Process for producing optically active succinimide derivatives
View Patent ↗A process for efficiently producing optically active succinimide derivatives as key intermediates of (3R)-2′-(4-bromo-2-fluorobenzyl)spiro{pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine}-1′,2,3′,5(2′H)-tetraone, which comprises the following reaction steps, and the step 2 is performed by using a non-animal-derived enzyme.
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 that defined above] and a halogenated acetic acid ester derivative represented by the formula (III):
[Formula III]
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 that defined above] or a salt thereof,
(B) the step of allowing a non-animal-derived enzyme, an isolated host cell that produces the enzyme, a culture of the cell, or a processed product of the cell or a culture of the cell 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 that defined above] or a salt thereof,
wherein the non-animal-derived enzyme is a protein selected from the following (a) to (d):
(a) a protein identified by the amino acid sequence shown in SEQ ID NO: 2,
(b) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2 and (ii) has an esterase activity similar to that of the protein of (a),
(c) a protein comprising the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted, and
(d) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted, and (ii) has an esterase activity similar to that of the protein of (a),
(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 that 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. A process for producing an optically active carboxylic acid derivative represented by the formula (V):
[in the formula (V), R 1 represents amino or an amino protected with a protective group, and R 2 and R 3 represent a lower alkyl] or a salt thereof,
which comprises the step of allowing a non-animal-derived enzyme, an isolated host cell that produces the enzyme, a culture of the cell, or a processed product of the cell or a culture of the cell to react on 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 that defined above] or a salt thereof,
wherein the non-animal-derived enzyme is a protein selected from the following (a) to (d):
(a) a protein identified by the amino acid sequence shown in SEQ ID NO: 2,
(b) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2 and (ii) has an esterase activity similar to that of the protein of (a),
(c) a protein comprising the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted, and
(d) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted, and (ii) has an esterase activity similar to that of the protein of (a).
3. The production process according to claim 1 , wherein R 1 and R 1A are benzyloxycarbonylamino groups, R 2 is ethyl, and R 3 is ethyl.
4. 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), which comprises the step of producing an optically active succinimide derivative represented by the formula (I) (compound I) by the production process according to claim 1 , and the step of converting the compound (I) obtained in the above step into the compound A.
5. 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), which comprises the following steps (a) to (e):
(a) the step of producing an optically active succinimide derivative represented by the formula (I) (compound I) by the method according to claim 1 ;
(b) the step of reacting the compound (I) obtained in the step (a) with 2,5-dimethoxytetrahydrofuran in the presence of an acid;
(c) the step of reacting the product obtained in the step (b) with a trichloroacetylating reagent;
(d) the step of reacting the product obtained in the step (c) with 4-bromo-2-fluorobenzylamine; and
(e) the step of isolating the compound A obtained in the step (d).
6. The production process according to claim 4 , wherein R 3 is ethyl.
7. The production process according to claim 2 , wherein R 1 and R 1A are benzyloxycarbonylamino groups, R 2 is ethyl, and R 3 is ethyl.
8. The production process according to claim 5 , wherein R 3 is ethyl.
9. The production process according to claim 5 , wherein the acid is acetic acid.
10. The production process according to claim 5 , wherein the trichloroacetylating reagent is selected from the group consisting of trichloroacetyl chloride, trichloroacetyl bromide, and trichloroacetic anhydride.
11. The production process according to claim 1 , wherein the non-animal-derived enzyme is (a) a protein identified by the amino acid sequence shown in SEQ ID NO: 2.
12. The production process according to claim 1 , wherein the non-animal-derived enzyme is (b) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2 and (ii) has an esterase activity similar to that of the protein of (a).
13. The production process according to claim 1 , wherein the non-animal-derived enzyme is (c) a protein comprising the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted.
14. The production process according to claim 1 , wherein the non-animal-derived enzyme is (d) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted, and (ii) has an esterase activity similar to that of the protein of (a).
15. The production process according to claim 2 , wherein the non-animal-derived enzyme is (a) a protein identified by the amino acid sequence shown in SEQ ID NO: 2.
16. The production process according to claim 2 , wherein the non-animal-derived enzyme is (b) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2, and (ii) has an esterase activity similar to that of the protein of (a).
17. The production process according to claim 2 , wherein the non-animal-derived enzyme is (c) a protein comprising the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted.
18. The production process according to claim 2 , wherein the non-animal-derived enzyme is (d) a homolog of the protein of (a), wherein the homolog (i) consists of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 2, except that 1 to 40 amino acid residues from the N-terminus of the amino acid sequence shown in SEQ ID NO: 2 are deleted, and (ii) has an esterase activity similar to that of the protein of (a).