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US 7,115,412 B2Granted
Process for the preparation of optically active 7-substituted-3-(2-aminopropyl)indole derivatives and intermediates therefor
AssigneesMercian Corporation, Dainippon Pharmaceutical Co., Ltd.
InventorsTakao Narita, Kunihiro Toyoda, Yoichiro Hirose, Toshio Tsuchida, Shiro Kato, Hiroshi Harada, Akihito Fujii
Life of this patent
Estimating the term…
Abstract
Disclosed are a process for preparation of an optically active 7-substituted 3-(2-aminopropyl)indole compound and an intermediate therefor. In the above preparation process, 7-substituted indole is reacted with L- or DL-serine in the presence of a tryptophan-synthesizing enzyme originating in microorganisms to form corresponding 7-substituted L-tryptophan, and it is subjected, if necessary, to reduction, protection, exchange and elimination.
Claims5
A process for preparing an optically active indole derivative of the Formula (I):
- wherein R1 is a hydrogen atom, a lower alkyl group or a group selected from the following (a) and (b):
- (a) a group of the formula —(CH2)m—CHRaRaa wherein Ra is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a carboxyl group or a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom;
- Raa is a lower alkoxycarbonyl group, a carboxyl group or a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom;
- and m represents an integer of 0 to 3, and
- (b) a group of the formula —(CH2)p—Rb wherein Rb is a lower alkanoyl group, a hydroxy group, a cyano group or a mono- or di(lower alkyl)aminocarbonyl group, and p is an integer of 1 to 4;
- R2 and R3 are each a hydrogen atom, or either of them is a hydrogen atom and the other is a lower alkanoyl group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, or together form a phthaloyl group;
- and
- R4 is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkylsulfonyloxy group or a phenylsulfonyloxy group which may be substituted by a lower alkyl group, a lower ailcoxy group or a halogen atom,
- comprising:
- (1) reacting L- or DL-serine with 7-substituted indole of the Formula (II):
- wherein R1a is a group (c) or (d) shown below:
- (c) a group of the formula —(CH2)m—CHRa′Raa′ wherein Ra′ is a hydrogen atom, a lower alkyl group or a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a bydroxy group or a halogen atom;
- Raa′ is a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom;
- and m is an integer of 0 to 3, and
- (d) a group of the formula —(CH2)p—Rb′ wherein Rb′ is a mono- or di(lower alkyl)aminocarbonyl group, and p is an integer of 1 to 4,
- in the presence of an effective amount of a tryptophan-synthesizing enzyme originating in E. coli to form a 7-substituted-L-tryptophan of the Formula (III):
- wherein R1a is the same as described above,
- (2) chemically reducing the carboxyl group of the 7-substituted-L-tryptophan of Formula (III) thus formed to a methylol group,
- (3) protecting the amino group of the compound of Formula (III),
- (4) converting the hydroxy group of the methylol group to sulfonyl to form a corresponding lower alkylsulfonyloxy compound or a phenylsulfonyloxy compound which may be substituted by a lower alkyl group, a lower alkoxy group or a halogen atom, and halogenating the resultant compound with alkali halide, or directly halogenating the hydroxy group of the methylol group, optionally in the presence of triphenyiphosphine, to form a corresponding halide,
- (5) converting the sulfonyloxy compound or the halide obtained in (4) to methyl by hydrogenation in the presence of a palladium catalyst or using a metal hydride salt,
- (6) subjecting the substituent of R1 to exchange reaction when R1 is the group (d) of the formula —(CH2)p—Rb′,
- (7) eliminating the protective group of the amino group, and
- (8) recovering the indole derivative of Formula (I).
21 more elements
A process for preparing 7-substituted L-tryptophan of the Formula (III):
- wherein R11a is defined below, which comprises reacting L- or DL-serine with 7-substituted indole of the Formula (II):
- wherein R1a is a group (c) or (d) shown below:
- (c) a group of the formula —(CH2)m—CHRa′Raa′ wherein Ra2′ is a hydrogen atom, a lower alkyl group or a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom;
- Raa ′ is a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom;
- and m is an integer of 0 to 3, and
- (d) a group of the formula —(CH2)p—Rb′ wherein Rb′ is a mono- or di(Lower alkyl)aminocarbonyl group, and p is an integer of 1 to 4,
- in the presence of an effective amount of a tryptophan-synthesizing enzyme originating in E. coli, and recovering the 7-substituted L-tryptophan of Formula (III).
4 more elements
Dependencies are inferred from the claim text.