Synthetic route to scopolamine and/or atropine

Patent metadata

Field	Value
Publication number	US-11739084-B2
Application number	US-202117450254-A
Country	US
Kind code	B2
Filing date	Oct 7, 2021
Priority date	Oct 7, 2021
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

A synthetic route to scopolamine and/or atropine. In such context, the present invention identifies a method for preparing 6,7-dehydro atropine, which can be converted into either scopolamine and/or atropine, along with a method for converting a protected pyrrole into a tetrachlorobicylic compound, such as benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

First claim

What is claimed is:

1. A method for preparing 6,7-dehydro atropine comprising:
(a) providing a protected pyrrole having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;
(b) reacting the protected pyrrole with pentachloroacetone and forming a first tetrachloro-bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;

(c) carrying out a reductive dechlorination of said first tetrachloro-bicyclic compound and forming a second bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;

(d) carrying out a reductive methylation of the second bicyclic compound formed in step (c) and forming or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula:

(e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into 6,7-dehydro tropene tosylate having the following formula:

wherein − OTs is reference to − OSO 2 —Ar—CH 3 ; and

(f) converting 6,7-dehydro tropene tosylate into 6,7-dehydro atropine having the following formula:

2. The method of claim 1 wherein 6,7-dehydro atropine is converted by oxidation into scopolamine having the following formula:

3. The method of claim 2 wherein said oxidation of 6,7-dehydro atropine occurs in the presence of manganese sulfate, hydrogen peroxide and sodium bicarbonate.

4. The method of claim 1 wherein 6,7-dehydro atropine is converted by reduction into atropine having the following formula:

5. The method of claim 4 wherein said reduction of 6,7-dehydro atropine occurs by diimide reduction wherein hydrazine is oxidized to a diimide in situ.

6. The method of claim 1 wherein R is a benzyl group, said first tetrachloro-bicyclic compound comprises benzyl 2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate and said second bicyclic compound comprises benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

7. The method of claim 1 wherein in step (b), said reaction of said pyrrole with pentachloroacetone takes place in the presence of N-methylmorpholine.

8. The method of claim 1 wherein in step (b), pentachloroacetone is provided in situ from hexachloroacetone.

9. A method for preparing scopolamine comprising:
(a) providing a protected pyrrole having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;
(b) reacting the protected pyrrole with pentachloroacetone, wherein said pentachloroacetone is provided in situ from hexachloroacetone and forming a first tetrachloro-bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;

(c) carrying out a reductive dechlorination of said first tetrachloro-bicyclic compound and forming a second bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;

(d) carrying out a reductive methylation of the second bicyclic compound formed in step (c) and forming or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula:

(e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into 6,7-dehydro tropene tosylate having the following formula:

wherein − OTs is reference to − OSO 2 —Ar—CH 3 ; and

(f) converting 6,7-dehydro tropene tosylate into 6,7-dehydro atropine having the following formula:

 and
(g) converting 6,7-dehydro atropine by oxidation into scopolamine having the following formula:

10. The method of claim 9 wherein said oxidation of 6,7-dehydro atropine occurs in the presence of manganese sulfate, hydrogen peroxide and sodium bicarbonate.

11. A method for preparing atropine comprising:
(a) providing a protected pyrrole having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;
(b) reacting the protected pyrrole with pentachloroacetone, wherein said pentachloroacetone is provided in situ from hexachloroacetone and forming a first tetrachloro-bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;

(c) carrying out a reductive dechlorination of said first tetrachloro-bicyclic compound and forming a second bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group;

(d) carrying out a reductive methylation of the second bicyclic compound formed in step (c) and forming or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula:

(e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into 6,7-dehydro tropene tosylate having the following formula:

wherein − OTs is reference to − OSO 2 —Ar—CH 3 ; and

(f) converting 6,7-dehydro tropene tosylate into 6,7-dehydro atropine having the following formula:

 and
converting 6,7-dehydro atropine by reduction into atropine having the following formula:

12. The method of claim 11 wherein said reduction of 6,7-dehydro atropine occurs by diimide reduction wherein hydrazine is oxidized to diimid

Assignees

• Southwest Res Inst

Inventors

• Blumberg Shawn T
• Miguel Paul W
• Hinojosa Daniel A

Classifications

• C07D451/10 Primary

  acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine · CPC title