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US 9,434,737 B2Granted
Process for producing optically active succinimide derivatives and intermediates thereof
AssigneesSumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko Bio Co., Ltd.
InventorsMasaji Kasai, Shinji Kita, Tadashi Ogawa, Hideaki Tokai
Life of this patent
Estimating the term…
Abstract
Provided is a process for producing (3R)-2′-(4-bromo-2-fluorobenzyl)spiro{pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine}-1′,2,3′,5(2′H)-tetraone (compound A). The method includes converting an optically active succinimide derivative of formula (I) to compound A, in which the compound of formula (I) has been prepared by reacting a base with an optically active amide derivative of formula (VI).
Claims8
A process for producing compound A,
- or a salt thereof,
- said process comprises:
- (A) reacting an ester derivative represented by formula (IV):
- or a salt thereof,
- [wherein in said formula (IV), R1 is an amino or an amino protected with a protective group and R2 and R3 are lower alkyls independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl] with a pig liver esterase or a rabbit liver esterase for conversion of said ester derivative into an optically active carboxylic acid derivative represented by formula (V):
- or a salt thereof,
- [wherein in said formula (V), each of R1, R2, and R3 has the same meaning as defined above];
- (B) reacting said optically active carboxylic acid derivative represented by formula (V) or said salt thereof with (i) an ammonia source in the presence of a condensing agent, or (ii) an activating reagent to produce a resultant intermediate, and reacting said resultant intermediate with an ammonia source for conversion of said intermediate into an optically active amide derivative represented by formula (VI):
- or a salt thereof,
- [wherein in said formula (VI), each of R1, R2, and R3 has the same meaning as defined above];
- (C1) when R1 is an amino group, reacting said optically active amide derivative represented by formula (VI) or said salt thereof with a base for conversion of said optically active amide derivative into an optically active succinimide derivative represented by formula (I):
- or a salt thereof,
- [wherein in said formula (I), R3 has the same meaning as defined above], or
- (C2) when R1 is an amino protected with a protective group, reacting said optically active amide derivative represented by formula (VI) or said salt thereof with a base for conversion into an intermediate represented by formula (VII)
- or a salt thereof,
- [wherein in said formula (VII), R1A is an amino protected with a protective group, and R3 has the same meaning as defined above];
- and eliminating said protective group of R1A on said intermediate represented by formula (VII) or salt thereof for conversion of said intermediate into an optically active succinimide derivative represented by formula (I):
- or a salt thereof,
- [wherein in said formula (I), R3 has the same meaning as defined above];
- (D) reacting said optically active succinimide derivative of formula (I) with 2,5-dimethoxytetrahydrofuran with an acid to produce a first product;
- (E) reacting said first product of step (D) with a trichloroacetylating reagent to produce a second product;
- (F) reacting said second product of step (E) with 4-bromo-2-fluorobenzylamine to produce said compound A or said salt thereof;
- and
- (G) isolating said compound A or said salt thereof.
21 more elements
Dependencies are inferred from the claim text.