WO2004003001A1 - Process for the enzymatic resolution of 1,3-dioxolane-4-carboxylates - Google Patents

Process for the enzymatic resolution of 1,3-dioxolane-4-carboxylates Download PDF

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WO2004003001A1
WO2004003001A1 PCT/US2003/019900 US0319900W WO2004003001A1 WO 2004003001 A1 WO2004003001 A1 WO 2004003001A1 US 0319900 W US0319900 W US 0319900W WO 2004003001 A1 WO2004003001 A1 WO 2004003001A1
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process according
formula
ester
enzyme
acylase
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PCT/US2003/019900
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French (fr)
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James J. Lalonde
Yiming Yao
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Altus Biologics Inc.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction

Definitions

  • the present invention relates to enzymatic resolution of enantiomeric mixtures of 1, 3 -dioxolane-4- carboxylate esters and more particularly to a process for preparing R and S enantiomers of methyl 2 , 2-dimethyl-l, 3- dioxolane- -carboxylate in high optical purity.
  • Optically active 1, 3 -dioxolane-4 -carboxylate esters are important intermediates in the synthesis of various pharmaceutically active compounds.
  • Such compounds include, for example, dioxolane nucleoside analogs for treating HIV and HBV infections (see e.g., PCT patent applications WO 01/32153, WO 00/47759, and WO 00/39143).
  • Methyl 2 , 2-dimethyl-l , 3 -dioxolane-4 - carboxylate is a particularly important C-3 chiral building block for the preparation of pharmaceuticals, such as dioxolane nucleoside analogs, as well as other natural products.
  • Amidohydrolase enzymes of subclass EC 3.5 have been employed in the resolution of amino acids via hydrolysis of the N-acetamide (see R. A. Sheldon,
  • amidohydrolases such as acylase I (EC 3.5.1.14), for the hydrolytic resolution of carboxylate esters (see e.g., L. T. Kanerva et al . , Tetrahedron: Asymmetry (2001), 12,
  • Penicillin acylase (EC 3.5.1.11) has been used to hydrolyze the phenacetyl amide bond in penicillin G (J. Bryjak et al . , Enzyme and Microbial Technology, 1996, 19, 196) .
  • Penicillin acylase has also been used to prepare alpha, beta, and gamma amino acids via enantioselective hydrolysis or acylation of amides (H. K. Chenault, J. Am. Chem. Soc . (1989) , ill, 6354; Soloshonok, Tetrahedron: Asymmetry, (1994), 5, 1225; PCT application WO 94/02628; United States patent 6,214,609) .
  • penicillin acylase for the hydrolysis of carboxylic acid esters.
  • penicillin acylase-catalyzed hydrolysis of phenacetyl esters of carbinol substrates C. Fuganti et al . , Tetrahedron (1988), 44, 2575-2582.
  • the present invention provides processes for preparing the R and S enantiomers of 1, 3 -dioxolane-4- carboxylate esters of Formula I, as defined herein.
  • the processes comprise the step of contacting or reacting a solution comprising an enantiomeric mixture of 1,3- dioxolane-4-carboxylate of Formula I with an amidohydrolase enzyme, under conditions which permit the stereoselective hydrolysis of one enantiomer to its corresponding carboxylate of Formula II.
  • the opposite enantiomer of the ester is maintained unreacted in enantiomerically enriched form.
  • Alkyl -- represents a substituted (by halogen, hydroxyl or C 6 -C 20 aryl) or unsubstituted straight chain, branched chain, or cyclic hydrocarbon moiety having 1 to 30 carbon atoms and preferably, from 1-8 carbon atoms.
  • Aryl -- represents a carbocyclic moiety which may be substituted by at least one heteroatom (e.g., N, 0, or S) and containing at least one benzenoid-type ring and preferably containing from 6-15 carbon atoms (e.g. phenyl and naphthyl) .
  • Chiral compound -- a compound that is not superimposable on its mirror image (e.g., an asymmetric carbon atom, where four different substituents are attached to the same carbon) .
  • Enantiomers pairs of stereoisomers that are nonsuperimposable mirror images of each other. Separate enantiomers rotate plane of polarized light in equal but opposite directions. Enantiomers are distinguished by absolute configuration (using the R and S designations) and by the direction of rotation of plane polarized light that has passed through the sample (dextrorotatory (+) right or levorotatory (-) left) .
  • Enantiomeric mixture a mixture of two enantiomers .
  • Enantiomeric excess in a mixture of two enantiomers where one enantiomer is present to a greater extent, the percentage of the enantiomer found in excess over that of the racemic mixture is the enantiomeric excess.
  • the enantiomeric excess is calculated as follows :
  • Racemic mixture an equimolar mixture of two enantiomers .
