US 8,618,312 B2Granted

Method of producing bicyclo[3.1.0] hexane derivative using enzyme

AssigneeTaisho Pharmaceutical Co., Ltd.

InventorsMitsuaki Hirotsuka, Joji Sasaki, Hiroaki Kamiyama, Motoko Oshida, Takaaki Ishii

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Abstract

Production of a bicyclo[3.1.0]hexane derivative, useful as a metabotropic glutamate receptor modulator, becomes possible by a production method that includes converting a compound represented by Formula (II) into a compound represented by Formula (III) by reaction with an acyl group donor in the presence of a microorganism-derived enzyme, without using an expensive optically active trans hydroxy ester as a starting material and without employing a fluorination reaction requiring an ultralow temperature reaction. Furthermore, since asymmetric synthesis can be carried out in a stage closer to the final product, the production method is useful as a production method that can mass produce a bicyclo[3.1.0]hexane derivative.

Claims23

Dependent claims

A method for producing a bicyclo[3.1.0]hexane derivative represented by Formula (I) and a salt thereof

(in Formula (I), R1 is
(1) —OH,
(2) —O—Ra, or
(3) —NRbRc,
Ra is a C1-6 alkyl group or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more C1-6 alkoxy groups, hydroxy groups, halogens, aryl groups, or heteroaryl groups),
Rb and Rc are identical or different and are each hydrogen, a halogen, a C1-6 alkyl group, or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more hydroxy groups, C1-6 alkoxy groups, aryl groups, or heteroaryl groups),
or Rb and Rc are bonded to each other and, together with the adjacent nitrogen atom, form a 4- to 7-membered saturated heterocycle (said saturated heterocycle being unsubstituted or substituted with a hydroxy group, a C1-6 alkyl group, or a C1-6 alkoxy group),
R2 and R3 are identical or different and are each hydrogen, a C1-6 alkyl group, a C3-8 cycloalkyl group, or a —(CH2)m-phenyl group, and
m is 0, 1, or 2), said method comprising:
(A) converting a compound represented by Formula (II) into a compound represented by Formula (III), wherein the compound represented by Formula (III) is produced by reacting the compound represented by Formula (II) with an acyl group donor in the presence of a microorganism-derived enzyme
(R1 in Formula (II) is as defined in Formula (I))
(in Formula (III), R1 is as defined in Formula (I),
R4 is hydrogen, a C1-6 alkyl group, a C3-8 cycloalkyl group, or a —(CH2)n-phenyl group (said C1-6 alkyl group, C3-8 cycloalkyl group, or —(CH2)n-phenyl group being unsubstituted or substituted with one or more halogens, hydroxy groups, C1-6 alkyl groups, or C1-6 alkoxy groups), and
n is 0, 1, or 2);
(B) converting said compound represented by Formula (III) into a compound represented by Formula (IV)
(R1 and R4 in Formula (IV) are as defined in Formula (I) and Formula (III));
(C) reacting said compound represented by Formula (IV) with a compound represented by Formula (V) to obtain a compound represented by Formula (VI)
(in Formula (V), R2 and R3 are as defined in Formula (I),
R5 is hydrogen or Si—(R6)(R7)(R8), and
R6, R7 and R8 are identical or different and are each a C1-6 alkyl group or a phenyl group)
(R1, R2, and R3 in Formula (VI) are as defined in Formula (I) and R4 is as defined in Formula (III)), and
(D) converting said compound represented by Formula (VI) into the compound represented by Formula (I).

