrystallization solvent.
[0017.] [Inventive Aspect 4]
The production method according to Inventive Aspect 1, wherein R1 in
the general formula [ 1 ] represents a substituted or unsubstituted straight or branched
alkyl group of 1 to 6 carbon atoms.
[0018.] [Inventive Aspect 5]
The production method according to Inventive Aspect 1, wherein P1 and
P2 in the general formula [1] represent an isopropylidene group or a cyclohexylidene
group.
[0019.] [Inventive Aspect 6]
The production method according to Inventive Aspect 1, wherein the
mixture of diastereoisomers of the lactone precursor is subjected to deprotection
followed by lactonization under the acidic conditions with the use of acetic acid,

sulfuric acid, hydrochloric acid, methanesulfonic acid, paratoluenesulfonic acid or
trifluoroacetic acid.
[0020.] [Inventive Aspect 7]
The production method according to Inventive Aspect 1, wherein R2 in
the general formula [1] represents a benzoyl group, a formyl group or an acetyl
group.
[0021.] The present invention provides the following advantages over the prior
art.
[0022.] In the present invention, it is possible by recrystallization of the
dihydroxylactone diastereomer mixture to efficiently separate the target (2R)-2-
fluoro-2-C-methyl-D-ribono-y-lactone from the dihydroxylactone diastereomer
mixture. It is further possible to achieve high-yield and high-reproducibility
production of the target (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone by adoption
of the suitable recrystallization conditions. The present invention is advantageous
over Patent Document 2 and Non-Patent Document 1 in that it is possible to
efficiently separate the diastereomers by simple operation, without the need for
conventional substrate-selective enzymatic hydrolysis, and ensure high
reproducibility and productivity improvement. The present invention is also
advantageous in meeting the requirements for industrial applications.
Detailed Description of the Embodiments
[0023.] The production method of the (2R)-2-fluoro-2-C-rnethyl-D-ribono-y-
lactone according to the present invention will be described below in detail.
[0024.] The production method of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone according to the present invention includes the following steps:
subjecting a diastereomer mixture of a lactone precursor of the general
formula [2] to deprotection followed by lactonization under acidic conditions,
thereby forming a diastereomer mixture of a dihydroxylactone of the general
formula [3];
separating a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the general
formula [4] with high purity by recrystallization of the diastereomer mixture of the
dihydroxylactone; and

acylating the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone.
[0025.] In the general formula [2], R1 represents an alkyl group or a substituted
alkyl group. The alkyl group can be of 1 to 12 carbon atoms in the form of a linear
or branched chain structure or a cyclic structure (in the case of 3 or more carbon
atoms). The substituted alkyl group can have any number of and any combination
of substituents on any of the carbon atoms of the above alkyl group. Examples of
such substituents are: halogen atoms such as fluorine, chlorine, bromine and iodine;
lower alkyl groups such as methyl, ethyl, propyl and butyl; and lower alkoxy groups
such as methoxy, ethoxy, propoxy and butoxy. It is noted that, in the present
specification, the term "lower" means that the group to which the term is attached
has 1 to 6 carbon atoms in the form of a linear or branched chain structure or a
cyclic structure (in the case of 3 carbons or more). Among others, an alkyl or
substituted alkyl group of 1 to 6 carbon atoms is preferred. Particularly preferred is
a methyl group or an ethyl group.
[0026.] Further, A represents an oxygen atom, a nitrogen atom or a sulfur atom
in the general formula [2]. Specific examples of the combination structure of A and
R1 are as follows. (In each formula, the chain line represents a bonding position.)


[0027.] In the general formula [2], P1 and P2 each independently represent a
hydroxyl protecting group. Examples of the hydroxyl protecting group are those
described in "Protective Groups in Organic Synthesis", Third Edition, 1999, John
Wiley & Sons, Inc. In the present invention, P1 and P2 can be the same protecting
group or different protecting groups or can be taken together as one protecting
group. Among other, it is preferable that P1 and P are taken together as one
protecting group (see below). Particularly preferred as the protecting group is an
isopropylidene group or a cyclohexylidene group.

[0028.] It is feasible to form the diastereomer mixture of the lactone precursor of
the general formula [2] in a similar manner to those of Patent Document 2 and Non-
Patent Document 1. The diastereomer mixture of the lactone precursor herein refers
to a mixture of four compounds of different configurations (formulas [2a] to [2d]) as
shown below.