  • Resolution the process of separating pairs of enantiomers from an enantiomeric mixture. According to the present invention, the resolution of an enantiomeric mixture of a 1 , 3-dioxolane- 4-carboxylate ester of Formula I:
  • Ri and R are each independently selected from hydrogen, - (C ⁇ -C 8 ) -straight or branched alkyl, - (C 3 -C ⁇ 2 ) - cycloalkyl, - (C 6 -C ⁇ 5 ) -aryl, - (C 1 -C 4 ) -straight or branched alkyl-O-C (O)Ph, - (C 1 -C 4 ) -straight or branched alkyl -O- (C 8 - C ⁇ S )-aryl, or - (C ⁇ -C 4 ) -straight or branched alkyl -O-benzyl ,
  • Ri and R may be taken together as an oxygen, or
  • Ri and R 2 may be taken together with the carbon atom to which they are bound to form a 3 to 6 member cycloalkyl group;
  • R 3 is - (C ⁇ -C 8 ) -straight or branched alkyl or - (C 6 -C 15 ) -aryl;
  • R 4 is hydrogen, - (C -C 8 ) -straight or branched alkyl, - (C 5 -C ⁇ 2 ) -cycloalkyl , or - (C 6 -C ⁇ 5 ) -aryl, is performed by a process comprising the steps of:
  • Ri, R 2 , and R 4 are each defined as in Formula I; and (b) separating said carboxylate of Formula II from the unhydrolyzed ester of Formula I.
  • the processes of present invention achieve high yields and enantioselectivity by employing amidohydrolases of subclass EC 3.5 which act on carbon- nitrogen bonds other than peptide bonds.
  • Amidohydrolases known for hydrolysis of the carbon-nitrogen bond in amides, are unexpectedly efficient in the hydrolysis of the 1,3 -dioxolane-4 - carboxylates in the processes of this invention.
  • Preferred enzymes for the processes of the present invention include those in the EC class of enzymes known as hydrolases acting on linear amides (EC 3.5.1.*; class, hydrolase; subclass, acting on carbon- nitrogen bonds, other than peptide bonds; sub-subclass linear amides) .
  • Most preferred enzymes are amidohydrolase enzymes of EC 3.5.1.11 and EC 3.5.1.14. Those most preferred enzymes and their common names are provided in Table I below.
  • Penicillin penicillin acylase amidase benzylpenicillin acylase; novozym 217; semacylase; ⁇ -acylamino- ⁇ -lactam acylhydrolase; ampicillin acylase
  • the enzymes may be used as a part of a whole cell culture, an enzyme extract, an isolated enzyme, an isolated enzyme attached to a solid support, or a cross- linked enzyme crystal .
  • the reaction processes may be performed in any conventional reaction vessel, such as a batch reactor, column, hollow-fiber membrane or membrane reactor.
  • the hydrolysis is generally carried out in buffer or buffer-organic solvent mixtures.
  • Any organic solvent may be used. These include, for example, alcohols, aromatics, ketone ethers, alkanes, halo- alkanes, acetone, and dimethyl sulfide. Additionally, multiple organic solvents may be used in combination. Either a homogenous or multiphasic solution may be employed.
  • the reaction can be carried out at any pH, ranging from about 5 to about 9. Typically, the pH of the reaction is about 7.
  • a suitable temperature for the reaction may be in the range of about 0°C to about 60°C. Typically, the temperature is lower than about 50°C.
  • the concentration of the enantiomeric mixture of dioxolane ester of Formula I (weight/volume) is between about 1% and about 70%, the preferred concentration being between about 5% and about 50%, and the most preferred concentration being between about 10% and about 20%.
  • the products prepared by the processes of this invention are substantially enriched in one enantiomer.
  • the high selectivity of the amidohydrolase for the hydrolysis of one enantiomer advantageously provides a high yield of the enantiomerically enriched acid of Formula II and the chiral, non-racemic unreacted ester of Formula I .
  • the processes of the present invention may be readily carried out on a large scale.
  • One advantage of the processes of this invention is that, depending on the enzyme used, they allow stereoselective hydrolysis of the R vs . S enantiomer, and vice versa.
  • the enzyme penicillin acylase from E. coli is used to stereoselectively hydrolyze predominantly the S- enantiomer of Formula I, leaving the R-enantiomer unreacted. This embodiment is illustrated in Scheme A below:
  • Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l , 3-dioxolane-4-carboxylate at 20°C Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate (0.55 g) was dissolved in 15 ml of 0.3 M, pH 7.5 phosphate buffer. A suspension of penicillin acylase from E. coli, obtained from Roche Diagnostics GmbH (50 ⁇ l of 1.68 U/ ⁇ l suspension) was then added to the mixture and the resulting reaction mixture was stirred for 2 h with gentle agitation at room temperature (20°C) . The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary.
  • the optical purity of the unreacted (R) -ester and (S) -acid product were monitored by HPLC using a chiral stationary phase column.
