Preparation method for optically active bicyclic gamma-amino acid compound

Patent metadata

Field	Value
Publication number	US-9469623-B2
Application number	US-201514615972-A
Country	US
Kind code	B2
Filing date	Feb 6, 2015
Priority date	Jul 8, 2013
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

An object of the present invention is to provide an optically active bicyclic γ-amino acid derivative in a high purity. The object can be attained by a mixture of compounds represented by the general formulas (I) and (I′), or a method for producing a compound represented by the general formula (VII) or a salt thereof via the compound (I):

wherein R 1 and R 2 each represent a C1-6 alkyl group or the like; and R 3 represents a cyano group or the like,

First claim

The invention claimed is:

1. A mixture of compounds of formulas (I) and (I′):

wherein R 1 and R 2 are each independently selected from a hydrogen atom and a C1-6 alkyl group, or R 1 and R 2 are bonded to each other to form an isopropylidene group; and
R 3 is a cyano group or a nitromethyl group.

2. A compound of formula (I) or (I′):

wherein R 1 and R 2 are each independently selected from a hydrogen atom and a C1-6 alkyl group, or R 1 and R 2 are bonded to each other to form an isopropylidene group; and
R 3 is a cyano group or a nitromethyl group.

3. A method of producing a compound of formula (Ia), an enantiomer thereof, or both a compound of formula (Ia) and an enantiomer thereof, comprising
mixing a compound of formula (II), an enantiomer thereof, or both a compound of formula (II) and an enantiomer thereof, with an alkali metal salt of hydrogen cyanide in a solvent to produce the compound of formula (Ia), an enantiomer thereof, or both a compound of formula (Ia) and an enantiomer thereof:

wherein R 1 and R 2 are each independently selected from a hydrogen atom and a C1-6 alkyl group, or R 1 and R 2 are bonded to each other to form an isopropylidene group.

4. A method of producing a compound of formula (Ib), an enantiomer thereof, or both a compound of formula (Ib) and an enantiomer thereof, comprising
mixing a compound of formula (II), an enantiomer thereof, or both a compound of formula (II) and an enantiomer thereof, with nitromethane in the presence of a base in a solvent to produce the compound of formula (Ib), an enantiomer thereof, or both a compound of formula (Ib) and an enantiomer thereof:

wherein R 1 and R 2 are each independently selected from a hydrogen atom and a C1-6 alkyl group, or R 1 and R 2 are bonded to each other to form an isopropylidene group.

5. A method of producing a compound of formula (Ia), an enantiomer thereof, or both a compound of formula (Ia) and an enantiomer thereof, comprising
producing a compound of formula (II), an enantiomer thereof, or both a compound of formula (II) and an enantiomer thereof, from a compound of formula (III), an enantiomer thereof, or both a compound of formula (III) and an enantiomer thereof, and a compound of formula (IV) using a Lewis acid, and
producing the compound of formula (Ia), an enantiomer thereof, or both a compound of formula (Ia) and an enantiomer thereof, from the compound of formula (II), an enantiomer thereof, or both a compound of formula (II) and an enantiomer thereof, by the method of claim 3 :

6. A method of producing a compound of formula (V), an enantiomer thereof, or both a compound of formula (V) and an enantiomer thereof, comprising
treating a compound of formula (I), an enantiomer thereof, or both a compound of formula (I) and an enantiomer thereof, with a base in a solvent to produce the compound of formula (V), an enantiomer thereof, or both a compound of formula (V) and an enantiomer thereof:

wherein R 1 and R 2 are each independently selected from a hydrogen atom and a C1-6 alkyl group; and
R 3 is a cyano group or a nitromethyl group.

7. A method of separating a compound of formula (V) and a compound of formula (V′), comprising
allowing a mixture of the compound of formula (V) and the compound of formula (V′) to form a salt with an optically active organic amine:

wherein R 3 is a cyano group or a nitromethyl group.

8. A method of producing a compound of formula (VI), comprising
allowing a compound of formula (V) to form a salt with an organic amine in the presence of a solvent:

wherein R 3 is a cyano group or a nitromethyl group.

9. The method of claim 8 , wherein
R 3 is a nitromethyl group,
the organic amine is an optically active organic amine, and
a racemic mixture of the compound of formula (V) and the compound of formula (V′) is optically resolved.

10. A method of producing a compound of formula (VII) from a compound of formula (V) or (VI), comprising
reducing the compound of formula (V) in the presence of a metal catalyst in a solvent under a hydrogen atmosphere, or
subjecting a solution of the compound of formula (V) obtained through the salt dissociation of the compound of formula (VI) to a reduction reaction in the presence of a metal catalyst under a hydrogen atmosphere
to produce the compound of formula (VII):

wherein R 3 is a cyano group or a nitromethyl group.

11. The method of claim 10 , comprising
converting the compound of formula (VI) to a compound of formula (V) through salt dissociation, and
subjecting the compound of formula (V) to a reduction reaction in the presence of a metal catalyst in a solvent under a hydrogen atmosphere to produce the compound represented by the formula (VII).

12. The method of claim 10 , wherein the metal catalyst is a sponge nickel catalyst or a sponge cobalt catalyst.

13. The method of claim 10 , wherein R 3 is a cyano group.

14. The method of claim 10 ,
wherein the solvent is water, and
the reduction reaction is performed under basic conditions by the addition of a hydroxide of an alkali metal.

15. The method of claim 11 , wherein
the metal catalyst is a sponge nickel catalyst or a sponge cobalt catalyst,
R 3 is a cyano group,
the solvent is water, and
the reduction reaction is performed under basic conditions by the addition of a hydroxide of an alkali metal.

16. A method of producing a compound of formula (Ib), an enantiomer thereof, or both a compound of formula (Ia) and an enantiomer thereof:

comprising
producing a compound of formula (II), an enantiomer thereof, or both a compound of formula (II) and an enantiomer thereof, from a compound of formula (III), an enantiomer thereof, or both a compound of formula (III) and an enantiomer thereof, and a compound of formula (IV) using a Lewis acid, and
producing the compound of formula (Ib), an enantiomer thereof, or both a compound of formula (Ia) and an enantiomer thereof, from the compound of formula (II), an enantiomer thereof, or both a compound of formula (II) and an enantiomer thereof, by the method of claim 3 or 4 :

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Nakamura Yoshitaka
• Ukai Kazutoshi
• Kitawaki Takafumi
• Nakajima Takumi
• Kitagawa Yutaka
• Furuya Yukito
• Imai Makoto
• Numagami Eiji
• Wakayama Masakazu
• Saito Ayako

Classifications

• C07C201/12

  by reactions not involving the formation of nitro groups · CPC title

• C07C253/34

  Separation; Purification · CPC title

• C07C2102/20

  Chemistry & Metallurgy · mapped topic

• C07C67/00

  Preparation of carboxylic acid esters · CPC title

• C07C253/00

  Preparation of carboxylic acid nitriles (of cyanogen or compounds thereof C01C3/00) · CPC title