Process for producing optically active succinimide derivatives and intermediates thereof

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), R 1 is an amino or an amino protected with a protective group and R 2 and R 3 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 R 1 , R 2 , and R 3 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 R 1 , R 2 , and R 3 has the same meaning as defined above];

(C1) when R 1 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), R 3 has the same meaning as defined above], or

(C2) when R 1 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), R 1A is an amino protected with a protective group, and R 3 has the same meaning as defined above]; and eliminating said protective group of R 1A 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), R 3 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.

2. The process of claim 1 , wherein R 1 is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

3. The process of claim 1 , wherein R 3 is ethyl.

4. The process of claim 1 , wherein each of R 1 and R 1A is benzyloxycarbonylamino.

5. The process of claim 1 , further comprising reacting an aminomalonate derivative represented by formula (II):

[wherein in said formula (II), R 1 and R 3 have the same meaning as defined above] with a halogenated acetic acid ester derivative represented by formula (III):

[wherein in said formula (III), R 2 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).

6. The process of claim 5 , wherein R 1 is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

7. The process of claim 5 , wherein R 3 is ethyl.

8. The process of claim 5 , wherein each of R 1 and R 1A is benzyloxycarbonylamino.