Method for preparing sitagliptin intermediate via asymmetrical reduction method

Patent metadata

Field	Value
Publication number	US-10189760-B2
Application number	US-201515319370-A
Country	US
Kind code	B2
Filing date	Oct 9, 2015
Priority date	Oct 11, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Disclosed is a method for synthesizing a sitagliptin intermediate, the method comprising: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce a compound of formula I, wherein, an R- or S-configuration of a stereocenter is represented by *; the compound of formula I of R configuration can be used to prepare sitagliptin, and a reaction formula is as follows: R 1 and R 2 are each independently selected from hydrogen, C 1 -C 12 linear or branched alkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl and C 7 -C 12 arylalkyl. The method has a high yield and a high ee % value, a mild reaction condition and a low production cost, and is simple to operate, convenient to purify, environmental friendly and suitable for industrial production.

First claim

The invention claimed is:

1. A method for synthesizing sitagliptin intermediate represented by formula I via asymmetric reduction, characterized in that, it comprises the following steps: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or an ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce sitagliptin intermediate of formula I, with the following reaction formula:

wherein, an R- or S-configuration of a stereocenter is represented by *; and
R 1 and R 2 are each independently selected from hydrogen, C 1 -C 12 linear or branched alkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl and C 7 -C 12 arylalkyl;
and wherein the acidic additive is an organic acid selected from salicylic acid, tartaric acid, p-toluenesulfonic acid, or a combination thereof.

2. The method according to claim 1 , characterized in that, R 1 and R 2 are each independently selected from hydrogen, C 1 -C 4 linear or branched alkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 7 -C 12 arylalkyl.

3. The method according to claim 1 , characterized in that, the transition metal catalyst having a chiral phosphine ligand is a transition metal catalyst having a (R)-dm-Segphos ligand.

4. The method according to claim 1 , characterized in that, the ammonium salt is selected from an ammonium salt of an inorganic acid or an ammonium salt of an organic acid.

5. The method according to claim 4 , characterized in that, the ammonium salt of an inorganic acid is selected from ammonium chloride, ammonium sulfate, or a combination thereof; and the ammonium salt of an organic acid is selected from ammonium acetate, ammonium formate, ammonium salicylate, ammonium benzoate, or a combination thereof.

6. The method according to claim 1 , characterized in that, the organic solvent is selected from alcohols, acetonitrile, toluene, N,N-dimethylformamide, 1,2-dichloroethane, or a combination thereof.

7. The method according to claim 1 , characterized in that, the organic solvent is selected from alcohols, and the alcohols are selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, or a combination thereof.

8. The method according to claim 1 , characterized in that, the mole percentage of the catalyst to the compound of formula II is 0.1 to 10.0 mol %.

9. The method according to claim 1 , characterized in that, the hydrogen pressure is 2 to 10 MPa in the asymmetric reductive amination.

10. The method according to claim 1 , characterized in that, the temperature of the asymmetric reductive amination is 50 to 100° C.

11. The method according to claim 2 , characterized in that, R 1 and R 2 are each independently selected from hydrogen, C 1 -C 4 linear or branched alkyl and C 7 -C 12 arylalkyl.

12. The method according to claim 2 , characterized in that, R 1 and R 2 are each independently selected from hydrogen, methyl, ethyl and benzyl.

13. The method according to claim 3 , characterized in that, the transition metal catalyst having a chiral phosphine ligand is a ruthenium catalyst having a (R)-dm-Segphos ligand.

14. The method according to claim 3 , characterized in that, the transition metal catalyst having a chiral phosphine ligand is selected from Ru(OAc) 2 ((R)-dm-Segphos) and/or Ru(Cl) 2 ((R)-dm-Segphos).

15. The method according to claim 7 , characterized in that, the alcohols are selected from methanol, ethanol, or a combination thereof.

16. The method according to claim 8 , characterized in that, the mole percentage of the catalyst to the compound of formula II is 1 to 3 mol %.

17. A method for synthesizing sitagliptin, comprising the following steps:
a) synthesizing sitagliptin intermediate represented by formula I with the method according to claim 1 , and
b) converting the sitagliptin intermediate obtained in step a) to sitagliptin.

Assignees

• Zhejiang Huahai Pharm Co Ltd
• Shanghai Syncores Tech Inc Ltd

Inventors

• Hong Jian
• Wang Yusheng
• Wang Boyu
• Huang Luning
• Gu Eric

Classifications

• B01J27/18

  with metals {other than Al or Zr} · CPC title

• C07C29/153 Primary

  characterised by the catalyst used · CPC title

• C07C229/34

  the carbon skeleton containing six-membered aromatic rings · CPC title

• C07C227/32

  by stereospecific synthesis · CPC title

• B01J2531/004

  Ligands · CPC title