Process for producing optically active succinimide derivatives and intermediates thereof

1. A process for producing an optically active succinimide derivative represented by the formula (I):

[in the formula (I), R 3 represents a lower alkyl] or a salt thereof, which comprises the following steps (A) to (D), and further comprises the step (E), if necessary:

(A) the step of reacting an aminomalonate derivative represented by the formula (II):

[in the formula (II), R 1 represents amino or an amino protected with a protective group, and two of R 3 represent the same lower alkyls having the same meaning as defined above] and a halogenated acetic acid ester derivative represented by the formula (III):

[Formula 3]

Y—CH 2 CO 2 R 2 (III)

[in the formula (III), R 2 represents a lower alkyl, and Y represents a halogen] in the presence of a base for conversion into an ester derivative represented by the formula (IV):

[in the formula (IV), each of R 1 , R 2 , and R 3 has the same meaning as defined above] or a salt thereof,

(B) the step of allowing an enzyme that is a pig liver esterase or a rabbit liver esterase to react on the ester derivative represented by the formula (IV) or a salt thereof for conversion into an optically active carboxylic acid derivative represented by the formula (V):

[in the formula (V), each of R 1 , R 2 , and R 3 has the same meaning as defined above] or a salt thereof,

(C) the step of reacting the optically active carboxylic acid derivative represented by the formula (V) or a salt thereof with an ammonia source in the presence of a condensing agent, or reacting the optically active carboxylic acid derivative represented by the formula (V) or a salt thereof with an activating reagent and then reacting the resultant with an ammonia source, for conversion into an optically active amide derivative represented by the formula (VI):

[in the formula (VI), each of R 1 , R 2 , and R 3 has the same meaning as that defined above] or a salt thereof,

(D) the step of allowing a base to react on the optically active amide derivative represented by the formula (VI) or a salt thereof for conversion into an optically active succinimide derivative represented by the formula (I) or (VII):

[in the formula (VII), R 1A represents an amino protected with a protective group, and R 3 has the same meaning as defined above] or a salt thereof, and

(E) the step of eliminating the protective group on R 1A of the optically active succinimide derivative represented by the formula (VII) or a salt thereof for conversion into an optically active succinimide derivative represented by the formula (I) or a salt thereof.

2. The production process according to claim 1 , wherein R 1 is benzyloxycarbonylamino, R 1A is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

3. A process for producing an optically active carboxylic acid derivative represented by the formula (V)

wherein R 1 is amino or an amino protected with a protective group, R 2 is a lower alkyl, and R 3 is a lower alkyl, or a salt thereof,

which process comprises the step of allowing an enzyme that is a pig liver esterase or a rabbit liver esterase to react on an ester derivative represented by the formula (IV)

wherein each of R 1 , R 2 , and R 3 has the same meaning as defined above, or a salt thereof.

4. The production process according to claim 3 , wherein R 1 is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

5. A process for producing an optically active amide derivative represented by the formula (VI)

wherein R 1 is amino or an amino protected with a protective group, R 2 is a lower alkyl, and R 3 is a lower alkyl, or a salt thereof,

which process comprises the step of reacting an optically active carboxylic acid derivative represented by the formula (V)

wherein each of R 1 , R 2 , and R 3 has the same meaning as defined above, or a salt thereof with an activating reagent, and further reacting the resultant with an ammonia source.

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

7. A process for producing an optically active amide derivative represented by the formula (VI)

wherein R 1 is amino or an amino protected with a protective group, R 2 is a lower alkyl, and R 3 is a lower alkyl, or a salt thereof,

which process comprises the step of reacting an optically active carboxylic acid derivative represented by the formula (V)

wherein each of R 1 , R 2 , and R 3 has the same meaning as defined above, or a salt thereof with an ammonia source in the presence of a condensing agent.

8. The production process according to claim 7 , wherein R 1 is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

9. A process for producing an optically active succinimide derivative represented by the formula (I)

or the formula (VII)

wherein R 1A represents an amino protected with a protective group, and R 3 is a lower alkyl, or a salt thereof,

which process comprises the step of allowing a base to react on an optically active amide derivative represented by the formula (VI)

wherein R 1 is amino or an amino protected with a protective group, R 2 is a lower alkyl, and R 3 is a lower alkyl, or a salt thereof.

10. The production process according to claim 9 , wherein R 1 is benzyloxycarbonylamino, R 1A is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

11. An optically active carboxylic acid derivative represented by the formula (V):

[in the formula (V), R 1 is amino or an amino protected with a protective group, R 2 represent a lower alkyl, and R 3 is a lower alkyl] or a salt thereof.

12. The derivative or a salt thereof according to claim 11 , wherein R 1 is benzyloxycarbonylamino, R 2 is ethyl, and R 3 is ethyl.

13. An optically active amide derivative represented by the formula (VI):

[in the formula (VI), R 1 is amino or an amino protected with a protective group, R 2 is a lower alkyl, and R 3 is a lower alkyl] or a salt thereof.