  • the optical purity of the unreacted (R) -ester was also monitored by gas chromatography using a chiral stationary phase capillary column.
  • the chemical conversion was monitored by reverse phase HPLC. After 2 hours, the enantiomeric excess of (R) -ester reached >99% and the conversion was 60%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester.
  • Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate (1.1 g) ' was dissolved in 30 ml of 0.3 M pH 7.5 phosphate buffer.
  • a 50 ⁇ l aliquot of 1.68 U/ ⁇ l of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at 15°C for 3 h. The temperature was maintained at 15°C. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 3 hours, the enantiomeric excess of (R) -ester reached 98.8%. The conversion was 54.7%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester.
  • Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l , 3 -dioxolane-4 -carboxylate at 10°C Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4- carboxylate (1.1 g) was dissolved in 30 ml of 0.3 M pH 7.5 phosphate buffer. A 100 ⁇ l aliquot of 1.68 U/ ⁇ l of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation 'at 10°C for 3.5 h. The temperature was maintained at 10°C.
  • Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate (0.55 g) was dissolved in 15 ml of 0.3 M pH 7.5 phosphate buffer.
  • a 50 ⁇ l aliquot of 1.68 U/ ⁇ l of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at room temperature for 20 h.
  • the pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 1 hour 35 min.
  • Racemic methyl-2, 2-dimethyl-l, 3-dioxolane-4- carboxylate (6 g) was dissolved in 24 ml of 0.3 M pH 7.5 phosphate buffer.
  • a 500 ⁇ l aliquot of 1.68 U/ ⁇ l of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at 10°C for 4 h.
  • the pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary.
  • the enantiomeric excess of (R) -ester reached 98.3%.
  • the conversion was 57.4%.
  • Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded 2.5 g (83% yield based on 50% yield) of the desired (R) -ester.
  • Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3 -dioxolane-4 -carboxylate at 20°C Racemic methyl-2 , 2-dimethyl-l, 3-dioxolane-4- carboxylate (1.1 g) was dissolved in 30 ml of 0.3 M pH 7.5 phosphate buffer. A 5 ⁇ l aliquot of 1.68 U/ ⁇ l of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation ' at 20°C for 20 h. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary.
  • Amano acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3 -dioxolane-4 -carboxylate at room temperature Racemic methyl-2 , 2-dimethyl-l , 3 -dioxolane-4 - carboxylate (0.55 g) was dissolved in 15 ml of 0.3 M pH 7.5 phosphate buffer.
  • a 66 mg aliquot of Amano acylase (Aspergillus melleus from Amano Pharma Corp. Ltd. as a lyophilized powder; 30,000 U/g) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at room temperature for 10 h.

Abstract

The present invention relates to enzymatic' resolution of enantiomeric mixtures of 1,3-dioxolane-4-carboxylate esters of Formula I. More particularly, the present invention relates to a process for preparing R and S enantiomers of methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate in high optical purity.

Description

PROCESS FOR THE ENZYMATIC RESOLUTION OF 1 , 3 -DIOXOLANE-4 -CARBOXYLATES
TECHNICAL FIELD
The present invention relates to enzymatic resolution of enantiomeric mixtures of 1, 3 -dioxolane-4- carboxylate esters and more particularly to a process for preparing R and S enantiomers of methyl 2 , 2-dimethyl-l, 3- dioxolane- -carboxylate in high optical purity.
BACKGROUND OF THE INVENTION Optically active 1, 3 -dioxolane-4 -carboxylate esters are important intermediates in the synthesis of various pharmaceutically active compounds. Such compounds include, for example, dioxolane nucleoside analogs for treating HIV and HBV infections (see e.g., PCT patent applications WO 01/32153, WO 00/47759, and WO 00/39143). Methyl 2 , 2-dimethyl-l , 3 -dioxolane-4 - carboxylate is a particularly important C-3 chiral building block for the preparation of pharmaceuticals, such as dioxolane nucleoside analogs, as well as other natural products. Conventional processes exist for synthesizing methyl 2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate from D- and L-serine or sugars, such as mannitol . However, such processes involve several steps and produce generally low yields of the desired product. Peptidase enzymes of subclass EC 3.4 and esterase enzymes of subclass EC 3.1 have been used to prepare optically active 1, 3 -dioxolane-4 -carboxylates, but the resulting yields and optical purity are low (see e.g., German Patent Nos . DD 277700 and DD 277698; S. Hans et al . , Liebigs Ann. Chem. (1993), 1, 103-04; M. Pottie et al . , Tetrahedron Lett . (1989), "30, 5319-22). Therefore, there remains a need for the development of processes for the economical, large-scale stereoselective synthesis of optically active 1, 3-dioxolane-4-carboxylate esters, such as methyl 2 , 2-dimethyl-l, 3 -dioxolane-4 -carboxylate .
