Enantioselective enzymatic aminolysis of a racemic 2-isoxazolylacetate alkyl ester

The process for the enantioselective enzymatic aminolysis of racemic 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate ((R/S)-I),

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• wherein R1 is selected from the group comprising of unsubstituted or substituted C1-C6 alkyl or alkenyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroaryl alkyl,
• by methyl Nα-Boc-L-αβ-diaminoproprionate .p-toluene-sulfonic acid, (S)-4,
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• to produce (R)-methyl-3-[[[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N-(butoxycarbonyl)-L-alanine, ((R,S)- 1),
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• further comprising:
• (a) contacting racemic ((R/S)-I) with a compound of formula (S)-4, an effective amount of enzyme catalyst which is optionally immobilized on an insoluble organic or inorganic carrier, an organic solvent, and optionally a desiccant, in a reaction mixture to form a compound of formula (R,S)-1;
• and
• (b) isolating the compound of formula (R,S)-1 from the reaction mixture of step (a). (c) isolating unreacted S-enantiomer ((S)-I)
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• from the reaction mixture of step(b);
• (c) heating the unreacted S-enantiomer ((S)-I) obtained from step (c) in toluene in the presence of a catalytic amount of potassium tert-butoxide to yield racemic 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]-acetate ((R/S)-I);
• and
• (e) recycling the racemic 2-[3-(4-cyanophenyl) -4,5-dihydro-5-isoxazolyl]acetate ((RIS) -I) obtained from step (d) by applying steps (a) to (e);
• the recycling step (e) is performed from 1 to 5 times.

A process for the preparation of (R)-methyl-3-[[[3-[4-(aminoiminomethyl) phenyl]-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N-(butoxycarbonyl)-L-alanine monoacetate (roxifiban)

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• comprising:
• (a) contacting racemic 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate ((RIS)-I),
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• wherein R1 is selected from the group comprising of unsubstituted or substituted C1-C6 alkyl or alkenyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroaryl alkyl,
• with methyl Nα-Boc-L-αβ-diaminoproprionate .p-toluene-sulfonic acid, (S)-4,
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• which is optionally immobilized on an insoluble organic or inorganic carrier, an organic solvent, and optionally a desiccant, in a reaction mixture to form a compound of formula(R,S)-1, (R)-methyl-3-[[[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N-(butoxycarbonyl)-L-alanine,
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• (b) isolating the compound of formula (R,S)-1 from the reaction mixture of step (a);
• (c1) contacting the compound of formula (R,S)-1, isolated in step (b) with HCl and methanol in methyl acetate to form an imidate compound,
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• (d1) contacting the imidate compound produced in step (c1) with ammonium acetate to produce R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N-(butoxycarbonyl) -L-alanine monoacetate;
• and
• (e1) recovering the product of step (d1).