[0029.] Next, an explanation will be given of the deprotection and lactonization
reaction of the diastereomer mixture of the lactone precursor.
[0030.] By reaction under the acidic conditions, the diastereomer mixture of the
lactone precursor of the general formula [2] is subjected to deprotection immediately
and sequentially followed by lactonization. As a result of such deprotection and
lactonization reaction, the diasteromer mixture of the dihydroxylactone of the
general formula [3] is obtained. The diastereomer mixture of the dihydroxylactone
herein refers to a mixture of four compounds of different configurations (formulas
[3a] to [3d]) as shown below.



[0031.] The deprotection and lactonication reaction is performed under the
acidic conditions with the use of the acid. Examples of the acid usable in the
deprotection and lactonication reaction are acetic acid, sulfuric acid, hydrochloric
acid, methanesulfonic acid, paratoluenesulfonic acid and trifluoroacetic acid. The
acid is not however limited to these acids. It is feasible to utilize any acid
commonly used for organic synthesis. Among others, acetic acid, sulfuric acid and
hydrochloric acid are particularly preferred. The above acids can be used solely or
in combination thereof.
[0032.] It suffice to use the acid in an amount of 0.05 mol or more per 1 mol of
the diastereomer mixture of the lactone precursor of the general formula [2]. The
amount of the acid used is preferably in the range of 0.1 to 50 mol, more preferably
0.2 to 20 mol, per 1 mol of the diastereomer mixture of the lactone precursor of the
general formula [2].
[0033.] Further, the deprotection and lactonication reaction is generally
performed in a reaction solvent. Examples of the reaction solvents usable in the
deprotection and lactonication reaction are: alcohol solvents such as methanol and
ethanol; amide solvents such as N,N-dimethylformarnide and l,3-dimethyl-2-
imidazolidinone; nitrile solvents such as acetonitrile and propionitrile; water;
tetrahydrofuran; and dimethyl sulfoxide.. Among others, methanol, ethanol, N,N-
dimethylformamide, acetonitrile, water, tetrahydrofuran and dimethyl sulfoxide are
preferred. Particularly preferred are methanol, ethanol, acetonitrile, water and
tetrahydrofuran. The above solvents can be used solely or in combination thereof.
[0034.] It suffices that the temperature of the deprotection and lactonication
reaction is in the range of-20 to +150°C. The temperature of the deprotection and
lactonication reaction is preferably in the range of-10 to +125°C, more preferably 0
to+100°C.
[0035.] It suffices that the time of the deprotection and lactonication reaction is
96 hours or less. As the reaction time varies depending on the raw substrate material

and reaction conditions, it is preferable to determine the time at which almost all of
the raw substrate material has disappeared as the end of the reaction while
monitoring the progress of the reaction by any analytical means such as gas
chromatography, liquid chromatography or nuclear magnetic resonance.
[0036.] Next, an explanation will be given of the recrystallization of the
diastereomer mixture of the dihydroxylactone of the general formula [3].
[0037.] The (2R)-2-fluoro-2-C-rnethyl-D-ribono-y-lactone of the general
formula [4] is separated and purified from the diastereomer mixture of the
dihydroxylactone of the general formula [3] by recrystallization with the use of a
recrystallization solvent. Examples of the recrystallization solvent are: aliphatic
hydrocarbon solvents such as n-pentane, n-hexane, cyclohexane and n-heptane;
aromatic hydrocarbon solvents such as benzene, toluene, ethylbenzene, xylene and
mesitylene; halogenated hydrocarbon solvents such as methylene chloride,
chloroform and 1,2-dichloroethane; ether solvents such as diethyl ether,
tetrahydrofuran, t-butyl methyl ether, di-i-propyl ether and 1,4-dioxane; ketone
solvents such as acetone, methyl ethyl ketone and methyl i-butyl ketone; ester
solvents such as ethyl acetate and n-butyl acetate; nitrile solvents such as acetonitrile
and propionitrile; alcohol solvents such as methanol, ethanol, n-propanol, i-propanol
and n-butanol; and water. These solvents can be used solely or in combination
thereof. Among others, a mixture of individual solvents is preferred. As such a
mixed solvent, there can preferably be used isopropanol/toluene, isopropanol/ethyl
acetate, isopropanol/toluene/n-heptane, isopropanol/ethyl acetate/n-heptane,
acetonitrile/toluene and acetonitrile/toluene/n-heptane. Particularly preferred is
isopropanol/toluene/n-heptane or isopropanol/ethyl acetate/n-heptane.
[0038.] It suffices to use the recrystallization solvent in an amount of 0.5 mL or
more per 1 g of the diastereomer mixture of the dihydroxylactone of the general
formula [3]. The amount of the recrystallization solvent used is preferably in the
range of 1 to 30 mL, more preferably 2 to 10 mL, per 1 g of the diastereomer
mixture of the dihydroxylactone of the general formula [3].
[0039.] There is no particular restriction on the recrystallization process. For
example, it is preferable to perform the recrystallization by heating and dissolving

