JPH08259552A - Production of optically active phenyl glycidate - Google Patents

Abstract

PURPOSE: To obtain an optically active phenyl glycidate which is useful as a synthetic intermediate for medicinal compounds by carrying out physically or chemically the optical resolution of a racemic mixture of a trans-phenyl glycidate. CONSTITUTION: A racemic mixture of trans-3-phenyl glycidate of the formula (ring A is benzene ring; R is the residual group of ester) is allowed to react with (A) an alcohol of the formula: R<1> OH (R<1> is an ester residue differing from R) in the presence of (B) an enzyme capable of performing transesterification stereo-selectively to esterify only one optical isomer selectively to collect either the one optically active transesterified isomer or the other not-transesterified isomer. Then, the remaining other optically active isomer is allowed to react with (C) another alcohol of the formula: R<2> OH (R<2> is an ester residue differing from the other ester) to effect the transesterification and the chemical isolation, thereby the D- and L-isomers are separately obtained from a racemate.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides a process for producing optical isomers of trans-3-phenylglycidic acid ester compounds useful as synthetic intermediates for pharmaceutical compounds.

[0002]

2. Description of the Related Art The (2R, 3S) -isomer of trans-3-phenylglycidic acid ester compounds contains diltiazem hydrochloride which is useful as a therapeutic agent for angina and the like (2S,
3S) -1,5-benzothiazepine derivatives are useful compounds as synthetic intermediates, while (2S, 3R) -trans-3-phenylglycidate compounds are useful as platelet aggregation inhibitors and the like. Na (2R, 3R)-
It is a compound useful as a synthetic intermediate for 1,5-benzothiazepine derivatives [Japanese Patent Publication No. 47-813, JP-A-59].
-225174, JP-A-60-202871, JP-A-60-13776, JP-A-61-145174,
JP-A-3-272691].

Trans-3- (4-methoxyphenyl)
From the racemic form of glycidic acid methyl ester to (2
A method for obtaining an undegraded (2R, 3S) -isomer by hydrolyzing the (S, 3R) -isomer stereoselectively with an enzyme is known [JP-A-2-109995, JP-A-3-1539].
No. 8, Tokushuhei 4-501360], Transformer-3-
There is also known a method of obtaining an undegraded (2S, 3R) -isomer by enzymatically hydrolyzing the (2R, 3S) -isomer from a racemic form of (4-methylphenyl) glycidic acid methyl ester with an enzyme. [JP-A-3-175995
issue〕.

Recently, the racemic form of trans-3- (4-methoxyphenyl) glycidic acid methyl ester was transesterified with a (2S, 3R) -isomer to give an unconverted (2R, 3R) -isomer. Methods for obtaining the (3S) -isomer have also been published [JP-A-4-228095, JP-A-5-76389, JP-A-6-78790].

However, in the method of enzymatically hydrolyzing a racemate to obtain an undegraded optical isomer, the hydrolyzed (2S, 3R) -3- (4-methoxyphenyl) glycidic acid is decarboxylated. , It is known to be easily converted into phenylacetaldehyde [Tokuhyo Hei 4-50136
No. 0], (2R, 3S) -isomer and (2S, 3R)-
It is virtually impossible to obtain both isomers in good yield.

Also in the case of a method of enzymatically transesterifying a racemate to obtain an unconverted (2R, 3S) -isomer, the transesterified (2S, 3R) -isomer has low crystallinity. They are n-propyl ester, n-butyl ester and the like, and a method for isolating and purifying them is not disclosed.

Further, in the case of the conventional chemical transesterification method using an acid or base catalyst, it is considered to be difficult to apply because the oxirane ring of glycidic acid is cleaved with an acid and the glycidic acid forms a salt with a base. In addition, an ester exchange method using an organic amine such as dimethylaminopyridine as a basic catalyst has been reported [Terahedron Letters (Terahedron lett).
ers, 28, 2713 (1987)], no examples of application to a compound having an oxirane ring have been reported.

[0008]

SUMMARY OF THE INVENTION The present invention is a transformer.
It is intended to provide a method for producing both a (2R, 3S) -isomer and a (2S, 3R) -isomer from a racemate of a 3-phenylglycidate compound in good yield.
Further, the present invention provides a method for efficiently and chemically transesterifying an unstable 3-phenylglycidate compound having an oxirane ring which is susceptible to cleavage.

[0009]

According to the present invention, the general formula [II]

[0010]

Embedded image

(However, ring A represents a substituted or unsubstituted benzene ring and R represents an ester residue.) A racemic trans-3-phenylglycidic acid ester compound represented by In the presence of an enzyme capable of transesterification, the compound of the general formula [III]

[0012]

[Chemical 19]

(Wherein R ¹ represents an ester residue different from R) to selectively transesterify only one optical isomer, and the transesterified optical isomer or ester One of the unexchanged optical isomers is separated and obtained, and the other optical isomer is obtained in the presence of the organic amine in the formula [IV]

[0014]

Embedded image

(Wherein R ² represents an ester residue different from the ester residue of the other optical isomer), and chemically transesterified to isolate it to give trans-. The 3-phenylglycidic acid ester compound is converted into (2R, 3S) -isomer and (2S, 3
The R) -isomer can be separated.

