Process for preparing AD-35

Patent metadata

Field	Value
Publication number	US-10399992-B2
Application number	US-201716087308-A
Country	US
Kind code	B2
Filing date	Mar 28, 2017
Priority date	Apr 11, 2016
Publication date	Sep 3, 2019
Grant date	Sep 3, 2019

Abstract

Disclosed are a method for preparing a benzodioxole derivative (AD-35) shown by Formula (I) and an intermediate thereof. The method of the present invention involves: using piperic acid as a raw material; and performing bromination, esterification, cyanidation, cyclopropane lactamization, amide nitrogen alkylation, deprotection, piperidine nitrogen alkylation and salification to obtain the compound of Formula (I). The method has cheap and easily available start raw materials, short synthesis routes and simple operation, and is suitable for industrial production.

First claim

The invention claimed is:

1. A compound of Formula V:

2. A method for preparing a compound represented by Formula V, the method comprises: performing a cyclopropane lactamization of a cyano ester shown by Formula IV under titanium (IV) isopropoxide (Ti(Oi-Pr) 4 ) and a Grignard reagent of ethylmagnesium halide to obtain a spirocyclopropane lactam shown by Formula V:

wherein R 3 is C 1 -C 6 alkyl; X is chlorine, bromine or iodine.

3. The method of claim 2 , characterized in that the Grignard reagent of ethylmagnesium halide is ethylmagnesium bromide.

4. The method of claim 2 , characterized in that a reaction solvent is selected from the group consisting of diethyl ether, dichloromethane, toluene, methyl tert-butyl ether or tetrahydrofuran.

5. The method of claim 2 , characterized in that a reaction temperature is controlled to be 0 to 35° C.

6. The method of claim 2 , characterized in that a molar ratio of the compound shown by Formula IV to titanium (IV) isopropoxide (Ti(Oi-Pr) 4 ) is 1:1 to 1:3.

7. The method of claim 2 , characterized in that a molar ratio of the compound shown by Formula IV to the Grignard reagent of ethylmagnesium halide is 1:1 to 1:5.

8. The method of claim 2 , characterized in that the method for preparing the compound shown by Formula IV comprises:
Step 1: In solvent, salifying piperic acid under the action of a base and following with a bromination under the action of N-bromosuccinimide (NBS) to obtain a compound shown by Formula II:

Step 2: Performing an esterification reaction of a compound shown by Formula II with an alcohol (R 3 OH) under a catalysis of an acid to obtain an ester shown by Formula III:

Step 3: Cyaniding a compound shown by Formula III under the action of a cyanide ion donor to obtain a cyano ester shown by Formula IV:

wherein R 3 is a C 1 -C 6 alkyl.

9. The method of claim 8 , wherein
in Step 1, a reaction solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, water, dichloromethane or chloroform; the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate or potassium carbonate; a molar ratio of the piperic acid, base and N-bromosuccinimide (NBS) is 1:1.2-2:1.4-2.4; a reaction temperature is controlled to be 0 to 70° C.;
in Step 2, R 3 is methyl, ethyl or isopropyl; the acid is concentrated sulfuric acid;
in Step 3, the cyanide ion donor is selected from metal cyanide.

10. A method for preparing a compound represented by Formula VII from a compound represented by Formula V, the method comprises: coupling a spirocyclopropane lactam shown by Formula V with a compound shown by Formula VI under the action of a base to obtain a compound shown by Formula VII:

wherein R 1 is a protecting group of amino; R 2 is halogen or p-toluenesulfonyloxy.

11. The method of claim 10 , characterized in that the base is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or cesium carbonate.

12. The method of claim 10 , characterized in that a molar ratio of the compound shown by Formula V to the base is 1:1 to 1:3.

13. The method of claim 10 , characterized in that a molar ratio of the compound shown by Formula V to the compound shown by Formula VI is from 1:1 to 1:3.

14. The method of claim 10 , characterized in that a reaction solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulphoxide or acetonitrile.

15. The method of claim 10 , characterized in that a reaction temperature is 25 to 75° C.

16. A method for preparing a compound represented by Formula (I),

comprising the following steps:
(a) coupling a spirocyclopropane lactam shown by Formula V with a compound shown by Formula VI under the action of a base to obtain a compound shown by the Formula VII:

wherein R 1 is a protecting group of amino; R 2 is halogen or p-toluenesulfonyloxy;
(b) removing a protecting group of amino of the compound shown by Formula VII to obtain a compound shown by Formula VIII or a salt thereof:

wherein R 1 is an protecting group of amino;
(c) reacting the compound shown by Formula VIII or a salt thereof with a compound shown by Formula IX or a salt thereof under the action of a base to obtain a compound shown by Formula XI:

wherein Y is halogen or sulfonyloxy;
(d) reacting the compound shown by Formula XI with phosphoric acid to obtain the compound of Formula I:

17. The method of claim 16 , wherein
in step (a), the base is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or cesium carbonate; a molar ratio of the compound shown by Formula V to the base is 1:1 to 1:3; a molar ratio of the compound shown by Formula V to the compound shown by Formula VI is 1:1 to 1:3; a reaction solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile, a reaction temperature is 25 to 75° C.;
in step (b), when R 1 is tert-butoxycarbonyl, and when removing the protecting group of amino under an acidic condition, the acid is selected from the group consisting of sulfuric acid, trifluoroacetic acid, hydrofluoric acid or hydrochloric acid; a reaction solvent used is selected from the group consisting of methanol, ethanol, ethyl acetate or a mixed solvent thereof; a reaction temperature is controlled to be 20 to 70° C.;
in step (c), when Y in the compound shown by Formula IX is a halogen or a sulfonyloxy; the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide; a molar ratio of the compound shown by Formula VIII to the compound shown by Formula IX is 1:1 to 1:3; a molar ratio of the compound shown by Formula VIII to the base is 1:1.5 to 1:4; a reaction solvent used is selected from the group consisting of methanol, ethanol, acetonitrile, water or a mixed solvent thereof;
in step (d), a reaction solvent used is selected from the group consisting of methanol, ethanol or isopropanol; a molar ratio of the compound shown by Formula XI to phosphoric acid is 1:0.95 to 1.05; a reaction temperature is controlled to be 20 to 80° C.

18. The method of claim 16 , characterized in that the compound shown by Formula V is prepared by the following method:

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Zhong Jinqing
• Zhao Xuyang
• Bai Hua
• Gong Yongxiang
• Zhang Xinlong
• Zhu Qifeng
• Liu Weiwei
• Zhou Ya

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

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D491/113

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D491/056 Primary

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title