the diastereomer mixture, gradually cooling down while leaving or stirring the
resulting solution such that the target lactone can be sufficiently crystallized in the
temperature range of-20 to +20°C over 1 to 48 hours, and then, filtering out the
resulting crystal. The recrystallization may be performed with the use of a seed
crystal.
[0040.] After the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone is obtained by
the above recrystallization process, the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone is acylated in the presence of a base and thereby converted to the (2R)-2-
fluoro-2-C-methyl-D-ribono-y-lactone of the general formula [1]. In the present
invention, the acylation refers to acetylation, benzoylation or formylation.
[0041.] The acylation is performed with the use of an acylation agent. Examples
of the acylation agent are: acetic anhydride, acetyl chloride and the like for the
acetylation; formic acid and the like for the formylation; and benzoyl chloride,
benzoic anhydride, benzoyl cyanide and trifluoromethanesulfonic acid benzoyl ester
for the benzoylation. The acylation agent is not however limited to these acylation
agents. In the present invention, the acetylation or benzoylation is preferred as the
acylation. Particularly preferred is the benzoylation. Among the above
benzoylation agents, benzoyl chloride is particularly preferred.
[0042.] It suffices to use the acylation agent in an amount of 1 to 20 mol per 1
mol of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone. The amount of the
acylation agent used is preferably in the range of 2 to 10 mol, more preferably 2.to 5
mol, per 1 mol of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone.
Further, the acylation is generally performed in a reaction solvent.
Examples of the reaction solvent usable in the acylation reaction are: aromatic
hydrocarbon solvents such as benzene, toluene, ethylbenzene, xylene and
mesitylene; halogenated hydrocarbon solvents such as methylene chloride,
chloroform and 1,2-dichloroethane; ether solvents such as diethyl ether,
tetrahydrofuran, t-butyl methyl ether, di-i-propyl ether and 1,4-dioxane; and nitrile
solvents such as acetonitrile and propionitrile. It is feasible to select and use the
reaction solvent as appropriate depending on the reaction conditions. The above
solvents can be used solely or in combination thereof.

[0043.] Examples of the base usable in the acylation reaction are: ammonia;
amines such as trimethylamine, pyridine, lutidine, collidine and N,N-
dimethylaniline; hydroxides such as sodium hydroxide, potassium hydroxide and
tetramethylammonium hydroxide; and alkali metal carbonates or
hydrogencarbonates such as potassium carbonate and sodium hydrogencarbonate.
These bases can be used solely or in combination thereof.
[0044.] The temperature of the acylation reaction can be set as appropriate
depending on the reaction condition. In general, it suffices that the temperature of
the acylation reaction is in the range of 0 to 30°C.
[0045.] In the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the general
formula [1], R2 represents an acyl group. Examples of the acyl group are those
corresponding to the above-mentioned acylation agents, such as benzoyl, formyl and
acetyl.
Examples
[0046.] The present invention will be described in more detail below by way of
the following examples. If should be understood that the following examples are
illustrative and are not intended to limit the present invention thereto. The
procedures of Examples 1 to 6 and Comparative Example 1 are follows. In the
following explanation, the abbreviation "Me" refers to a methyl group.
[0047.] [Example 1]
In a 100-ml eggplant-shaped flask, 17.47 g of a mixture of lactone
precursor diastereomers of the following formulas [6] to [9] (diastereomer [6]: 22.3
mmol, diastereomer [7]: 16.1 mmol, diastereomers [8]+[9]: 9.9 mmol, each
quantified by l9F-NMR internal standard method), 24 ml (0.5 L/mol) of methanol
and 1.5 ml (18 mmol, 0.37 eq) of 12N hydrochloric acid were placed. The resulting
solution was stirred at room temperature for 18 hours.



The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 15 ml of
toluene under a reduced pressure, and then, vacuum dried. By this, 11.90 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
. and [11] was obtained.

The l9F-NMR data of the crude product mixture was as follows.
19F-NMR [reference material: CeF6, deuterated solvent: CD3CN]
Diastereomer [4]: 5 ppm: -6.60 (m, IF)