In this method, the substituted benzene ring of the racemic compound [II] of the trans-3-phenylglycidate compound is a lower alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.). And those substituted with a lower alkoxy group (for example, a methoxy group, an ethoxy group, a propyloxy group, a butoxy group, etc.) and the like, and among others, those having a substituent at the 4-position of the benzene ring are preferable. As the ester residue (R), a methyl group, an ethyl group, an n-propyl group, a 2-propyl group,
Examples thereof include n-butyl group, 2-butyl group, 2-methyl-1-propyl group, lower alkyl group of t-butyl group, phenyl group, and the like, and the racemic compound in which the ester residue is a methyl group [II]. Is a crystal in various organic solvents [aromatic organic solvents (eg, benzene, toluene, xylene), lower alkanols (eg, ethanol, 2-propanol), aliphatic organic solvents (eg, hexane, heptane, cyclohexane)] Since it has good properties, it is convenient for separation and acquisition of optical isomers by fractional crystallization after transesterification in the presence of an enzyme.

Trans-3- (4-methoxyphenyl)
The reaction between the racemate [II] of the glycidic acid ester compound and the alcohol [III] is carried out in the presence of an enzyme capable of transesterifying in a stereoselective manner. Such an enzyme is trans-3- (4- (2R, 3S) -isomer of methoxyphenyl) glycidic acid ester compound,
Any of the (2S, 3R) -isomers may be selectively transesterified.

Examples of the enzyme for selectively transesterifying the (2S, 3R) -isomer of trans-3-phenylglycidic acid ester compound include, for example, Serratia (Ser).
genus ratia, genus Candida, genus Mucor, Pseudomonas (Pseudo)
genus monas, Aspergill
Us) genus, Alcaligenes
Genus, Absidia, Fusarium, Giberella
a) genus, Neurospora genus, Trichoderma genus, Rhizopus genus, Achromobacter (Achr)
genus Omobacterium, Bacillus
s) genus, Brevibacterium
ium, Corynebac (Corynebac)
terium, Providencia (Providen)
genus Cia, Saccharomyces
genus mycopsis, Nocardi
a) Esterase derived from a genus microorganism, α-chymotrypsin, pig liver esterase, pig pancreatic esterase, etc. can be used.
O 4009, IFO 4010, Aspergillus
Ocraceus (Aspergillus ochrac)
eus) IFO 4346, Aspergillus terreus IFO
6123, Fusarium oxysporum (Fusari)
um oxysporum) IFO 5942, AT
CC 659, Fusarium Fusarium
solani) IFO 5232, Gibberella fujikuroi I
FO 5368, Mucor anglimacrosporus
IAM 6149, Mucor Sir Cineroides (Muc
or circinelloides) IFO 674
6. Mucor flavus
IAM 6143, Mucor Fragilis (Mucor
fragilis) IFO 6449, Mucor genevensis I
AM 6091, Mucor Globosus (Mucor
Globosus IFO 6745, Mucor janssenii IFO 5
398, Mucor javis
anicus) IFO 4569, IFO 457
0, IFO 4572, IFO 5382, Mucor ramprospo
rus) IFO 6337, Mucor petrinsularis IFO
6751, Mucor Prunbeusu (Mucor p
lumbeus IAM 6117, Mucor prini IAM 6120, Mucor pusillus IA
M 6122, Mukoru Racemosus (Mucor r
acemosus) IFO 4581, Mucor ramanianus IA
M6128, Mucor recal bath (Mucor re
curvus) IAM6129, Mucor silvaticus IFO 6
753, Mucor spinescence (Mucor sp
inescens) IAM 6071, Mucor subtilissimu
s) IFO 6338, Neurospora Classa (Ne
urospora crassa) IFO 6068,
Rhizopus arrhiz
us) IFO 5780, Rhizopus delemar (Rhi
zopus delemar) ATCC 34612,
Rhizopus japoñas (Rhizopus japo
nice) IFO 4758, Trichoderma viride IFO 4
847, Achromobacter Cyclocrustes (Ac
homobacterium cyclolastes)
IAM 1013, Bacillus sphaericus (Baci
Illus sphaericus) IFO 3525,
Brevibacterium ketoglutamicum (Brevib
bacterium ketoglutamicum) A
TCC15588, Corynebacterium alkanicum
oliticum) ATCC 21511, Corynebacterium hydrocarbocluster (Coryneb)
acterium hydrocarboclastu
m) ATCC 15592, Corynebacterium plymorioxidans (Corynebacterium p
rimorioxydans) ATCC 31015,
Providencier Alkaline Faciens (Provide
encia alcalifaciens) JCM 1
673, Pseudomonas mutabilis
onas mutabilis) ATCC 3101
4. Pseudomonas
putida) ATCC 17426 and ATCC1
7453, ATCC 33015, Serratia liquefaciens
ens) ATCC 27592, Serratia marcescens AT
CC 13880, ATCC 14764, ATC
C 19180, ATCC 21074, ATCC
27117, ATCC 21212, Serratia
Marcessens (Serratia marcesce)
ns) Sr41 (FERM BP-487), Candida parapsilosis (Candida parapsil)
sis) IFO 0585, Saccharomycopsis
Lipolitica (Saccharomycopsis l
ipolytica) IFO 0717, IFO 0
746, IFO 1195, IFO 1209, IFO 1548, Nocardia Asteroides (N
ocardia asteroides) IFO 33
84, the same IFO 3424, the same IFO 3423, and Nocardia Gardneri.
ri) Esterase derived from ATCC 9604 and the like can be mentioned.