Amidohydrolase enzymes of subclass EC 3.5 have been employed in the resolution of amino acids via hydrolysis of the N-acetamide (see R. A. Sheldon,
Chirotechnology, 1993, Marcel Dekker, New York, NY). However, there are relatively few instances of the use of amidohydrolases, such as acylase I (EC 3.5.1.14), for the hydrolytic resolution of carboxylate esters (see e.g., L. T. Kanerva et al . , Tetrahedron: Asymmetry (2001), 12,
2059-2066; L. T. Kanerva et al . , Tetrahedron: Asymmetry (2000), 11, 3957-3966; L. T. Kanerva et al . , Tetrahedron: Asymmetry (1999), 10, 4405-4415).
In another example, Penicillin acylase (EC 3.5.1.11) has been used to hydrolyze the phenacetyl amide bond in penicillin G (J. Bryjak et al . , Enzyme and Microbial Technology, 1996, 19, 196) . Penicillin acylase has also been used to prepare alpha, beta, and gamma amino acids via enantioselective hydrolysis or acylation of amides (H. K. Chenault, J. Am. Chem. Soc . (1989) , ill, 6354; Soloshonok, Tetrahedron: Asymmetry, (1994), 5, 1225; PCT application WO 94/02628; United States patent 6,214,609) . There have been relatively few instances of the use of penicillin acylase for the hydrolysis of carboxylic acid esters. One example is the penicillin acylase-catalyzed hydrolysis of phenacetyl esters of carbinol substrates (C. Fuganti et al . , Tetrahedron (1988), 44, 2575-2582).
SUMMARY OF THE INVENTION
The present invention provides processes for preparing the R and S enantiomers of 1, 3 -dioxolane-4- carboxylate esters of Formula I, as defined herein. The processes comprise the step of contacting or reacting a solution comprising an enantiomeric mixture of 1,3- dioxolane-4-carboxylate of Formula I with an amidohydrolase enzyme, under conditions which permit the stereoselective hydrolysis of one enantiomer to its corresponding carboxylate of Formula II. The opposite enantiomer of the ester is maintained unreacted in enantiomerically enriched form.
DETAILED DESCRIPTION
In the following description, terms are defined as follows:
Alkyl -- represents a substituted (by halogen, hydroxyl or C6-C20 aryl) or unsubstituted straight chain, branched chain, or cyclic hydrocarbon moiety having 1 to 30 carbon atoms and preferably, from 1-8 carbon atoms. Aryl -- represents a carbocyclic moiety which may be substituted by at least one heteroatom (e.g., N, 0, or S) and containing at least one benzenoid-type ring and preferably containing from 6-15 carbon atoms (e.g. phenyl and naphthyl) . Chiral compound -- a compound that is not superimposable on its mirror image (e.g., an asymmetric carbon atom, where four different substituents are attached to the same carbon) .
Enantiomers -- pairs of stereoisomers that are nonsuperimposable mirror images of each other. Separate enantiomers rotate plane of polarized light in equal but opposite directions. Enantiomers are distinguished by absolute configuration (using the R and S designations) and by the direction of rotation of plane polarized light that has passed through the sample (dextrorotatory (+) right or levorotatory (-) left) .
Enantiomeric mixture -- a mixture of two enantiomers .
Enantiomeric excess -- in a mixture of two enantiomers where one enantiomer is present to a greater extent, the percentage of the enantiomer found in excess over that of the racemic mixture is the enantiomeric excess. The enantiomeric excess is calculated as follows :
( [R] - [S] ) ÷ ([R] + [S]) X 100 = % enantiomer excess.
Racemic mixture -- an equimolar mixture of two enantiomers .
Resolution -- the process of separating pairs of enantiomers from an enantiomeric mixture. According to the present invention, the resolution of an enantiomeric mixture of a 1 , 3-dioxolane- 4-carboxylate ester of Formula I:
Figure imgf000005_0001
wherein:
Ri and R are each independently selected from hydrogen, - (Cι-C8) -straight or branched alkyl, - (C3-Cι2) - cycloalkyl, - (C6-Cι5) -aryl, - (C1-C4) -straight or branched alkyl-O-C (O)Ph, - (C1-C4) -straight or branched alkyl -O- (C8- CιS)-aryl, or - (Cχ-C4) -straight or branched alkyl -O-benzyl ,
Ri and R may be taken together as an oxygen, or
Ri and R2 may be taken together with the carbon atom to which they are bound to form a 3 to 6 member cycloalkyl group;
R3 is - (Cι-C8) -straight or branched alkyl or - (C6-C15) -aryl;
R4 is hydrogen, - (C -C8) -straight or branched alkyl, - (C5-Cι2) -cycloalkyl , or - (C6-Cι5) -aryl, is performed by a process comprising the steps of:
(a) contacting a solution comprising said enantiomeric mixture of ester of Formula I with an amidohydrolase enzyme, under conditions which permit selective hydrolysis of one of the enantiomers to produce a carboxylate of Formula II:
Figure imgf000006_0001
wherein:
Ri, R2, and R4 are each defined as in Formula I; and (b) separating said carboxylate of Formula II from the unhydrolyzed ester of Formula I. The processes of present invention achieve high yields and enantioselectivity by employing amidohydrolases of subclass EC 3.5 which act on carbon- nitrogen bonds other than peptide bonds. Amidohydrolases, known for hydrolysis of the carbon-nitrogen bond in amides, are unexpectedly efficient in the hydrolysis of the 1,3 -dioxolane-4 - carboxylates in the processes of this invention.