Diastereomer [5]: 8 ppm: 6.51 (m, IF)
Diastereomer [10] or [11]: 8 ppm: -8.70 (m, IF)
Diastereomer [10] or [11]: S ppm: 7.70 (m, IF)
Subsequently, 11.90 g of the mixture of the dihydroxylactone
diastereomers was recrystallized with a mixed solvent of 17.9 ml (1.5 vol) of
isopropanol, 59.5 ml (5 vol) of toluene and 11.9 ml (1 vol) of n-heptane. The thus-
formed crystal was filtered out, washed with 11.9 ml of ice-cooled n-heptane and
vacuum dried. By this, 3.17 g (19.3 mmol) of a light brown crystalline product of
the (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the above formula [4] was
obtained. The yield of the crystalline product was 86.5%. The gas chromatographic
purity of the crystalline product was 94.4%. As a main impurity in the crystalline
product, the diastereomer of the above formula [5] was present in an amount of
3.7%. •
To 3.17 g (19.3 mmol) of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone, 19.3 ml (1 L/mol) of acetonitrile and 3.51 g (44.4 mmol, 2.30 eq) of
pyridine were added. Further, 5.97 g (42.5 mmol, 2.20 eq) of benzoyl chloride was
added under ice cooling. The resulting solution was stirred at room temperature for
2 hours. To the thus-obtained reaction completed solution, 18 ml of water was
added under ice cooling. After that, the reaction completed solution was stirred at
room temperature for 10 minutes and extracted with 36 ml of ethyl acetate. The
recovered organic layer was washed with 18 ml of 5% aqueous sodium
hydrogencarbonate solution, washed with 18 ml of 5% aqueous sodium chloride
solution, concentrated under a reduced pressure, and then, vacuum dried. As a
result, 7.52 g of (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the following
formula [28] was obtained.

The l9F-NMR data of the crude product compound was as follows.
I9F-NMR [reference material: C6F6, deuterated solvent: CD3CI3] 8 ppm: -5.44 (m,
IF)

The whole of 7.18 g of the crude product compound (regarded as 19.3
mmol for the sake of convenience) was recrystallized with a mixed solvent of 10.8
ml (1.5 vol) of ethyl acetate, 10.8 ml (1.5 vol) of isopropanol and 64.6 ml (9 vol) of
n-heptane. The thus-formed crystal was filtered out, washed with 14.9 ml of n-
heptane and vacuum dried. There was thus obtained 6.52 g (17.5 mmol) of the (2R)-
2-fluoro-2-C-methyl-D-ribono-y-lactone of the above formula as a white crystalline
product. The yield of the crystalline product was 90.7%. The gas chromatographic
purity of the crystalline product was 99.3%.
[0048.] [Example 2]
In a 100-ml eggplant-shaped flask, 20.58 g of a mixture of lactone
precursor diastereomers of the following formulas [12] to [15] (diastereomer [12]:
23.1 mmol, diastereomer [13]: 16.2-mmol, diastereomers [14]+[15]: 6.7 mmol, each
quantified by l9F-NMR internal standard method), 23 ml (0.5 L/mol) of methanol
and 1.4 ml (16.8 mmol, 0.37 eq) of 12N hydrochloric acid were placed. The
resulting solution was stirred at room temperature for 18 hours.

The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 15 ml of

toluene under a reduced pressure, and then, vacuum dried. By this, 13.90 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
and [11] was obtained.

The ' F-NMR data of the crude product mixture were the same as those
in Example 1.
Subsequently, 13.90 g of the mixture of the dihydroxylactone
diastereomers was recrystallized with a mixed solvent of 20.9 ml (1.5 vol) of
isopropanol, 69.5 ml (5 vol) of toluene and 27.8 ml (2 vol) of n-heptane. The thus-
formed crystal was filtered out, washed with 13.9 ml of ice-cooled toluene and
vacuum dried. By this, 3.73 g (22.7 mmol) of a light brown crystalline product of
the (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the above formula [4] was
obtained. The yield of the crystalline product was 98.3%. The gas chromatographic
purity of the crystalline product was 90.3%. As a main impurity in the crystalline
product, the diastereomer of the above formula [5] was present in an amount of
6.3%. Then, 3.73 g of the crystalline product was again recrystallized with a mixed
solvent of 5.6 ml (1.5 vol) of isopropanol, 18.7 ml (5 vol) of toluene and 3.7 ml (1
vol) of n-heptane. The thus-formed crystal was filtered out, washed with 3.7 ml of
ice-cooled toluene and vacuum dried. By this, 2.94 g (17.9 mmol) of the light
brown crystalline product of the (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the

above formula [4] was recovered. The recovery rate of the crystalline product was
78.8%. The gas chromatographic purity of the crystalline product was 99.1%. The
amount of the diastereomer of the above formula [5] as the main impurity was 0.4%.
To 2.94 g (17.9 mmol) of the (2R)-2-fluoro-2-C-methyl-D-ribono-y- .
lactone, 17.9 ml (1 L/mol) of acetonitrile and 3.26 g (41.2 mmol, 2.30 eq) of
pyridine were added. Further, 5.54 g (39.4 mmol, 2.20 eq) of benzoyl chloride was
added under ice cooling. The resulting solution was stirred at room temperature for
2 hours. To the thus-obtained reaction completed solution, 17 ml of water was
added under ice cooling. After that, the reaction completed solution was stirred at
room temperature for 10 minutes and extracted with 34 ml of ethyl acetate. The
recovered organic layer was washed with 17 ml of 5% aqueous sodium
hydrogencarbonate solution, washed with 17 ml of 5% aqueous sodium chloride
solution, concentrated under a reduced pressure, and then, vacuum dried. As a
result, 7.09 g of (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the following
formula [28] was obtained.