Also, alkaline lipase [derived from Achromobacter, manufactured by Wako Pure Chemical Industries, Ltd.], lipase B [Pseudomonas fragii 22-39B]
Origin, manufactured by Wako Pure Chemical Industries, Ltd.], Lipase M "Amano" 10 [Mucor Jabanikasu (Mucor ja
vanicus), manufactured by Amano Pharmaceutical Co., Ltd.], lipase type XI [Rhizopus alizas (Rhizopu
s arrhizus), manufactured by Sigma], talipase [Rhizopus delemer (Rhizopus delemer
derived from Tanabe Seiyaku Co., Ltd.], lipase NK-
116 [Rhizopus
derived from Japonicus, manufactured by Nagase & Co., Ltd.], Lipase N (Rhizopus n
iveus) origin, manufactured by Amano Pharmaceutical Co., Ltd.), lipase
Type VII [Candida Cylindracia (Candi
dacylindracea), manufactured by Sigma], lipase (derived from pig pancreas, manufactured by Wako Pure Chemical Industries, Ltd.), esterase (derived from pig liver, manufactured by Sigma), cholesterol esterase [Candida gossa (Candida).
rugasa), manufactured by Nagase & Co., Ltd.), lipase OF [Candida cylindracea (Candida)
derived from Cylindracea, manufactured by Meito Sangyo Co., Ltd.], Lipase QL [Alkaline Genes SP (Al
kaligenes sp. ) Origin, manufactured by Meito Sangyo Co., Ltd.], lipase AL [Achromobacter sp.
chromobacter sp. ) Origin, manufactured by Meito Sangyo Co., Ltd., and lipase PL [derived from Alcaligenes sp., Manufactured by Meito Sangyo Co., Ltd.].

Among these enzymes, Serratia marcescens and Candida cylindracea (Candia cylind)
It is preferred to use an esterase derived from racea) microorganism.

On the other hand, examples of the enzyme for selectively transesterifying the (2R, 3S) -isomer of trans-3-phenylglycidic acid ester compounds include, for example, the genus Micrococcus, Agrobacterium. ) Genus, Microbacterium genus, Rhizobium genus, Citrobacter (Cit)
rober), Debaryomyces (Debary)
omyces), Hansenia spora (Hanseni)
Aspora genus, Hansenula
Genus, Pichia genus, Rhodosporidium genus, Schizosaccharomyces genus,
Sporoboromyces
Esterase derived from a genus, Kloeckera genus, Torula spora genus, Streptomyces genus microorganism and the like can be used.

Specific examples of such microbial enzymes include Micrococcus uree.
ae) IAM 1010 (FERM BP-299
6), Agrobacterium radiobactor (Agro
Bacterium Radiobacterium) IAM
1526, the same IFO 13259, Microbacterium sp.
p. ) ATCC 21376, Rhizobium meliotti IFO 13
336, Citrobaca Frondy
cter freundii) ATCC 8090, Debaryomyces Hansenny Barb Fabry (Deba)
ryomyces hansenii var. fa
bryi) IFO 0015, Debaryomyces nepalensis
is) IFO 0039, Hansenia spora valbyen
s) IFO 0115, Hansenula Polymofa (H
ansenula polymorpha) IFO 1
024, Hansenula
saturnus) HUT 7087, Pichia farinosa IFO
0607, Pichia pastoris (Pichia pas
toris) IFO 0948, IFO 1013, IAM 12267, Pichia Whiker Hammy (Pic
hia wicker hamii) IFO 1278,
Rhodosporium toruroides
ridium toruloides) IFO 055
9. Schizosacromyces pombe (Schizosac
charomyces pombe) IFO 035
8. Sporobolomyces gracilis (Sporobol
omyces gracilis) IFO 103
3. Kloeckera
cortisis IFO 0633, Torula spora del bruky
eckii) IFO 0422, Streptomyces griseus Subsp Griseus (Streptomy)
ces griseus subsp. griseu
s) IFO 3430, IFO 3355, Streptomyces lavenduler (Streptomyces lavendulae)
subsp. lavendulae) IFO 336
1, the same IFO 3415, the same IFO 3146-derived esterase and the like.

