Processes for the preparation of substituted tetrahydro beta-carbolines

Patent metadata

Field	Value
Publication number	US-10947231-B2
Application number	US-201916580078-A
Country	US
Kind code	B2
Filing date	Sep 24, 2019
Priority date	May 27, 2009
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

Provided herein are improved processes for the synthesis of substituted tetrahydro beta-carboline derivatives. In particular, provided herein are improved processes useful for the preparation of (S)-4-chlorophenyl 6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate. Formula (I):

First claim

What is claimed is:

1. A process for preparing a compound of Formula (IIa):

comprising the steps of:
i) preparing a mixture by adding 2% water to absolute ethanol then adding N-acetyl-(L) phenylalanine;
ii) heating the mixture to reflux;
iii) cooling the refluxed mixture from step ii) to a temperature between about 58° C. and 52° C.;
iv) preparing a solution by adding 2% water to absolute ethanol then adding a compound of Formula (IVa):

v) heating the solution to reflux;
vi) cooling the refluxed solution from step v) to a temperature between about 58° C. and 52° C.;
vii) preparing a reaction mixture by adding 0.1 equivalents of N-acetyl-(L) phenylalanine from the mixture from step iii) to one equivalent of Formula (IVa) from the solution from step vi) while maintaining a temperature between about 58° C. and 52° C.;
viii) seeding the reaction mixture by adding (S)-piperindinoindole Form B, wherein (S)-piperindinoindole Form B is a crystalline form of the compound of Formula (IIa), and stirring for about 5 minutes;
ix) forming a suspension by adding an additional 0.4 equivalents of N-acetyl-(L)-phenylalinine from the mixture from step iii) to the reaction mixture from step viii) while maintaining a temperature of between about 58° C. and 52° C.;
x) cooling the suspension from step ix) to a temperature of between about 17° C. and 13° C. at a linear rate over a period of about 2 hours;
xi) stirring the cooled suspension from step x) while maintaining the temperature between about 17° C. and 13° C. for about 1 hour; and
xii) filtering the stirred suspension of step xi) and washing with a mixture of absolute ethanol and 2% water.

2. The process of claim 1 , wherein the refluxing in step ii) is conducted over a time period of about 30 to about 60 minutes.

3. The process of claim 1 , wherein the refluxing in step v) is conducted over a time period of about 50 to about 70 minutes.

4. The process of claim 1 , wherein in step vii) the mixture of step ii) is added to the solution of step v) over a time period of about 15 minutes.

5. The process of claim 1 , wherein in step ix) the mixture of step ii) is added to the reaction mixture solution of step viii) over a time period of about 2 hours.

6. The process of claim 1 , wherein the concentration of N-acetyl-(L)-phenylalanine in the mixture of step i) is 0.17 M, and the concentration of Formula (IVa) in the solution of step iv) is 0.16 M.

Assignees

• Ptc Therapeutics Inc

Inventors

• Hwang Peter Seongwoo
• Moon Young-Choon
• Tamil Arasu
• Qi Hongyan
• Almstead Neil

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title