4-substituent-2-hydroxylmorpholine-3-one and preparation method thereof

Patent metadata

Field	Value
Publication number	US-9676736-B2
Application number	US-201314394041-A
Country	US
Kind code	B2
Filing date	Apr 15, 2013
Priority date	Apr 13, 2012
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

A molecule with neural activities, especially 4-substituent-2-hydroxymorpholin-3-one, as a new intermediate of neurokinin-1 receptor antagonist aprepitant, and preparation method thereof.

First claim

The invention claimed is:

1. A compound of Formula I:

wherein,
G is selected from the group consisting of:
(i) groups of Formula II

wherein,
R 1 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted or unsubstituted phenyl, chloro, bromo, iodo, —CN, —CX 3 , —NO 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —(CH 2 ) m —NR 4 R 5 , —NR 4 COR 5 , —NR 4 CO 2 R 5 , —CONR 4 R 5 , —COR 4 , —CO 2 R 4 , or hydroxyl;
R 2 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted or unsubstituted phenyl, halo, —CN, —CX 3 , —NO 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —(CH 2 ) m —NR 4 R 5 , —NR 4 COR 5 , —NR 4 CO 2 R 5 , —CONR 4 R 5 , —COR 4 , —CO 2 R 4 , or hydroxyl;
R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted or unsubstituted phenyl, halo, —CN, —CX 3 , —NO 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —(CH 2 ) m —NR 4 R 5 , —NR 4 COR 5 , —NR 4 CO 2 R 5 , —CONR 4 R 5 , —COR 4 , —CO 2 R 4 , or hydroxyl;
when the C 1 -C 6 alkyl or C 2 -C 6 alkenyl of R 1 , R 2 , or R 3 is substituted, the substituent is, or the substituents are independently, selected from the group consisting of: hydroxyl, oxo-, C 1 -C 6 alkoxy, phenyl, —CN, —NO 2 , halo, —NR 4 R 5 , —NR 4 COR 5 , —NR 4 CO 2 R 5 , —CONR 4 R 5 , —COR 4 , and —CO 2 R 4 ;
when the phenyl of R 1 , R 2 , or R 3 is substituted, the substituent is, or the substituents are independently, selected from the group consisting of: hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, halo, —CN, —NO 2 , —CF 3 , —(CH 2 ) m —NR 4 R 5 , —NR 4 COR 5 , —NR 4 CO 2 R 5 , —CONR 4 R 5 , —COR 4 , and —CO 2 R 4 ;
provided that R 1 , R 2 , and R 3 are not hydrogen at the same time;
R 4 and R 5 are independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, monohydroxyl substituted C 1 -C 6 alkyl, and phenyl;
R 6 is hydrogen or C 1 -C 6 alkyl;
X is selected from the group consisting of Cl, Br, and F; and
m is 1, 2, 3 or 4; and
(ii) groups of Formula III

wherein,
R 7 , R 8 , and R 9 are independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted or unsubstituted phenyl, halo, —CN, —CX 3 , —NO 2 , —SR 12 , —SOR 12 , —SO 2 R 12 , —(CH 2 ) m —NR 10 R 11 , —NR 10 COR 11 , —NR 10 CO 2 R 11 , —CONR 10 R 11 , —COR 10 , —CO 2 R 10 , hydroxyl, or C 1 -C 6 alkoxy;
when the C 1 -C 6 alkyl or C 2 -C 6 alkenyl of R 7 , R 8 , or R 9 is substituted, the substituent is, or the substituents are independently, selected from the group consisting of: hydroxyl, oxo-, C 1 -C 6 alkoxy, phenyl, —CN, —NO 2 , halo, —NR 10 R 11 , —NR 10 COR 11 , —NR 10 CO 2 R 11 , —CONR 10 R 11 , —COR 10 , and —CO 2 R 10 ;
when the phenyl of R 7 , R 8 , or R 9 is substituted, the substituent is, or the substituents are independently, selected from the group consisting of: hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, halo, —CN, —NO 2 , —CF 3 , —(CH 2 ) m —NR 10 R 11 , —NR 10 COR 11 , —NR 10 CO 2 R 11 , —CONR 10 R 11 , —COR 10 , and —CO 2 R 10 ;
R 10 and R 11 are independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, monohydroxyl substituted C 1 -C 6 alkyl, and phenyl;
R 12 is hydrogen or C 1 -C 6 alkyl;
X is selected from the group consisting of Cl, Br, and F; and
m is 1, 2, 3 or 4.

2. The compound according to claim 1 , wherein G is of Formula II

3. The compound according to claim 1 , wherein G is of Formula II:

wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of: hydrogen, —NO 2 , —Cl, and —CF 3 ; provided that R 1 , R 2 , and R 3 are not hydrogen at the same time.

4. The compound of according to claim 1 , where the compound is of the formula:

5. A method for preparing the compound according to claim 1 comprising reacting a compound of Formula IV:

wherein G is as defined in claim 1 with an aqueous glyoxalic acid solution.

6. The method according to claim 5 , wherein the step of reacting further comprises the presence of a solvent, wherein the solvent is ethyl acetate, C 6 -C 12 alkane, benzene, toluene, paraxylene, chlorobenzene, orthodichlorobenzene, acetone, dichloromethane, chloroform, nitromethane, N,N-dimethyl formamide, dimethyl sulfoxide, 2-butanone, C 1 -C 6 alcohols, 1,3-dioxane, 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethyl ethyl, water, or a mixture thereof.

7. The method according to claim 5 , wherein the reaction temperature of the step of reacting is from 30 to 100° C.

8. The method according to claim 5 , wherein the aqueous glyoxalic acid solution is an aqueous solution of glyoxalic acid monohydrate, or an aqueous glyoxalic acid solution with a mass ratio of glyoxalic acid to water being between 1% and 99%.

9. A method of preparing a compound of Formula IX:

comprising:
i) reacting a compound of claim 1 with trifluoroacetic anhydride to provide a compound of Formula X:

wherein G is as defined in claim 1
ii) under the catalysis of boron trifluoride, reacting the compound of Formula X with a compound of Formula XI:

to provide a compound of Formula XII:

wherein G is as defined in claim 1
iii) chirally transforming the compound of Formula XII in the presence of potassium linaloolate to provide a compound of formula XIII:

wherein G is as defined in claim 1
iv) reacting the compound of Formula XIII with p-fluorophenyl magnesium bromide; and
v) hydrogenating the product of step iv) under the catalysis of palladium/carbon to provide the compound of Formula IX.

10. The compound according to claim 1 , wherein R 1 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted or unsubstituted phenyl, chloro, —CN, —CX 3 , —NO 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —(CH 2 ) m —NR 4 R 5 , —NR 4 COR 5 , —NR 4 CO 2 R 5 , —CONR 4 R 5 , —COR 4 , —CO 2 R 4 , or hydroxyl.

11. The compound according to claim 1 , wherein G is of Formula II:

Assignees

• Zhejiang Hisun Pharm Co Ltd
• Shanghai Inst Pharmaceutical Ind

Inventors

• Zhang Fuli
• Liu Chonghao
• Qiu Pengcheng
• Chai Jian
• Cai Qingfeng

Classifications

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D265/32 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title