The enzyme may be a commercially available enzyme or may be one obtained from a culture solution of microbial cells. Also,
The enzyme may be obtained from a wild strain or mutant strain of a microorganism, or may be a bacterium induced by a bioengineering method such as gene recombination or cell fusion.

Although these enzymes can be used as they are, known methods such as polyacrylamide method, sulfur-containing polysaccharide gel method (for example, carrageenan gel method), agar gel method, photocrosslinkable resin method, polyethylene glycol method, celite method, etc. It can also be used after being immobilized by the method.

Specific examples of the alcohol [III] include:
Chain alkanol (for example, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, n-pentanol, 3-pentanol, n-hexanol, n-heptanol, 2-heptanol, n-octanol, 2-octanol), cyclic alkanols (eg cyclohexanol, cyclopentanol), substituted chain alkanols (eg 2,2-dimethyl-1,3-dioxolane-4) -Methanol, 4-carboxy-n-butanol) and the like can be appropriately selected and used.

The reaction can be carried out in a suitable solvent or in the absence of a solvent. Examples of the solvent include aromatic organic solvents (eg, benzene, toluene, xylene), halogenated aromatic organic solvents (eg, chlorobenzene, diene). Chlorobenzene), aliphatic organic solvents (eg hexane, heptane,
Cyclohexane), halogenated aliphatic organic solvent (eg dichloromethane, chloroform, carbon tetrachloride, trichloroethane), ketone solvent (eg acetone, methyl ethyl ketone, methyl isobutyl ketone), ether solvent (eg dimethyl ether, diethyl ether, diisopropyl) Examples thereof include ether, tert.-butyl methyl ether, tetrahydrofuran, 1,4-dioxane) and ester solvents (eg, ethyl acetate, butyl acetate), among others, and especially benzene, xylene, hexane, carbon tetrachloride, trichloroethane. It is preferable to use diisopropyl ether.

The concentration of the racemic compound [II] as a substrate is generally 0.02-2 mol / liter, especially 0.02-.
It is preferably 2 mol / liter, and alcohol [I
The concentration of II] is preferably 0.01-16 mol / liter, and more preferably 0.1-8 mol / liter. The molar ratio of compound [II] and alcohol [III] is 1:
It is preferably 0.5-1: 8, especially 1: 1-1: 4.

The amount of the enzyme used varies depending on the kind of the enzyme used, the form of use, etc., but is usually a racemic compound [II] 1 of trans-3-phenylglycidic acid ester compound.
It is preferable to use an enzyme having an olive oil-degrading activity of 1.0 × 10 ^{4 to} 1.0 × 10 ⁷ units per gram, and especially 2.0 × per 1 g of racemate [II].
It is preferred to use an enzyme having an olive oil-degrading activity of 10 ⁵ -1.0 × 10 ⁶ units. The reaction suitably proceeds at room temperature or under heating, preferably 20-60 ° C, particularly preferably 30-40 ° C.

The separation and acquisition of one optical isomer from the mixture of two optical isomers after transesterification can be carried out by utilizing the difference in the physicochemical properties of both optical isomers based on the difference in the ester residue. For example, a known method such as a fractional crystallization method using a difference in solubility, a chromatography method, or a distillation method can be appropriately used. In general, an ester having an ester residue having a small number of carbon atoms has lower solubility in an organic solvent than an ester having an ester residue having a long carbon number, and for example, a methyl ester is used as a racemate [II] and an alcohol [III] is used. ], One of the optical isomers is selectively transesterified using n-butyl alcohol, or n-butyl ester is used as the racemate [II] and methanol is used as the alcohol [III]. When the optical isomers are selectively transesterified, the methyl ester optical isomers are n-
Aromatic organic solvent (eg, benzene, toluene, xylene), lower alkanol (eg, ethanol, 2-propanol) rather than optical isomer which is butyl ester,
Since it has low solubility in aliphatic organic solvents (eg, hexane, heptane, cyclohexane) and the like, it can be obtained in a pure form by a preferential crystallization method in these solvents. At this time, racemate [II] and alcohol [III]
It is also possible to separate the two optical isomers by fractional crystallization using the solvent used for the reaction with.

In this way, of the two resolved optical isomers, the optical isomers which were not separated and obtained were treated with an alcohol [I] in the presence of an organic amine in a suitable solvent or without a solvent.
V] to be chemically transesterified and isolated.