The l9F-NMR data of the crude product compound was the same as that
in Example 1.
The whole of 7.09 g of the crude product compound (regarded as 17.9
mmol for the sake of convenience) was recrystallized with a mixed solvent of 10.6
ml (1.5 vol) of ethyl acetate, 10.6 ml (1.5 vol) of isopropanol and 63.8.4 ml (9 vol)
of n-heptane. The thus-formed crystal was washed with 13.8 ml of n-heptane and
vacuum dried. There was thus obtained 6.17 g (16.6 mmol) of the (2R)-2-fluoro-2-
C-methyl-D-ribono-yTactone of the above formula as a white crystalline product.
The yield of the crystalline product was 92.6%. The gas chromatographic purity of
the crystalline product was 99.8%.
[0049.] [Example 3]
In a 100-ml eggplant-shaped flask, 35.26 g of a mixture of lactone
precursor diastereomers of the following formulas [6] to [9] (diastereomer [6]: 44.4

mmol, diastcreomer [7]: 31.7 mmol, diastereomers [8]+[9]: 22.7 mmol, each
quantified by l9F-NMR internal standard method), 79 ml (0.8 L/mol) of water and
88.99 g (1.48 mol, 15 eq) of acetic acid were placed. The resulting solution was
stirred at 90°C for 1 hour.

The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 30 ml of
toluene under a reduced pressure, and then, vacuum dried. By this, 24.80 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
and [11] was obtained.



Subsequently, 24.80 g of the mixture of the dihydroxylactone
diastereomers was recrystallized with a mixed solvent of 10 ml (0.4 vol) of
isopropanol, 42 ml (1.7 vol) of ethyl acetate and 52 ml (2.1 vol) of n-heptane. The
thus-formed crystal was filtered out, washed with 20 ml of n-heptane and vacuum
dried. By this, 5.85 g (35.6 mol) of a light brown crystalline product of the (2R)-2-
fluoro-2-C-methyl-D-ribono-y-lactone of the above formula [4] was obtained. The
yield of the crystalline product was 80.1%. The gas chromatographic purity of the
crystalline product was 95.4%. As a main impurity in the crystalline product, the
diastereomer of the above formula [5] was present in an amount of 3.9%.
To 5.85 g (35.6 mmol) of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone, 35.8 ml (1 L/mol) of acetonitrile and 6.48 g (81.9 mmol, 2.30 eq) of
pyridine were added. Further, 11.01 g (78.3 mmol, 2.20 eq) of benzoyl chloride was
added under ice cooling. The resulting solution was stirred at room temperature for
2 hours. To the thus-obtained reaction completed solution, 33 ml of water was
added under ice cooling. After that, the reaction completed solution was stirred at
room temperature for 10 minutes and extracted with 66 ml of ethyl acetate. The
recovered organic layer was washed with 33 ml of 5% aqueous sodium
hydrogencarbonate solution, washed with 33 ml of 5% aqueous sodium chloride
solution, concentrated under a reduced pressure, and then, vacuum dried. As a
result, 13.81 g of (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the following
formula [28] was obtained.


The l9F-NMR data of the crude product compound was the same as that
in Example 1.
The whole of 13.81 g of the crude product compound (regarded as 35.6
mmol for the sake of convenience) was recrystallized with a mixed solvent of 20.7
ml (1.5 vol) of ethyl acetate, 20.7 ml (1.5 vol) of isopropanol and 124.3 ml (9 vol) of
n-heptane. The thus-formed crystal, was filtered out, washed with 27.4 ml of n-
heptane and vacuum dried. There was thus obtained 11.99 g (32.2 mmol) of the
(2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the above formula as a white
crystalline product. The yield of the crystalline product was 90.5%. The gas
chromatographic purity of the crystalline product was 95.8%.
[0050.] [Example 4]
In a 100-ml eggplant-shaped flask, 16.73 g of a mixture of lactone
precursor diastereomers of the following formulas [16] to [19] (diastereomer [16]:
18.5 mmol, diastereomer [17]: 12.0 mmol, diastereomers [18]+[19]: 8.9 mmol, each
quantified by l9F-NMR internal standard method), 19.7 ml (0.5 L/mol) of methanol
and 1.2 ml (14.4 mmol, 0.36 eq) of 12N hydrochloric acid were placed. The
resulting solution was stirred at room temperature for 18 hours.