Preferred enzymes for the processes of the present invention include those in the EC class of enzymes known as hydrolases acting on linear amides (EC 3.5.1.*; class, hydrolase; subclass, acting on carbon- nitrogen bonds, other than peptide bonds; sub-subclass linear amides) . Most preferred enzymes are amidohydrolase enzymes of EC 3.5.1.11 and EC 3.5.1.14. Those most preferred enzymes and their common names are provided in Table I below.
Table I EC Number Common Name Other Names
EC 3.5.1.11 Penicillin penicillin acylase; amidase benzylpenicillin acylase; novozym 217; semacylase; α-acylamino-β-lactam acylhydrolase; ampicillin acylase
EC 3.5.1.14 Aminoacylase Amano acylase; acylase I; dehydropeptidase II; histozyme; hippuricase; benzamidase; hippurase; amido acid deacylase; L- aminoacylase; acylase ,- aminoacylase I ; -amino-acid acylase; α-N-acylaminoacid hydrolase; long acyl amidoacylase; short acyl amidoacylase Many of the enzymes useful, in the processes of the present invention are commercially available. Alternatively, they may be derived from a variety of sources, such as plants, animals, microbes, or fungi. The enzymes may be used as a part of a whole cell culture, an enzyme extract, an isolated enzyme, an isolated enzyme attached to a solid support, or a cross- linked enzyme crystal . The reaction processes may be performed in any conventional reaction vessel, such as a batch reactor, column, hollow-fiber membrane or membrane reactor.
The hydrolysis is generally carried out in buffer or buffer-organic solvent mixtures. Any organic solvent may be used. These include, for example, alcohols, aromatics, ketone ethers, alkanes, halo- alkanes, acetone, and dimethyl sulfide. Additionally, multiple organic solvents may be used in combination. Either a homogenous or multiphasic solution may be employed. The reaction can be carried out at any pH, ranging from about 5 to about 9. Typically, the pH of the reaction is about 7. A suitable temperature for the reaction may be in the range of about 0°C to about 60°C. Typically, the temperature is lower than about 50°C. The concentration of the enantiomeric mixture of dioxolane ester of Formula I (weight/volume) is between about 1% and about 70%, the preferred concentration being between about 5% and about 50%, and the most preferred concentration being between about 10% and about 20%.
Conventional techniques for separating an ester from an acid may be used to separate the unreacted ester of Formula I from the acid of Formula II. Typically, the reaction mixture is adjusted to a basic pH (e.g., pH >7.0) and then extracted with an appropriate organic solvent. As a result, the unreacted ester is dissolved in the organic solvent, while the carboxylic acid remains in the aqueous layer. Drying and evaporation of the organic solvent provides the desired chiral ester. Similarly, adjustment of the pH of the aqueous layer, followed by extraction with an organic solvent, leads to isolation of the acid. Alternatively, the separation process may be carried out without the addition of solvent, in cases in which the ester is sparingly soluble in water. Other standard separation techniques, such as the use of ion exchange resins or distillation, may be also used to separate the ester from the acid. The products prepared by the processes of this invention are substantially enriched in one enantiomer. The high selectivity of the amidohydrolase for the hydrolysis of one enantiomer advantageously provides a high yield of the enantiomerically enriched acid of Formula II and the chiral, non-racemic unreacted ester of Formula I .
The processes of the present invention may be readily carried out on a large scale. One advantage of the processes of this invention is that, depending on the enzyme used, they allow stereoselective hydrolysis of the R vs . S enantiomer, and vice versa.
In one embodiment of the present invention, the enzyme penicillin acylase from E. coli is used to stereoselectively hydrolyze predominantly the S- enantiomer of Formula I, leaving the R-enantiomer unreacted. This embodiment is illustrated in Scheme A below:
Figure imgf000010_0001
I (R) -I (S) -II
In another embodiment of this invention, either A ano acylase from Aspergillus melleus or acylase I from porcine kidney is used to stereoselectively hydrolyze predominantly the R-enantiomer of Formula I, leaving the S-enantiomer unreacted. This embodiment is illustrated in Scheme B :
Figure imgf000010_0002
I (S) -I (R) -II
It will be apparent to those of skill in the art that the general processes outlined in Schemes A and B may also be used to prepare optically active acids of Formula II. Accordingly, the isolated optically active ester resulting from the processes of Schemes A or B may be hydrolyzed using organic acids to provide access to both enantiomers of Formula II, by means of a single stereoselective reaction. The isolated, optically active esters of Formula I may also be hydrolyzed enzymatically.