As the alcohol [IV], an alcohol having an ester residue different from the ester residue of the optical isomer which has not been separated and obtained can be used, and a chain alkanol (for example, ethanol, n-propanol,
2-propanol, n-butanol, 2-butanol,
2-methyl-1-propanol, t-butanol, n-
Pentanol, 3-pentanol, n-hexanol,
n-heptanol, 2-heptanol, n-octanol, 2-octanol), cyclic alkanol (for example,
Cyclohexanol, cyclopentanol), substituted chain alkanol (eg, 2,2-dimethyl-1,3-dioxolane-4-methanol, 4-carboxy-n-butanol) and the like are used by appropriately selecting them. You can

Examples of organic amines include monoalkylamines (eg, methylamine, ethylamine, propylamine, butylamine), dialkylamines (eg, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dicyclohexylamine), trialkylamines. Amines (eg trimethylamine, triethylamine), cyclic amines (eg morpholine), aromatic amines (eg pyridine) and the like can be used, but especially dialkyls such as diethylamine, dipropylamine, diisopropylamine, dicyclohexylamine and the like. Preference is given to using amines.

As the solvent, any of the solvents used for the reaction between the racemate [II] and the alcohol [III] can be used, and when the two optical isomers are separated by fractional crystallization, The mother liquor obtained during the separation can also be used as it is.

The concentration of the optical isomer to be chemically transesterified is preferably 0.01-3 mol / liter, and more preferably 0.1-2 mol / liter, and the concentration of the alcohol [IV] is It is preferably 0.01 to 30 mol / liter, and more preferably 1 to 20 mol / liter. The molar ratio of the optical isomer to the alcohol [IV] is 1:
It is preferably 1-1: 1000, especially 1: 2-1: 10. The organic amine is used in a molar ratio of 1: 10000-1: 1, particularly 1: 100-1: to the optical isomer.
It is preferable to use it so as to be 10. The reaction suitably proceeds at room temperature or under heating, preferably 0-80 ° C, particularly preferably 30-40 ° C.

The chemically transesterified compound can be isolated from the solution after the reaction by utilizing known methods such as a fractional crystallization method using a difference in solubility, a chromatography method and a distillation method. When chemically transesterified with methanol, the produced methyl ester is various organic solvents [aromatic organic solvents (eg, benzene, toluene, xylene), lower alkanols (eg, ethanol, 2-propanol), aliphatic Since the crystallinity in an organic solvent (eg, hexane, heptane, cyclohexane) is good, a pure product can be easily isolated by preferential crystallization.

The chemical transesterification method carried out in the presence of an organic amine can be applied not only to the optically active compound but also to the racemic compound.

The (2R, 3S) -isomer of the trans-3-phenylglycidic acid ester compound thus obtained can be converted into a (2S, 3S) -1,5-benzothiazepine derivative by a known method. You can For example,
The (2R, 3S) -isomer is reacted with an aminothiophenol derivative [V] or a nitrothiophenol derivative [VI] according to the following formula, and then the nitro group is reduced to give (2S, 3S). -3- (2-aminophenylthio)
-3-Phenyl-2-hydroxypropionic acid ester compound [VII] was produced, hydrolyzed if necessary, and then intramolecularly ring-closed to (2S, 3S) -2-phenyl-
A 3-hydroxy-1,5-benzothiazepine derivative [X] was prepared, and this compound was treated with dimethylaminoethyl at the 5-position nitrogen atom and acetylated at the 3-position-substituted hydroxy group to give hydrochloric acid. (2S, 3S) -1,5-benzothiazepine derivative [X such as diltiazem [X
I].

[0038]

[Chemical 21]

(However, R ³ represents an ester residue, and the ring B
Represents a substituted or unsubstituted benzene ring, and ring A has the same meaning as described above. On the other hand, the (2S, 3R) -isomer of trans-3-phenylglycidic acid ester compound is obtained by a known method.
It can be induced to a (2R, 3R) -1,5-benzothiazepine derivative. For example, the (2S, 3R) -isomer is reacted with an aminothiophenol derivative [V] or a nitrothiophenol derivative [V] according to the following formula.
I], the nitro group of the product is reduced to (2R,
3R) -3- (2-aminophenylthio) -3-phenyl-2-hydroxypropionic acid ester compound [X
II] is produced, and if necessary, hydrolyzed, and then intramolecularly ring-closed to give a (2R, 3R) -2-phenyl-3-hydroxy-1,5-benzothiazepine derivative [XV]. , Dimethylaminoethylation of the 5-position nitrogen atom and acetylation of the 3-substituted hydroxy group in any order can lead to a (2R, 3R) -1,5-benzothiazepine derivative [XVI]. it can.

[0040]

[Chemical formula 22]

(However, R ³ represents an ester residue, and ring A
And ring B has the same meaning as above. ) In the present specification, a lower alkyl group, a lower alkoxy group and a lower alkanol respectively have 1-carbon atoms.
It means an alkyl group having 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and an alkanol having 1 to 6 carbon atoms.

