Process for production of optically active-3-amino-2-hydroxypropionic cyclopropylamide derivatives and salts thereof
View Patent ↗An objective of the present application is to provide an industrially practicable method for producing an optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivative or salt thereof from an inexpensive easily-available starting material. The derivative or salt thereof is useful as an intermediate for a medicine. It is also intended by the present application to provide a useful intermediate of the derivative. The objective is attained by the following method. First, an easily-available 2-halo-3-oxopropionic acid derivative is asymmetrically reduced, and then epoxidated to produce an optically-active epoxycarboxylic acid derivative. Next, the derivative is converted into an optically-active epoxyamide derivative by reaction with cyclopropylamine, and then reacted with a nitrile to obtain an optically-active oxazolinamide derivative. Subsequently, selective acid solvolysis of the oxazoline skeleton gives the optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivative or salt thereof.
1. An optically-active oxazolinamide derivative represented by the following formula (1):
wherein, * indicates an asymmetric carbon atom; R 1 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent.
2. An optically-active oxazoline carboxylic acid derivative represented by the following formula (5):
wherein, * indicates an asymmetric carbon atom; R 1 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 2 represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent.
3. A compound represented by the following formula (17):
wherein, * indicates an asymmetric carbon atom; R 1 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent.
4. A method for producing an optically-active 2-halo-3-hydroxypropionic acid derivative;
comprising a step of asymmetric reduction of a 2-halo-3-oxopropionic acid derivative represented by the following formula (10):
wherein, R 2 represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; X represents a halogen atom; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent;
wherein the optically-active 2-halo-3-hydroxypropionic acid derivative is represented by the following formula (11):
wherein, * indicates an asymmetric carbon atom; R 2 , R 4 and X are the same as above.
5. A method for producing an optically-active epoxyamide derivative;
comprising a step of reacting an optically-active epoxycarboxylic acid derivative represented by the following formula (7):
wherein, * indicates an asymmetric carbon atom; R 2 represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent
with a cyclopropylamine represented by the following formula (6):
wherein, the optically-active epoxyamide derivative is represented by the following formula (3):
wherein, * is the same as above; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent.
6. The method for producing the optically-active epoxyamide derivative according to claim 5 ; wherein
the compound (7) wherein R 2 is a hydrogen atom is reacted with an alkoxycarbonyl chloride, a dialkyl dicarbonate or pivaloyl chloride in a presence of a base to obtain a mixed acid anhydride; and
the mixed acid anhydride is reacted with the cyclopropylamine of the formula (6).
7. A method for producing an optically-active oxazolinamide derivative;
comprising a step of reacting an optically-active epoxyamide derivative represented by the following formula (3):
wherein, * indicates an asymmetric carbon atom; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent
with a nitrile represented by the following formula (4):
R 1 CN (4)
wherein, R 1 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent in a presence of an acid catalyst; and
wherein the optically-active oxazolinamide derivative is represented by the following formula (1):
wherein, *, R 1 and R 4 are the same as above.
8. The method for producing the optically-active oxazolinamide derivative according to claim 7 , wherein the compound (3) is obtained by a method comprising a step of reacting an optically-active epoxycarboxylic acid derivative represented by the following formula (7):
wherein, * and R 4 are the same as above; R 2 represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent
with a cyclopropylamine represented by the following formula (6):
9. A method for producing an optically-active oxazolinamide derivative;
comprising steps of reacting an optically-active epoxycarboxylic acid derivative represented by the following formula (7):
wherein, * indicates an asymmetric carbon atom; R 2 represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent
with a nitrile represented by the following formula (4):
R 1 CN (4)
wherein R 1 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent
in a presence of an acid catalyst to produce an optically-active oxazolinecarboxylic acid derivative represented by the following formula (5):
wherein, *, R 1 , R 2 and R 4 are the same as above; and
then reacting the optically-active oxazolinecarboxylic acid derivative with a cyclopropylamine represented by the following formula (6):
wherein the optically-active oxazolinamide derivative is represented by the following formula (1):
wherein, *, R 1 and R 4 are the same as above.
10. A method for producing an optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivative or salt thereof;
comprising a step of selective acid hydrolysis or acid alcoholysis of an oxazoline ring of an optically-active oxazolinamide derivative represented by the following formula (1):
wherein, * indicates an asymmetric carbon atom; R 1 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, an alkenyl group having 2 to 20 carbon atoms and optionally having a substituent, an aryl group having 6 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent; R 4 represents an alkyl group having 1 to 20 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 20 carbon atoms and optionally having a substituent;
wherein the optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivative is represented by the following formula (2):
wherein, * and R 4 are the same as above.
11. The optically-active oxazolinamide derivative according to claim 1 , wherein R 4 is an n-propyl group.
12. The optically-active oxazoline carboxylic acid derivative according to claim 2 , wherein R 4 is an n-propyl group.
13. The compound according to claim 3 , wherein R 4 is an n-propyl group.
14. The method according to claim 4 , wherein R 4 is an n-propyl group.
15. The method according to claim 5 , wherein R 4 is an n-propyl group.
16. The method according to claim 7 , wherein R 4 is an n-propyl group.
17. The method according to claim 9 , wherein R 4 is an n-propyl group.
18. The method according to claim 10 , wherein R 4 is an n-propyl group.