The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 15 ml of
toluene under a reduced pressure, and then, vacuum dried. By this, 8.72 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
and [11] was obtained. .-••

The l9F-NMR data of the crude product mixture were the same as those
in Example 1.
Subsequently, 8.72 g of the mixture of the dihydroxylactone
diastereomers was recrystallized with a mixed solvent of 13.1 ml (1.5 vol) of
isopropanol, 43.6 ml (5 vol) of toluene and 8.7 ml (1 vol) of n-heptane. The thus-
formed crystal was filtered out, washed with 8.7 ml of ice-cooled toluene and
vacuum dried. By this, 2.45 g (14.9 mmol) of a light brown crystalline product of
the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the above formula [4] was
obtained. The yield of the crystalline product was 80.5%. The gas chromatographic
purity of the crystalline product was 81.8%. As a main impurity in the crystalline
product, the diastereomer of the above formula [5] was present in an amount of
8.0%. Then, 2.31 g of the crystalline product was again recrystallized with a mixed
solvent of 3.5 ml (1.5 vol) of isopropanol, 11.6 ml (5 vol) of toluene and 2.3 ml (1

vol) of n-heptane. The thus-formed crystal was filtered out, washed with 2.3.ml of
ice-cooled toluene and vacuum dried. By this, 1.78 g (10.8 mmol) of the light
brown crystalline product of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the
above formula [4] was recovered. The recovery rate of the crystalline product was
77%. The gas chromatographic purity of the crystalline product was 99.7%. The
amount of the diastereomer of the above formula [5] as the main impurity was 0.3%.
To 1.78 g (10.8 mmol) of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone, 10.8 ml (1 L/mol) of acetonitrile and 1.96 g (24.8 mmol, 2.30 eq) of
pyridine were added. Further, 3.34 g (23.7 mmol, 2.19 eq) of benzoyl chloride was
added under ice cooling. The resulting solution was stirred at room temperature for
2 hours. To the thus-obtained reaction completed solution, 10 ml of water was
added under ice cooling. After that, the reaction completed solution was stirred at
room temperature for 10 minutes and extracted with 20 ml of ethyl acetate. The
recovered organic layer was washed with 10 ml of 5% aqueous sodium
hydrogencarbonate solution, washed with 10 ml of 5% aqueous sodium chloride
solution, concentrated under a reduced pressure, and then, vacuum dried. As a
result, 4.16 g of (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the following
formula [28] was obtained.

The ' F-NMR data of the crude product compound was the same as that
in Example 1.
. The whole of 4.16 g of the crude product compound (regarded as 10.8
mmol for the sake of convenience) was recrystallized with a mixed solvent of 6.2 ml
(1.5 vol) of ethyl acetate, 6.2 ml (1.5 vol) of isopropanol and 37.4 ml (9 vol) of n-
heptane. The thus-formed crystal was filtered out, washed with 8.3 ml of ice-cooled
methanol and vacuum dried. There was thus obtained 3.63 g (9.7 mmol) of the
(2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the above formula as a white

crystalline product. The yield of the'crystalline product was 89.8%. The gas
chromatographic purity of the crystalline product was 99.1 %.
[0051.] [Example 5]
In a 100-ml eggplant-shaped flask, 1.01 g of a mixture of lactone
precursor diastereomers of the following formulas [20] to [23] (diastereomer [20]:
1.08 mmol, diastereomer [21]: 0.77 mmol, diastereomers [22]+[23]: 0.54 mmol,
each quantified by l9F-NMR internal standard method), 1.2 ml (0.5 L/mol) of
methanol and 1.2 ml (0.9 mmol, 036 eq) of 12N hydrochloric acid were placed.
The resulting solution was stirred at room temperature for 18 hours.

The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 10 ml of
toluene under a reduced pressure, and then, vacuum dried. By this, 0.52 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
and [11] was obtained.