The present invention is illustrated in the following examples. These are for illustrative purposes only and are not to be construed as limiting the invention in any manner. EXAMPLE 1
Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l , 3-dioxolane-4-carboxylate at 20°C. Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate (0.55 g) was dissolved in 15 ml of 0.3 M, pH 7.5 phosphate buffer. A suspension of penicillin acylase from E. coli, obtained from Roche Diagnostics GmbH (50 μl of 1.68 U/μl suspension) was then added to the mixture and the resulting reaction mixture was stirred for 2 h with gentle agitation at room temperature (20°C) . The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. The optical purity of the unreacted (R) -ester and (S) -acid product were monitored by HPLC using a chiral stationary phase column. The optical purity of the unreacted (R) -ester was also monitored by gas chromatography using a chiral stationary phase capillary column. The chemical conversion was monitored by reverse phase HPLC. After 2 hours, the enantiomeric excess of (R) -ester reached >99% and the conversion was 60%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester.
Chiral HPLC Conditions: CHIRALCEL® OJ, 0.46 cm x 25 cm HPLC column (Daicel Chemical Inc.), mobile phase = Hexane:Acetonitrile:TFA (95:5:0.1), flow rate = 1 ml/min., UV detection at 220 nm. Retention times: (S) - ester, 6.3 min. ; (R) -ester, 7.5 min. ; (S) -acid, 9.3 min.; (R) -acid, 13.5 min. Chiral gas chromatography conditions: J&W
Scientific Cyclodex B column 0.25 micron, 30 M X 0.25 mm column. Temperature program: after 4 minutes at 130°C, - li ¬
the temperature of the oven was increased at a rate of 10°C/min. to 140°C (column head pressure 20 psi) . Retention times: S-methyl ester 2.84 min, R-methyl ester 2.92 min. Reverse Phase HPLC Conditions: Varian
Microsorb-MV™ 100 A, C18, 0.46 cm x 15 cm HPLC column, mobile phase = Water:Acetonitrile :TFA (90:10:0.1), flow rate = 1 ml/min., UV detection at 220 nm. Retention times: methyl ester, 13.31 min.; acid, 5.75 min. EXAMPLE 2
Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3 -dioxolane-4-carboxylate at 15°C.
Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate (1.1 g) ' was dissolved in 30 ml of 0.3 M pH 7.5 phosphate buffer. A 50 μl aliquot of 1.68 U/μl of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at 15°C for 3 h. The temperature was maintained at 15°C. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 3 hours, the enantiomeric excess of (R) -ester reached 98.8%. The conversion was 54.7%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester.
EXAMPLE 3
Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l , 3 -dioxolane-4 -carboxylate at 10°C. Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4- carboxylate (1.1 g) was dissolved in 30 ml of 0.3 M pH 7.5 phosphate buffer. A 100 μl aliquot of 1.68 U/μl of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation 'at 10°C for 3.5 h. The temperature was maintained at 10°C. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 3.5 hours, the enantiomeric excess of (R) -ester reached 98.5%. The conversion was 50.9%. Extraction of the unreacted ester from the reaction mixture with tert- butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester.
EXAMPLE 4
Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3-dioxolane-4-carboxylate at room temperature.
Racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 - carboxylate (0.55 g) was dissolved in 15 ml of 0.3 M pH 7.5 phosphate buffer. A 50 μl aliquot of 1.68 U/μl of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at room temperature for 20 h. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 1 hour 35 min. , the enantiomeric excess of the (R) -ester reached 95.8% and a further 0.50 g of racemic methyl-2 , 2-dimethyl-l, 3 -dioxolane-4 -carboxylate was added to the reaction mixture.
After 2.5 hours, the enantiomeric excess of the (R) -ester reached 63.1% and a further 1.1 g of racemic methyl-2, 2-dimethyl-l, 3 -dioxolane-4 -carboxylate was added to the reaction mixture. After 5 hours 20 min., the, enantiomeric excess of (R) -ester reached 69% and a further 2.2 g of racemic methyl-2, 2-dimethyl-l, 3-dioxolane-4-carboxylate was added to the reaction mixture. After 20 hours, the enantiomeric excess of (R) - ester reached 81.7%. The conversion was 58.2%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester. EXAMPLE 5
Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3-dioxolane-4-carboxylate at 10°C.