Example 1 208 g (1 mole) of racemic-trans-3- (4-methoxyphenyl) glycidic acid methyl ester was dissolved in a mixed solution of 1000 ml of xylene and 300 ml of n-butanol, and then Serratia marcescens (Serrati).
a marcescens) Sr41 (FERM BP
-487) -derived esterase (2.5 g of olive oil-decomposing activity 5 × 10 ⁵ units) was suspended, and the suspension was dried at 30 ° C. for 2 hours.
Stir for 4 hours. In order to remove by-produced methanol, 1/3 of the reaction solution was distilled off under reduced pressure, 2.5 g of esterase was added to the concentrated solution, and the reaction was continued for 16 hours.

The reaction solution was subjected to high performance liquid chromatography (H
PLC) [Filler: Chiralcel OD, 4.6 mm × 25
0 mm, manufactured by Daicel Chemical Industries, Ltd.], the result was (2R, 3S) :( 2S, 3R) = 90: 10, 3
108 g of-(4-methoxyphenyl) glycidic acid methyl ester, and (2R, 3S) :( 2S, 3R) =
It was found to consist of 105 g of 3- (4-methoxyphenyl) glycidic acid butyl ester 3:97.

After removing the enzyme from the reaction solution by filtration, the solvent is distilled off under reduced pressure. 200 ml of 2-propanol is added to the concentrated residue, cooled to 5 ° C, and stirred for 1 hour. The precipitated crystals are separated by filtration and washed with 50 ml of 2-propanol cooled to 5 ° C to obtain 80 g of (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester.
The mother liquor and the washing liquid are combined and subjected to HPLC [filler: chiralcel O
D, 4.6 mm x 250 mm, manufactured by Daicel Chemical Industries, Ltd.], (2R, 3S): (2S, 3
R) = 56:44 3- (4-methoxyphenyl) glycidic acid methyl ester 30 g, and (2R, 3S):
It was found to consist of 105 g of 3- (4-methoxyphenyl) glycidic acid butyl ester with (2S, 3R) = 3: 97.

The solvent was distilled off under reduced pressure from the above mother washing solution, and 500 ml of methanol and diisopropylamine 1 were added to the concentrated residue.
0 ml was added, and the mixture was reacted at 30 ° C for 4 hours. At this time,
The reaction solution was subjected to HPLC [filler: chiralcel OD, 4.6 m
m × 250 mm, manufactured by Daicel Chemical Industries, Ltd.], as a result, (2R, 3S) :( 2S, 3R) = 16: 8
83 g of 3- (4-methoxyphenyl) glycidic acid methyl ester of 4 and (2R, 3S) :( 2S, 3R)
= 3: 97 of 3- (4-methoxyphenyl) glycidic acid butyl ester.

About 10 mg of (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester was added to the reaction solution.
Is inoculated, stirred for 1 hour, cooled to 5 ° C., and further stirred for 1 hour for crystallization. The precipitated crystals were separated by filtration and washed with 50 ml of methanol cooled to 5 ° C to obtain (2S, 3R) -3.
78 g of-(4-methoxyphenyl) glycidic acid methyl ester are obtained.

(2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester :.

Melting point: 86-87 ° C.

[Α] _D ²⁰ : -20 8 ° (C = 1,
methanol).

Optical purity: 99% or more (HPL
C).

(2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester :.

Melting point: 85-86 ° C.

[Α] _D ²⁰ : 20 5 ° (C = 1,
methanol).

Optical purity: 99% or more (HPL
C).

Example 2 Serratia mar
cesces) Sr41 (FERM BP-487)
The results shown in Table 1 are obtained by reacting in the same manner as in Example 1 with various hydrolases in place of the derived esterase.

[0056]

[Table 1]

Example 3 The same procedure as in Example 1 was carried out to obtain (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester from the reaction solution after the enzymatic transesterification reaction. (2R, 3S) :( 2S, 3R) = 3: 97 3-
To a concentrated solution of the mother washing liquid containing 105 g of (4-methoxyphenyl) glycidic acid butyl ester, 5 times v / w amount of methanol and 1/10 v / w times amount of various organic amines were added, and 3- ( The results in Table 2 are obtained by subjecting 3- (4-methoxyphenyl) glycidic acid methyl ester to 4- (methoxyphenyl) glycidic acid butyl ester by chemical transesterification for 4 hours in the same manner as in Example 1.

[0058]

[Table 2]

Reference Example 1 Dextrin 1%, ammonium sulfate 0.2%, Mist S (Asahi Breweries, Ltd.) 2%, potassium monophosphate 0.2%, magnesium sulfate 0.05%, ferrous sulfate 0. 001%, Span85 (manufactured by Kao Corporation) 1.5
% W / v and polyalkylene glycol derivative-based surfactant (Kararin 102, manufactured by Sanyo Chemical Industries, Ltd.)
18 liters of liquid medium consisting of 0.2% v / v (pH
7.0) was sterilized by placing it in a 30 liter jar fermenter, and then preliminarily shake-cultured in the same medium at 27.5 ° C for 20 hours with reciprocal shaking, and Serratia marcescens (Serratia)
marcescens) Sr41 (FERM BP-
487) inoculated with 200 ml of pre-cultured solution, 0.33 vvm at 25 ° C, 0.5 kg / cm2 · G, 300 rp
Under the condition of m, the cells were cultured for 28 hours while continuously adding 1.5% of L-proline. 10 liters of this culture solution was centrifuged to remove bacteria, and then adsorbent resin SP207 (manufactured by Mitsubishi Kasei Co., Ltd.)
To remove impurities. The resulting supernatant is concentrated to 1 liter with an ultrafiltration membrane (SLP1053, manufactured by Asahi Kasei Kogyo Co., Ltd.), freeze-dried, and 1.96 × 10 ⁵ units / g of esterase having olive oil degrading activity. 54
g was obtained.