The l9F-NMR data of the crude product mixture were the same as those
in Example 1.
Subsequently, 0.52 g of the mixture of the dihydroxylactone
diastereomers was recrystallized with a mixed solvent of 0.8 ml (1.5 vol) of
isopropanol, 2.6 ml (5 vol) of toluene and 0.5 ml (1 vol) of n-heptane. The thus-
formed crystal was filtered out, washed with 3.0 ml of ice-cooled n-heptane and
vacuum dried. By this, 0.14 g (0.84 mmol) of a light brown crystalline product of
the (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the above formula [4] was
obtained. The yield of the crystalline product was 77.55%. The gas
chromatographic purity of the crystalline product was 87.6%. As a main impurity in
the crystalline product, the diastereomer of the above formula [5] was present in an
amount of 5.3%. Then, 2.31 g of the crystalline product was again recrystallized
with a mixed solvent of 3.5 ml (1.5 vol) of isopropanol, 11.6 ml (5 vol) of toluene
and 2.3 ml (1 vol) of n-heptane. The thus-formed crystal was filtered out, washed
with 2.3 ml of ice-cooled toluene and vacuum dried. By this, 1.78 g (10.8 mmol) of
the light brown crystalline product of the (2R)-2-fluoro-2-C-methyl-D-ribono-y-
lactone of the above formula [4] was recovered. The recovery rate of the crystalline
product was 72%. The gas chromatographic purity of the crystalline product was
99.7%. The amount of the diastereomer of the above formula [5] as the main
impurity was 0.3%.

[0052.] [Example 6]
In a 100-ml eggplant-shaped flask, 13.8 g of a mixture of lactone
precursor diastereomers of the following formulas [24] to [27] (diastereomer [24]:
13.9 mmol, diastereomer [25]: 11.0 mmol, diastereomers [26]+[27]: 6.2 mmol, each
quantified by l9F-NMR internal standard method), 15.6 ml (0.5 L/mol) of methanol
and 0.96 ml (11.5 mmol, 0.37 eq) of 12N hydrochloric acid were placed. The
resulting solution was stirred at room temperature for 18 hours.

The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 15 ml of
toluene under a reduced pressure, and then, vacuum dried. By this, 8.72 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
and [11] was obtained.



The 19F-NMR data of the crude product mixture were the same as those
in Example 1.
Subsequently, 6.84 g of the mixture of the dihydroxylactone
diastereomers was recrystallized with a mixed solvent of 10.3 ml (1.5 vol) of
isopropanol, 34.2 ml (5 vol) of toluene and 6.8 ml (1 vol) of n-heptane. The thus-
formed crystal was filtered out, washed with 6.8 ml of ice-cooled n-heptane and
vacuum dried. By this, 1.80 g (11.0 mmol) of a light brown crystalline product of
the (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the above formula [4] was
obtained. The yield of the crystalline product was 78.8%. The gas chromatographic
purity of the crystalline product was 81.8%. As a main impurity in the crystalline
product, the diastereomer of the above formula [5] was present in an amount of
8.0%. Then, 2.31 g of the crystalline product was again recrystallized with a mixed
solvent of 3.5 ml (1.5 vol) of isopropanol, 11.6 ml (5 vol) of toluene and 2.3 ml (1
vol) of n-heptane. The thus-formed crystal was filtered out, washed with 2.3 ml of
ice-cooled toluene and vacuum dried. By this, 1.78 g (10.8 mmol) of the light
brown crystalline product of the (2R)-2-fluoro-2-C-methyl-D-ribono-Y-lactone of the
above formula [4] was recovered. The recovery rate of the crystalline product was
72%. The gas chromatographic purity of the crystalline product was 99.1%. The
amount of the diastereomer of the above formula [5] as the main impurity was 0.3%.
[0053.] [Comparative Example 1]
In a 100-ml eggplant-shaped flask, 79.03 g of a mixture of lactone
precursor diastereomers of the following formulas [6] to [9] (diastereomer [6]: 73.6
mmol, diastereomer [7]: 62.1 mmol, diastereomers [8]+[9]: 30.4 mmol, each
quantified by l9F-NMR internal standard method), 83 ml (0.5 L/mol) of methanol
and 5.1 ml (61.4 mmol, 0.37 eq) of 12N hydrochloric acid were placed. The
resulting solution was stirred at room temperature for 18 hours.


The thus-obtained reaction completed solution was concentrated under a
reduced pressure, concentrated five times by azeotropic distillation with 55 ml of
toluene under a reduced pressure, and then, vacuum dried. By this, 70.27 g of a
mixture of dihydroxylactone diastereomers of the following formulas [4], [5], [10]
and [ 11 ] was obtained.

The ' F-NMR data of the crude product mixture were the same as those
in Example 1.