Racemic methyl-2, 2-dimethyl-l, 3-dioxolane-4- carboxylate (6 g) was dissolved in 24 ml of 0.3 M pH 7.5 phosphate buffer. A 500 μl aliquot of 1.68 U/μl of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at 10°C for 4 h. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 4 hours, the enantiomeric excess of (R) -ester reached 98.3%. The conversion was 57.4%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded 2.5 g (83% yield based on 50% yield) of the desired (R) -ester.
EXAMPLE 6
Penicillin acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3 -dioxolane-4 -carboxylate at 20°C. Racemic methyl-2 , 2-dimethyl-l, 3-dioxolane-4- carboxylate (1.1 g) was dissolved in 30 ml of 0.3 M pH 7.5 phosphate buffer. A 5 μl aliquot of 1.68 U/μl of penicillin acylase (from E. coli, obtained from Roche Diagnostics GmbH) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation 'at 20°C for 20 h. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 20 hours, the enantiomeric excess of (R) -ester reached 80%. The conversion was 60%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (R) -ester.
EXAMPLE 7
Amano acylase-catalyzed resolution of methyl 2 , 2-dimethyl-l, 3 -dioxolane-4 -carboxylate at room temperature. Racemic methyl-2 , 2-dimethyl-l , 3 -dioxolane-4 - carboxylate (0.55 g) was dissolved in 15 ml of 0.3 M pH 7.5 phosphate buffer. A 66 mg aliquot of Amano acylase (Aspergillus melleus from Amano Pharma Corp. Ltd. as a lyophilized powder; 30,000 U/g) was then added to the mixture and the resulting reaction mixture was stirred with gentle agitation at room temperature for 10 h. The pH was maintained at 7.5 by the addition of 1 M aqueous sodium hydroxide as necessary. After 10 hours, the enantiomeric excess of (S) -ester reached 99.1%. The conversion was 51.5%. Extraction of the unreacted ester from the reaction mixture with tert-butyl methyl ether and evaporation of the organic solvent yielded the desired (S) -ester.
While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the process of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.

Claims

CLAIMS We claim:
1. A process for the resolution of an enantiomeric mixture of a 1, 3 -dioxolane-4 -carboxylate ester of Formula I:
Figure imgf000017_0001
wherein :
Ri and R2 are each independently selected from hydrogen, - (Cι-C8) -straight or branched alkyl, - (C5-Cι2) - cycloalkyl, - (C6-Cι5) -aryl, - (Cι-C4) -straight or branched alkyl-O-C(O) Ph, - (C!-C4) -straight or branched alkyl-O- (C6- Cι5)-aryl, or - (Cι-C4) -straight or branched alkyl-O-benzyl ,
Ri and R2 may be taken together as an oxygen, or
Ri and R2 may be taken together with the carbon atom to which they are bound to form a 3 to 6 member cycloalkyl group;
R3 is - (Ci-C8) -straight or branched alkyl or
Figure imgf000017_0002
R4 is hydrogen, - (Cι-C8) -straight or branched alkyl, - (C5-C12) -cycloalkyl , or - (C6-Cι5) -aryl, the process comprising the steps of: ■ (a) contacting a solution comprising said enantiomeric mixture of ester of Formula I with an amidohydrolase enzyme, under conditions which permit selective hydrolysis of one of the enantiomers to produce a carboxylate of Formula II:
Figure imgf000018_0001
wherein:'
Ri, R2, and R4 are each defined as in Formula I; and (b) separating said carboxylate of Formula II from the unhydrolyzed ester of Formula I .
2. The process according to claim 1, wherein said solution comprises an aqueous buffer.
3. The process according to claim 2, wherein said aqueous buffer has a pH between about 5 and about 9.
4. The process according to claim 3 , wherein said aqueous buffer has a pH of about 7.
5. The process according to claim 1, wherein said solution comprises an aqueous buffer and an organic solvent .
6. The process according to claim 5, wherein said aqueous buffer has a pH between about 5 and about 9.
7. The process according to claim 6, wherein said aqueous buffer has a pH of about 7.
8. The process according to any one of claims 1 to 7, wherein said amidohydrolase enzyme is penicillin acylase .
9. The process according to claim 8, wherein said penicillin acylase is E. coli penicillin acylase.
10. The process according to claim 8, wherein said process is carried out at a temperature between about 0°C and about 60°C.
11. The process according to claim 10, wherein said unhydrolyzed ester of Formula I is the R-enantiomer.
12. The process according to claim 10, wherein Ri, R2 and R3 are each methyl and R4 is hydrogen.
13. The process according to claim 8, wherein said amidohydrolase enzyme is a soluble enzyme.
14. The process according to claim 8, wherein said amidohydrolase enzyme is an immobilized enzyme.
15. The process according to claim 8, wherein said amidohydrolase enzyme is a crosslinked enzyme crystal.
16. The process according to claim 8, wherein said enantiomeric mixture of ester of Formula I is a racemic mixture .
17. The process according to claim 8, wherein the concentration (weigh /volume) of said enantiomeric mixture of ester of Formula I is between about 1% and about 70%.
