Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2000-07-19
2002-06-25
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S198000, C435S280000
Reexamination Certificate
active
06410279
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for producing an optically active azetidine-2-carboxylic acid derivatives.
DESCRIPTION OF THE RELATED ART
The optically active azetidine-2-carboxylic acid has been known as an intermediate for producing a pharmaceutical such as an antithrombotic agent disclosed in EP 542525.
Optically active azetidine-2-carboxylic acid has been produced by a process which has the steps of;
reacting azetidine-2-carboxylic acid, which is obtained by a process disclosed in Journal of Heterocyclic Chemistry, 6, 435 (1969), with benzyloxycarbonyl chloride to give N-(benzyloxycarbonyl)-azetidine-2-carboxylic acid, subjecting N-(benzyloxycarbonyl)-azetidine-2-carboxylic acid to optical resolution using an optically active tyrosine hydrazide, and then subjecting the obtained optically active N-(benzyloxycarbonyl)-azetidine-2-carboxylic acid to hydrogenolysis to give an optically active azetidine-2-carboxylic acid [Journal of Heterocyclic Chemistry, 6, 993 (1969)].
The prior art methods for preparing optically active azetidine-2-carboxylic acid, however, had difficulties in that it requires, as a reagent for optical resolution, an optically active tyrosine hydrazide which is expensive and not readily available on the industrial scale.
SUMMARY OF THE INVENTION
Therefore, an object of the invention is to provide a process for producing the desired compound in a simple step.
The present invention provides:
1. a process for producing N-substituted azetidine-2-carboxylic acid of the formula I:
wherein R
1
denotes an aralkyl group or an arylated lower alkoxycarbonyl group and * designates an asymmetric carbon atom, which comprises:
reacting an N-substituted azetidine-2-carboxylic acid ester of the formula II:
wherein R
1
has the same meaning as defined above and R
2
denotes an alkyl group, an aralkyl group or an allyl group, with an enzyme capable of selectively hydrolyzing a stereoisomer based on the carbon atom of the 2-position of the azetidine ring;
2. a process for producing an optically active azetidine-2- carboxylic acid of the formula III:
wherein * designates an asymmetric carbon atom, which comprises: reacting the optically active N-substituted azetidine-2-carboxylic acid of the formula I as defined above obtainable according to the method described in item 1 above, with a reducing agent in the presence of a catalyst; and
3. a process for improving optical purity of azetidine-2-carboxylic acid of the formula III as defined above, which comprises:
preparing a solution of azetidine-2-carboxylic acid; and
cooling the said solution in the presence of a seed crystal of one optional optical isomer of the azetidine-2-carboxylic acid to selectively recrystalize the optical isomer of the azetidine-2-carboxylic acid having the same configuration with respect to the carbon atom of the 2-position of the azetidine ring as the seed crystal.
DESCRIPTION OF THE PREFERRED EMBODIMENT
First description will be made to the process for producing N-substituted azetidine-2-carboxylic acid of the formula I as defined above, which comprises:
reacting an N-substituted azetidine-2-carboxylic acid ester of the formula II as defined above with an enzyme capable of selectively hydrolyzing a stereoisomer based on the carbon atom of the 2-position of the azetidine ring.
The aralkyl group for R
1
in N-substituted azetidine-2-carboxylic acid ester of the formula I includes a benzyl group, a phenethyl group and a phenylpropyl group, all of which may have an asymmetric carbon and further includes a benzhydryl group and a triphenylmethyl group.
The arylated lower alkoxycarbonyl group for R
1
includes (C
1
-C
2
)alkoxyl group having a phenyl substituent which may be substituted, for example, a benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and 2-phenylethyloxycarbonyl group.
Examples of the alkyl group for R
2
include a (C
1
-C
8
) alkyl group such as a methyl group, an ethyl group, a propyl group such as n-propyl or i-propyl, and a butyl group such as n-butyl, sec-butyl, i-butyl or t-butyl group.