To 70.27 g (regarded as 166.1 mmol for the sake of convenience) of the
mixture of the dihydroxylactone diastereomers, 166.1 ml (1 L/mol) of acetonitrile
and 30.29 g (382.9 mmol, 2.31 eq) of pyridine were added. Further, 51.60 g (367.1
mmol, 2.21 eq) of benzoyl chloride was added under ice cooling. The resulting
solution was stirred at room temperature for 2 hours. To the thus-obtained reaction
completed solution, 150 ml of water was added under ice cooling. After that, the
reaction completed solution was stirred at room temperature for 10 minutes and
extracted with 300 ml of ethyl acetate. The recovered organic layer was washed
with 150 ml of 5% aqueous sodium hydrogencarbonate solution, washed with 150
ml of 5% aqueous sodium chloride solution, concentrated under a reduced pressure,
and then, vacuum dried. As a result, 131.74 g of a diastereomer mixture of (2R)-2-
fluoro-2-C-methyl-D-ribono-y-lactones of the following formulas [1] and [28] to
[31] was obtained (diastereomer [1]: 75.7 mmol, diastereomer [20]: 69.8 mmol,
diastereomers [21]+[22]: 24.2 mmol, each quantified by l9F-NMR internal standard
method).

Subsequently, the above-obtained mixture was recrystallized with a
mixed solvent of 197 ml (1.5 vol) o.f ethyl acetate, 197 ml (1.5 vol) of isopropanol
and 1180 ml (9 vol) of n-heptane. The thus-formed crystal was filtered out, washed
with 132 ml of ice-cooled methanol and vacuum dried. By this, 40.36 g of a white

crystalline product was obtained. It was confirmed by gas chromatographic analysis
that the crystalline product contained 61% of the diastereomer [1] and 33% of the
diastereomer [20]. The whole of 40.36 g of the crystalline product was again
recrystallized with 60 ml (1.5 vol) of ethyl acetate, 60 ml (1.5 vol) of isopropanol
and 364 ml (9 vol) of n-heptane. The thus-formed crystal was filtered out, washed
with 81 ml of ice-cooled methanol and vacuum dried. By this, 33.25 g of the white
crystalline product was recovered. It was confirmed by gas chromatographic
analysis that the crystalline product contained 67% of the diastereomer [1] and 33%
of the diastereomer [20].
[0054.] Although the present invention has been described above with reference
to the specific exemplary embodiments, the present invention is not limited to the
above-described exemplary embodiments. Various modifications and variations of
the embodiments described above will occur within the scope of the present
invention based on the common knowledge of those skilled in the art:
Industrial Applicability
[0055.] The target compound of the present invention, (2R)-2-fluoro-2-C-
methyl-D-ribono-y-lactone, is useful as an important intermediate for production of
antivirally active 2'-deoxy-2'-fluoro-2'-C-metylcytidine.
WE CLAIM:
1. A production method of a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone of the
general formula [1], comprising:.
subjecting a mixture of diastereomers of a lactone precursor of the
general formula [2] to deprotection followed by lactonization under acidic
conditions, thereby forming a mixture of diastereomers of a dihydroxylactone of the
general formula [3];
separating and purifying a (2R)-2-fluoro-2-C-methyl-D-ribono-y-lactone
of the general formula [4] by recrystallization of the mixture of diastereomers of the
dihydroxylactone; and
acylating the (2R)-2-f]uoro-2-C-methyl-D-ribono-y-lactone,

where R2 represents an acyl group

where R represents an alkyl group or a substituted alkyl group; A represents an
oxygen atom, a nitrogen atom or a sulfur atom; P1 and P2 each independently
represent a hydroxyl protecting group; and * represents an asymmetric carbon

where * represents an asymmetric carbon


2. The production method as claimed in claim 1, wherein the mixture of
diastereomers of the dihydroxylactone is recrystallized with the use of at least one
kind of solvent selected from the group consisting of alcohol solvents, aromatic
hydrocarbon solvents, ester solvents, nitrile solvents, ether solvents, halogenated
hydrocarbon solvents, ketone solvents, water and aliphatic hydrocarbon solvents.
3. The production method as claimed in claim 1 or 2, wherein the mixture of
diastereomers of the dihydroxylactone is recrystallized with the use of isopropanol,
toluene, ethyl acetate or n-heptane.
4. The production method as claimed in claim 1, wherein R in the general
formula [1] represents a substituted or unsubstituted straight or branched alkyl group
of 1 to 6 carbon atoms.
5. The production method as claimed in claim 1, wherein P1 and P2 in the general
formula [1] represent an isopropylidene group or a cyclohexylidene group.
6. The production method as claimed in claim 1, wherein the mixture of
diastereomers of the lactone precursor is subjected to deprotection followed by
lactonization under the acidic conditions with the use of acetic acid, sulfuric acid,
hydrochloric acid, methanesulfonic acid, paratoluenesulfonic acid or trifluoroacetic
acid.
7. The production method as claimed in claim 1, wherein R in the general
formula [1 ] represents a benzoyl group, a formyl group or an acetyl group.