18. The process according to any one of claims 1 to 7, wherein said enzyme is acylase I.
19. The process according to claim 18, wherein said acylase I is porcine kidney acylase I.
20. The process according to claim 18, wherein said process is carried out at a temperature between about 0°C and about 60°C.
21. The process according to claim 20, wherein said unhydrolyzed ester of Formula I is the S-enantiomer .
22. The process according to claim 20, wherein Rl f R2 and R3 are each methyl and R4 is hydrogen.
23. The process according to claim 18, wherein said amidohydrolase enzyme is a soluble enzyme.
24. The process according to claim 18, wherein said amidohydrolase enzyme is an immobilized enzyme.
25. The process according to claim 18, wherein said amidohydrolase enzyme is a crosslinked enzyme crystal.
26. The process according to claim 18, wherein said enantiomeric mixture of ester of Formula I is a racemic mixture .
27. The process according to claim 18, wherein the concentration (weight/volume) of said enantiomeric mixture of ester of Formula I is between about 1% and about 70%.
28. The process according to any one of claims 1 to 7, wherein said amidohydrolase enzyme is an Amano acylase.
29. The process according to claim 28, wherein said Amano acylase is Aspergillus melleus Amano acylase.
30. The process according to c.laim 28, wherein said process is carried out at a temperature between about 0°C and about 60°C.
31. The process according to claim 30, wherein said unhydrolyzed ester of Formula I is the S-enantiomer .
32. The process according to claim 30, wherein R1# R and R3 are each methyl and R is hydrogen.
33. The process according to claim 28, wherein said amidohydrolase enzyme is a soluble enzyme.
34. The process according to claim 28, wherein said amidohydrolase enzyme is an immobilized enzyme.
35. The process according to claim 28, wherein said amidohydrolase enzyme is a crosslinked enzyme crystal.
36. The process according to claim 28, wherein said enantiomeric mixture of ester of Formula I is a racemic mixture .
37. The process according to claim 28, wherein the concentration (weight/volume) of said enantiomeric mixture of ester of Formula I is between about 1% and about 70%.
38. The process according to claim 1, wherein Rl r R2 are each methyl .
39. The process according to claim 38, wherein R3 is methyl and R4 is hydrogen.
40. The process according to claim 1, wherein said process is carried out at a temperature between about 0°C and about 60°C.
95 41. The process according to claim 1, wherein said enantiomeric mixture of ester of Formula I is a racemic mixture .
42. The process according to claim 1, wherein the concentration (weight/volume) of said enantiomeric 100 mixture of ester of Formula I is between about 1% and about 70%.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2397474A1 (en) 2010-06-17 2011-12-21 Construction Research & Technology GmbH 2-Oxo-1,3-dioxolan-4-carbolic acid esters, production and use of same
WO2013092011A1 (en) 2011-12-22 2013-06-27 Construction Research & Technology Gmbh 2-oxo-1,3-dioxolane-4-carboxamides, their preparation and use
US8742137B2 (en) 2010-06-17 2014-06-03 Construction Research & Technology Gmbh 2-oxo-1, 3-dioxolane-4-carboxylic acid and derivatives thereof, their preparation and use
EP2762471A1 (en) 2013-01-31 2014-08-06 Construction Research & Technology GmbH 2-oxo-1,3-dioxolane-4-carboxamide building blocks, their preparation and use
EP2818465A1 (en) 2013-06-26 2014-12-31 Construction Research & Technology GmbH 2-Oxo-1,3-dioxolane-4-acyl halides, their preparation and use
US9079871B2 (en) 2011-12-29 2015-07-14 Basf Se Preparing cyclocarbonate-functionalized compounds
US20160194680A1 (en) * 2012-12-21 2016-07-07 Lek Pharmaceuticals D.D. Enzymatic Route For The Preparation Of Chiral Gamma-Aryl-Beta-Aminobutyric Acid Derivatives
US10059685B2 (en) 2014-03-07 2018-08-28 Construction Research & Technology, Gmbh 2-hydroxyethyl 2-oxo-1,3-dioxolane-4-carboxylates, their preparation and use
US10899866B2 (en) 2015-08-10 2021-01-26 Construction Research & Technology Gmbh Process for producing a ring-opening polymerization product

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6541625B2 (en) * 2000-02-11 2003-04-01 Biochem Pharma, Inc. Stereoselective synthesis of nucleoside analogues

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6541625B2 (en) * 2000-02-11 2003-04-01 Biochem Pharma, Inc. Stereoselective synthesis of nucleoside analogues

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