Examples of the aralkyl group for R
2
include a benzyl group, a phenethyl group and a phenylpropyl group, all of which may have an asymmetric carbon.
Examples of the aryl group for R
2
include a phenyl group.
Specific examples of the N-substituted azetidine-2-carboxylic acid ester include: for example, methyl N-benzylazetidine-2-carboxylate, methyl N-[(S)-phenylethyl]azetidine-2-carboxylate, methyl N-[(R)-phenylethyl]azetidine-2-carboxylate, methyl N-phenylpropylazetidine-2-carboxylate, methyl N-benzhydrylazetidine-2-carboxylate, methyl N-triphenylmethylazetidine-2-carboxylate, and corresponding an ethyl, a propyl group such as n-propyl, or i-propyl ester, or a butyl such as n-butyl, sec-butyl, i-butyl, or t-butyl ester.
The N-substituted azetidine-2-carboxylic acid ester of the formula II has two stereoisomers based on the carbon atom of the 2-position of the azetidine ring. Therefore, it may be a racemic mixture of both of the stereoisomers or contain an excess amount of one stereoisomer.
The enzyme of the present invention which is capable of selectively hydrolyzing a stereoisomer based on the carbon atom of the 2-position of the azetidine ring may be any one derived from a microorganism, an animal, or a plant.
Examples of the enzyme derived from a microorganism include such an enzyme belonging to Candida, Mucor, Humicola, Rhizopus, Aspergillus, Penicillium, Bacillus, Arthrobacter, Pseudomonas, Chromobacterium, Alkaligenes or Achromobacter. An enzyme produced by a transformant microorganism transformed by introducing the gene coding for the enzyme of interest also can be used. The said microorganisms can be readily cultured by such a conventional method as liquid culturing which comprises inoculating the said microorganism to a sterilized liquid culture and culturing at 20 to 40° C. under shaking, or by solid culturing, if necessary.
The enzymes may be purchased commercially. Examples of the commercially available enzyme include: Chirazyme L-2 (originated from
Candida antarctica
, Product of Boehringer Mannheim Com, Ltd), Novozyme 435 (originated from
Candida antarctica
, Product of Novo-Nordisk Com., Ltd), Lipase AY (originated from
Candida rugosa
, Product of Anano Phrmaceuticals Com., Lts) and Lipase MY (originated from
Candida cylindracea
, Meito Sangyo Com., Ltd).
Examples of the animal derived enzyme include, for example, Steapsin or Pancreatin of sheep or hog internals.
Examples of the plant derived enzyme include an enzyme of wheat germ.
These enzymes can be used in various forms, for example, in a form of purified enzyme, crude enzyme, culture broth of microorganism, culture, cell-culture or treated product thereof. The enzyme or cells can be used in a form of immobilized enzyme or immobilized cells.
The amount of the enzyme to be used is optionally set in a range within which deferring of the reaction should not occur or the selectivity of the reaction should not lower.
For example, the amount of the commercially available enzyme is 0.001 to 0.5 parts by weight, preferably 0.002 to 0.2 parts by weight based on one part by weight of the N-substituted azetidine-2-carboxylic acid ester.
The reaction of the enzyme and the N-substituted azetidine-2-carboxylic acid ester is usually conducted in an aqueous solution, which may be an aqueous buffer solution. Examples of the buffer solution include those of inorganic acid salts such as an aqueous solution of alkali metal phosphate salt (e.g., aqueous sodium phosphate, aqueous potassium phosphate) or aqueous buffer solution of an organic acid salt such alkali metal acetate(e.g., aqueous solution of sodium acetate, potassium acetate).
The amount of the aqueous solution to be used is usually not less than 0.5 part per 1 part by weight of the N-substituted azetidine-2-carboxylic acid ester, or not more than 100 parts by weight per 1 part by weight of the ester.
The reaction can be also conducted in the presence of a hydrophobic organic solvent or a hydrophilic organic solven
Hazama Motoo
Hirata Norihiko
Kudo Junko
Lilling Herbert J.
Sumitomo Chemical Company Limited
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