# US 9,434,737 B2 · Process for producing optically active succinimide derivatives and intermediates thereof

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- Number: US 9,434,737 B2
- Document ID: US9434737B2
- Status: Granted
- Kind: B2
- Application number: 14/104,597
- Filed: 2013-12-12
- Published: 2014-04-10
- Granted: 2016-09-06
- Earliest claimed: 2009-02-06
- Assignees: Sumitomo Dainippon Pharma Co., Ltd.; Kyowa Hakko Bio Co., Ltd.
- Applicants: Dainippon Sumitomo Pharma Co., Ltd.; Kyowa Hakko Bio Co., Ltd.
- Inventors: Masaji Kasai; Shinji Kita; Tadashi Ogawa; Hideaki Tokai
- Web page: https://patentgrep.com/patent/US9434737B2

## CPC

- C07D 487/20: Spiro-condensed systems
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07D 207/416: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C12P 7/62: Carboxylic acid esters
- C12P 17/10: Nitrogen as only ring hetero atom
- C12P 17/182: {Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system (alloxazine or isoalloxazine, e.g. riboflavine C12P25/00)}
- C12P 41/005: {by esterification of carboxylic acid groups in the enantiomers or the inverse reaction}
- C07B 2200/07: Optical isomers
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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).

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The process of claim 1, wherein R1 is benzyloxycarbonylamino, R2 is ethyl, and R3 is ethyl.

### Claim 3 (depends on 1)

The process of claim 1, wherein R3 is ethyl.

### Claim 4 (depends on 1)

The process of claim 1, wherein each of R1 and R1A is benzyloxycarbonylamino.

### Claim 5 (depends on 1)

The process of claim 1, further comprising reacting an aminomalonate derivative represented by formula (II):
[wherein in said formula (II), R1 and R3 have the same meaning as defined above] with a halogenated acetic acid ester derivative represented by formula (III):
[wherein in said formula (III), R2 has the same meaning as defined above; and Y is a halogen] in the presence of a base for conversion into said ester derivative represented by formula (IV):
or said salt thereof of step (A).

### Claim 6 (depends on 5)

The process of claim 5, wherein R1 is benzyloxycarbonylamino, R2 is ethyl, and R3 is ethyl.

### Claim 7 (depends on 5)

The process of claim 5, wherein R3 is ethyl.

### Claim 8 (depends on 5)

The process of claim 5, wherein each of R1 and R1A is benzyloxycarbonylamino.