(Measurement Method of Olive Oil Degrading Activity) A mixed solution of 225 ml of 2% polyvinyl alcohol (trade name: Poval 117, manufactured by Kuraray Co., Ltd.) and 75 ml of pharmacopoeia olive oil was stirred at 5,500 ° C. for 10 minutes at 14,500 rpm. 5.0 ml and 0.25 of emulsified olive oil emulsion
M Tris-HCl buffer (pH 8.0) 4.0 ml (2.5
(including mM calcium chloride) at 37 ° C. for 20 minutes, and then acetone-ethanol mixed solution (1: 1) 20 m
The reaction was stopped by adding 1 and titrated with 0.05N NaOH solution using phenolphthalein as an indicator. The amount of enzyme that liberates 1 μmole of fatty acid per minute by the above method was set to 1 unit.

[0061]

According to the method of the present invention, trans-3-
Racemic phenylglycidate compounds [I
From [I], both the (2R, 3S) -form and the (2S, 3R) -form can be produced in good yield. After transesterification,
Based on the difference in ester residues, the difference in physicochemical properties is used for division.For example, in the case of division by fractional crystallization, even if the transesterification is not completed,
It is possible to obtain pure optical isomers in good yield.
The mother liquor remaining after the division can be reused as a raw material.

Furthermore, the chemical transesterification using the organic amine in the method of the present invention proceeds in good yield,
Although the phenylglycidic acid ester compound has an oxirane ring that is easily cleaved, transesterification can be performed substantially without loss of a reactant regardless of whether it is a racemate or an optical isomer.

Claims (18)