19 more elements

A method for producing a compound represented by Formula (II) and a salt thereof

(in Formula (II), R1 is
(1) —OH,
(2) —O—Ra, or
(3) —NRbRc,
Ra is a C1-6 alkyl group or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more C1-6 alkoxy groups, hydroxy groups, halogens, aryl groups, or heteroaryl groups),
Rb and Rc are identical or different and are each hydrogen, a halogen, a C1-6 alkyl group, or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more hydroxy groups, C1-6 alkoxy groups, aryl groups, or heteroaryl groups),
or Rb and Rc are bonded to each other and, together with the adjacent nitrogen atom, form a 4- to 7-membered saturated heterocycle (said saturated heterocycle being unsubstituted or substituted with a hydroxy group, a C1-6 alkyl group, or a C1-6 alkoxy group)), said method comprising:
(A) reacting a compound represented by Formula (VIII) with a compound represented by Formula (IX) to obtain a mixture formed from a compound represented by Formula (Xa) and a compound represented by Formula (Xb)
(in Formula (IX), R9 and R10 are identical or different and are each
(1) —OH,
(2) —O—Ra, or
(3) —NRbRc,
Ra is a C1-6 alkyl group or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more C1-6 alkoxy groups, hydroxy groups, halogens, aryl groups, or heteroaryl groups),
Rb and Rc are identical or different and are each hydrogen, a halogen, a C1-6 alkyl group, or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more hydroxy groups, C1-6 alkoxy groups, aryl groups, or heteroaryl groups),
or Rb and Rc are bonded to each other and, together with the adjacent nitrogen atom, form a 4- to 7-membered saturated heterocycle (said saturated heterocycle being unsubstituted or substituted with a hydroxy group, a C1-6 alkyl group, or a C1-6 alkoxy group))
(R9 and R10 in Formulae (Xa) and (Xb) are as defined in Formula (IX));
(B) converting the mixture formed from said compound represented by Formula (Xa) and said compound represented by Formula (Xb) into a mixture formed from a compound represented by Formula (XIa) and a compound represented by Formula (XIb)
(R1 in Formulae (XIa) and (XIb) is as defined in Formula (II));
(C) converting the mixture formed from said compound represented by Formula (XIa) and said compound represented by Formula (XIb) into a mixture formed from a compound represented by Formula (XIIa) and a compound represented by Formula (XIIb)
(R1 in Formulae (XIIa) and (XIIb) is as defined in Formula (II));
and
(D) converting the mixture formed from said compound represented by Formula (XIIa) and said compound represented by Formula (XIIb) into the compound represented by Formula (II).

19 more elements

A method for producing a compound represented by Formula (III) and a salt thereof

(in Formula (III), R1 is
(1) —OH,
(2) —O—Ra, or
(3) —NRbRc,
Ra is a C1-6 alkyl group or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more C1-6 alkoxy groups, hydroxy groups, halogens, aryl groups, or heteroaryl groups),
Rb and Rc are identical or different and are each hydrogen, a halogen, a C1-6 alkyl group, or a C3-8 cycloalkyl group (said C1-6 alkyl group or C3-8 cycloalkyl group being unsubstituted or substituted with one or more hydroxy groups, C1-6 alkoxy groups, aryl groups, or heteroaryl groups),
or Rb and Rc are bonded to each other and, together with the adjacent nitrogen atom, form a 4- to 7-membered saturated heterocycle (said saturated heterocycle being unsubstituted or substituted with a hydroxy group, a C1-6 alkyl group, or a C1-6 alkoxy group),
R4 is hydrogen, a C1-6 alkyl group, a C3-8 cycloalkyl group, or a —(CH2 )n-phenyl group (said C1-6 alkyl group, C3-8 cycloalkyl group, or —(CH2 )n-phenyl group being unsubstituted or substituted with one or more halogens, hydroxy groups, C1-6 alkyl groups, or C1-6 alkoxy groups), and
n is 0, 1, or 2), said method comprising:
converting a compound represented by Formula (XIII) into said compound represented by Formula (III), wherein the compound represented by Formula (III) is produced by reacting the compound represented by Formula (XIII) with an acyl group acceptor in the presence of a microorganism-derived enzyme
(in Formula (XIII), R4 and R4a are identical or different and are each hydrogen, a C1-6 alkyl group, a C3-8 cycloalkyl group, or a —(CH2)n-phenyl group (said C1-6 alkyl group, C3-8 cycloalkyl group, or —(CH2 )n-phenyl group being unsubstituted or substituted with one or more halogens, hydroxy groups, C1-6 alkyl groups, or C1-6 alkoxy groups) and
n is 0, 1, or 2).

9 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/950,609Filed 19 Nov 2010 · continuation in part
Priority: JP 2008-13305621 May 2008
Published: US 2011/0065934 A117 Mar 2011
Granted: 31 Dec 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C12P 7/62
Preparation of oxygen-containing organic compounds: carboxylic acid esters
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 67/31
By modifying the acid moiety of the ester, such modification not being an introduction of an ester group: by introduction of functional groups…
C07C 67/313
By modifying the acid moiety of the ester, such modification not being an introduction of an ester group: by introduction of doubly bound oxygen…