Preparation method for rivastigmine, intermediates thereof, and preparation method for said intermediates

Patent metadata

Field	Value
Publication number	US-9353049-B2
Application number	US-201214118411-A
Country	US
Kind code	B2
Filing date	May 16, 2012
Priority date	May 18, 2011
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The present invention provides a preparation method for (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate, preparation methods for intermediates (S)-1-(3-methoxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium, (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium and (S)-1-(3-(ethyl(methyl)carbamoyloxy)phenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium, as well as a method for using (S)-1-(3-(ethyl(methyl)carbamoyloxy)phenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium to prepare rivastigmine which can be used for the treatment of Alzheimer's disease.

First claim

The invention claimed is:

1. A compound corresponding to Formula IX:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 , SO 3 CF 3 , SO 3 F, Cl, Br, and I.

2. A compound corresponding to Formula VIII:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 , SO 3 CF 3 , SO 3 F, CI, Sr, and I.

3. A compound corresponding to formula VI:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 , SO 3 CF 3 , SO 3 F, CI, Br, and I.

4. A method for preparing the compound corresponding to formula IX as described in claim 1 , the method comprising:
methylating a compound corresponding to formula V to obtain a compound corresponding to formula VIII,
wherein the compound of formula V corresponds to:

wherein the compound of formula VIII corresponds to:

and
allowing the compound corresponding to formula VIII to undergo a condensation reaction with ethyl(methyl)carbamic chloride to obtain the compound corresponding to formula IX,
wherein the compound of formula IX corresponds to:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 , SO 3 CF 3 , SO 3 F, CI, Br, and I.

5. A method for preparing a compound corresponding to formula IX, the method comprising:
methylating a compound of formula III to obtain a compound corresponding to formula VI,
wherein the compound of formula III corresponds to:

wherein the compound of formula VI corresponds to:

demethylating a compound corresponding to formula VI to obtain a compound comes to formula VIII;
wherein the compound of formula VIII corresponds to:

performing a condensation reaction between the compound corresponding formula VIII and ethyl(methyl)carbamic chloride to obtain a compound corresponding formula IX,
wherein the compound of formula IX corresponds to:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 ; SO 3 CF 3 , SO 3 F, Cl, Br, and I.

6. A method for preparing a compound corresponding to formula IX, the method comprising:
methylating a compound corresponding to formula IV to obtain a compound corresponding to formula VI
wherein the compound of formula IV corresponds to:

wherein the compound of formula VI corresponds to:

demethylating the compound corresponding to formula VI to obtain a compound corresponding to formula VIII,
wherein the compound of formula VIII corresponds to:

and
performing a condensation reaction between the compound corresponding to formula VIII and ethyl(methyl)carbamic chloride to obtain a compound corresponding to formula IX,
wherein the compound of formula IX corresponds to:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 , SO 3 CF 3 , SO 3 F, Cl, Br, and I.

7. A method for preparing a compound corresponding to formula IX, the method comprises:
performing a condensation reaction between a compound corresponding to formula V with ethyl(methyl)carbamic chloride to obtain a compound corresponding to formula VII,
wherein the compound of formula V corresponds to:

wherein the compound of formula VII corresponds to:

and
methylating the compound corresponding to formula VII to obtain a compound corresponding to formula IX
wherein the compound of formula IX corresponds to:

wherein Y is selected from the group consisting of SO 4 CH 3 , CO 3 CH 3 , SO 3 CF 3 , SO 3 F, CI, Br, and I.

8. The method according to any one of claims 5 and 6 , wherein demethylation is performed in the presence of hydrobromic acid, aluminum chloride or concentrated sulfuric acid.

9. The method according to any one of the claims 4 - 7 ,
wherein the methylation agents are selected from the group consisting of methyl fluoride, methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, dimethyl carbonate, methyltrifluoromethane sulfonate, and methyl fluorosulfonate;
wherein the methylation is performed between 0° C.-100° C.;
wherein methylation uses an inert solvent as a reaction solvent in which the inert solvent is selected from the group consisting of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an alcohol solvent, an amide solvent, acetonitrile, ethyl acetate, and acetone;
wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane, and 2-methyltetrahydrofuran;
wherein the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, and xylene;
wherein the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, chloroform, and dichloroethane;
wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, and isopropanol; and
wherein the amide solvent is selected from the group consisting of N,N-dimethylformamide, and N,N-dimethylacetamide.

10. The method according to any one of claims 4 - 6 , wherein at least one of an alkaline substance is added to the condensation reaction in which the alkaline substance is selected from the group consisting of an inorganic alkali compound, an alkali metal alcoholate compound, and an organic alkali compound;
wherein the inorganic alkali compound is selected from the group consisting of sodium carbonate potassium carbonate, sodium hydroxide, potassium hydroxide, sodium amide, and sodium hydride;
wherein the alkali metal alcoholate compound is selected from the group consisting of sodium methylate, sodium ethoxide, and potassium tert-butoxide; and
wherein the organic alkali compound is selected from the group consisting of triethylamine, pyridine, quinoline, and diisopropyl ethyl amine;
wherein the condensation reaction temperature is between 0° C.-120° C.;
wherei

Assignees

• Zhang Fuli
• Yang Zhezhou
• Yang Chunbo
• Chen Daoxin
• Yang Zhiqing
• Sun Rentong
• Bai Hua
• Zhejiang Hisun Pharm Co Ltd
• Shanghai Inst Pharm Industry

Inventors

• Zhang Fuli
• Yang Zhezhou
• Yang Chunbo
• Chen Daoxin
• Yang Zhiqing
• Sun Rentong
• Bai Hua

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07C215/66

  with quaternised amino groups bound to the carbon skeleton · CPC title

• C07C269/06

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

• C07B2200/07

  Optical isomers · CPC title

• C07C217/58

  with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain · CPC title