[Claims] 1. A compound represented by the general formula [II]: (However, ring A represents a substituted or unsubstituted benzene ring, and R represents an ester residue.) The trans racemic form of the trans-3-phenylglycidic acid ester compound is stereoselectively transesterified. In the presence of a competent enzyme,
General formula [III] (Provided that R ¹ represents an ester residue different from R.) to selectively transesterify only one optical isomer, and the transesterified optical isomer or transesterified One of the optical isomers is obtained by separating and obtaining the other optical isomer in the presence of an organic amine, the compound of the general formula [IV] (However, R ² represents an ester residue different from the ester residue of the other optical isomer.), And chemically transesterified to isolate the compound,
The racemic form of trans-3-phenylglycidic acid ester compound is converted into (2R, 3S) -isomer and (2S, 3
R) -a method of separating into isomers. 2. An enzyme having the ability to transesterify stereoselectively includes genus Serratia, genus Candida, genus Mucor, genus Pseudomonas, genus Aspergillus, and Alcaligenes (genus). Alcaligenes, Absidia (Abs)
genus dia, Fusarium genus, Giberella genus, Neurospora (Ne)
urospora, Trichoderma (Trichod)
erma, Rhizopus, Achromobacter, Bacillus, Brevibacterium (B)
genus revivobacterium, genus Corynebacterium, genus Providencia, genus Saccharomycopsis, esterase derived from microorganisms of the genus Nocardia, alpha-chymotrypsin, pig liver esterase. The method of claim 1, wherein: 3. An enzyme having the ability to stereoselectively transesterify is Serratia marcescens (Serrati).
a marcescens), an esterase derived from a Candida cylindracea microorganism. 4. An enzyme capable of transesterifying stereoselectively is an enzyme which selectively transesterifies a (2S, 3R) -isomer of a trans-3-phenylglycidate compound. Method 1, 2 or 3. 5. An enzyme having the ability to transesterify stereoselectively is Micrococcus.
Genus, Agrobacterium
m) genus, Microbacterium (Microbacte
genus Rium, genus Rhizobium,
Citrobacterium genus, Debaryomyces genus, Hansenia spora (Hansenia spora) genus, Hansenula (Hansenula) genus, Pichia (Pichia)
Genus Rhodosporidiu
m) genus, Schizosacch
aromyces), Sporoboromyces (Sporo)
genus bolomyces, Kloecke
Ra) genus, Torula spora
The method according to claim 1, which is an esterase derived from a microorganism belonging to the genus Streptomyces. 6. The enzyme having the ability to transesterify stereoselectively is an enzyme which selectively transesterifies the (2R, 3S) -isomer of trans-3-phenylglycidate compounds. Method 1 or 5. 7. The method according to claim 1, wherein R and R ² are lower alkyl groups. 8. A method for separating and obtaining after enzymatic transesterification and isolation after chemical transesterification by a fractional crystallization method, a chromatography method or a distillation method.
Method 5, 6 or 7. 9. An optical isomer which has not been enzymatically transesterified is reacted with an alcohol [IV].
Method 3, 4, 5, 6, 7 or 8. 10. An enzymatically transesterified optical isomer is reacted with an alcohol [IV],
4, 5, 6, 7 or 8 methods. 11. R and R ² are methyl groups, and R ¹ is n.
The method according to claim 10, which is a butyl group. 12. The organic amine is a monoalkylamine, a dialkylamine, a trialkylamine, a cyclic amine or an aromatic amine, and
Method of 8, 9, 10 or 11. 13. The method of claim 12 wherein the organic amine is a dialkylamine. 14. Claims 1, 2, 3, 4, 5, 6, 7,
Using the (2R, 3S) -isomer of the trans-3-phenylglycidic acid ester compound obtained by the method of any one of 8, 9, 10, 11, 12 or 13, the compound of the general formula [XI] (However, ring A and ring B represent a substituted or unsubstituted benzene ring.) A method for producing a (2S, 3S) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. 15. Claims 1, 2, 3, 4, 5, 6, 7,
The (2R, 3S) -isomer of the trans-3-phenylglycidic acid ester compound obtained by the method of any one of 8, 9, 10, 11, 12 and 13 is represented by the general formula [V] (However, ring B represents a substituted or unsubstituted benzene ring), or
Or the general formula [VI] (However, ring B has the same meaning as described above.) After the reaction with the nitrothiophenol derivative represented by the formula, the nitro group is reduced to give a compound of the general formula [VII] (However, ring A represents a substituted or unsubstituted benzene ring, and R ³
Represents an ester residue, and ring B has the same meaning as described above. ), A (2S, 3S) -3- (2-aminophenylthio) -3-phenyl-2-hydroxypropionic acid ester compound is produced, and if necessary, hydrolyzed and then intramolecularly ring-closed. General formula [X] (However, ring A and ring B have the same meanings as described above.) A (2S, 3S) -2-phenyl-3-hydroxy-1,5-benzothiazepine derivative represented by In order, the nitrogen atom at the 5-position was dimethylaminoethylated, and the hydroxyl group substituted at the 3-position was acetylated to give a compound of the general formula [XI] (However, ring A and ring B have the same meanings as described above.) A method for producing a (2S, 3S) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. 16. The method according to claim 1, 2, 3, 4, 5, 6, 7,
Using the (2S, 3R) -isomer of the trans-3-phenylglycidic acid ester compound obtained by the method of any one of 8, 9, 10, 11, 12 or 13, the compound represented by the general formula [XVI] (However, ring A and ring B represent a substituted or unsubstituted benzene ring.) A method for producing a (2R, 3R) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. 17. A method according to claim 1, 2, 3, 4, 5, 6, 7,
The (2S, 3R) -isomer of the trans-3-phenylglycidic acid ester compound obtained by the method of any one of 8, 9, 10, 11, 12 and 13 is represented by the general formula [V] (However, ring B represents a substituted or unsubstituted benzene ring), or
Or a general formula [VI] (However, ring B has the same meaning as described above.) After the reaction with the nitrothiophenol derivative represented by the formula, the nitro group of the product is reduced to give a compound of the general formula [XII] (However, ring A represents a substituted or unsubstituted benzene ring, and R ³
Represents an ester residue, and ring B has the same meaning as described above. (2R, 3R) -3- (2-aminophenylthio) -3-phenyl-2-hydroxypropionic acid ester compound represented by) is produced, and if necessary, hydrolyzed, and then intramolecularly ring-closed. General formula [XV] (However, ring A and ring B have the same meanings as described above.) A (2R, 3R) -2-phenyl-3-hydroxy-1,5-benzothiazepine derivative represented by In sequence, the nitrogen atom at the 5-position was dimethylaminoethylated and the hydroxyl group substituted at the 3-position was acetylated to give a compound of the general formula [XVI] (However, ring A and ring B have the same meanings as described above.) A method for producing a (2R, 3R) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. 18. A method according to claim 1, 2, 3, 4, 5, 6, 7,
The (2S, 3R) -isomer of the trans-3-phenylglycidic acid ester compound obtained by the method of any one of 8, 9, 10, 11, 12 and 13 is represented by the general formula [VI]: (However, ring B represents a substituted or unsubstituted benzene ring) and is reacted with a nitrothiophenol derivative represented by the general formula [XIII] (However, ring A represents a substituted or unsubstituted benzene, R ³ represents an ester residue, and ring B has the same meaning as described above.) (2R, 3R) -3- (2-nitrophenyl) A method for producing a thio) -3-phenyl-2-hydroxypropionic acid ester compound.