Process for preparing pridopidine

Patent metadata

Field	Value
Publication number	US-10047049-B2
Application number	US-201615217683-A
Country	US
Kind code	B2
Filing date	Jul 22, 2016
Priority date	Jul 22, 2015
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

This invention provides a pridopidine base in a solid form, a method of preparing the solid pridopidine base, and a composition comprising the pridopidine base including a pharmaceutical composition.

First claim

The invention claimed is:

1. A process for preparing solid pridopidine base comprising
a) obtaining a solution comprising pridopidine base,
b) washing the solution comprising pridopidine base with water, and
c) precipitating pridopidine base from the solution to form solid pridopidine base.

2. The process of claim 1 further comprising precipitating pridopidine base with a volume of one or more alkanes.

3. The process of claim 1 ,
(a) wherein the solution comprises one or more organic solvents or water, or a mixture thereof,
(b) wherein the solution is a mixture of toluene and water,
(c) further comprising adding a strong base to the solution,
(d) wherein the solution comprises an aqueous layer and an organic layer, and the process further comprises separating the organic layer from the aqueous layer and washing the organic layer with water, or
(e) wherein the step of washing the organic layer with water removes Compound 1:

from the organic layer.

4. The process of claim 1 , wherein the process further comprises
(a) forming the pridopidine base with a chemical purity in which the weight percent of Compound 1 is less than 0.2% of the total amount of pridopidine base and Compound 4 and/or
(b) removing an amount of the organic solvent under vacuum distillation to obtain a mixture comprising a volume of the organic solvent wherein the ratio of the volume of organic solvent to the volume of one or more alkanes during the step of precipitating the pridopidine base is between 1:1.3 to 1:3 and/or
(c) precipitating pridopidine base after the vacuum distillation and forming the pridopidine base.

5. The process of claim 1 , further comprising a catalytic reduction of the compound of Compound 8

at a predetermined reduction temperature and with an amount of a reduction catalyst to form pridopidine base and wherein
(a) the reduction catalyst is selected from the group consisting of a palladium catalyst, a platinum catalyst, a ruthenium catalyst, a palladium on carbon catalyst, and JM type 402 catalyst,
(b) the amount of the reduction catalyst is 5%-20% w/w,
(c) the catalytic reduction is complete in 0.1-20 hours
(d) wherein the predetermined reduction temperature is 5-60° C.
(e) the predetermined reduction temperature is 0-39° C. or
(f) the pridopidine base formed is free of pridopidinium.

6. The process of claim 5 , further comprising dissolving Compound 8 in water and mixing Compound 8 with a weak acid.

7. The process of claim 5 , wherein the process further comprises cold addition of weak acid and reduction catalyst at a temperature between 9 and 21° C. before slowly warming the reaction mixture to a temperature between 20 and 30° C. to prevent the formation of pridopidinium.

8. The process of claim 1 , further comprising oxidizing Compound 10:

with a catalytic oxidizing agent and an oxidant; to give Compound 8:

and wherein
(a) the step of oxidizing Compound 10 is conducted at a temperature of 40-60° C.,
(b) the catalytic oxidizing agent is a tungsten oxidizing agent, or
(c) wherein the oxidant is a peroxide.

9. The process of claim 8 , further comprising adding the oxidant in two batches, a first batch and a second batch.

10. The process of claim 1 further comprising dehydrating Compound 9:

with a strong acid for an amount of time and at a temperature; to give Compound 10 or a solution comprising Compound 10 and wherein
(a) the yield of the step of dehydrating Compound 9 is 20-95%,
(b) wherein the amount of strong acid is 1.5-4.5 equivalents,
(c) the amount of time is 1-22 hours,
(d) wherein the temperature is below 118° C.,
(e) the strong acid is sulfuric acid,
(f) the dehydration of Compound 9 with a strong acid is conducted in solvent selected from toluene, xylene, or hexanes,
(g) Compound 10 is extracted from the solution comprising Compound 10 using water and without the use of NaOH,
(h) the chemical purity of Compound 10 is 90-99.4%, or
(i) the yield of the step of dehydrating Compound 9 is 20-95%.

11. The process of claim 3 , further comprising lithiating 3-bromothioanisole with an alkylithium using a continuous flow reactor to obtain 3-lithium thioanisole.

12. The process of claim 11 ,
(a) wherein the continuous flow reactor comprises a solvent and wherein the solvent is THF,
(b) wherein lithiation of 3-bromothioanisole has an average residence time of 1-60 seconds,
(c) further comprising performing a coupling reaction between 3-lithium thioanisole and 1-propyl-4-piperidone to form Compound 9 or a solution comprising Compound 9 using a continuous flow reactor,
(d) wherein the coupling has an average residence time of 8-480 seconds,
(e) wherein the lithiation of 3-bromothioanisole and/or the coupling is performed at a temperature of between 15° C. and −100° C.,
(f) wherein the amount of equivalents of the lithiating agent used is between 0.97 and 1.20,
(g) wherein the lithiating agent is an alkylithium,
(h) further comprising precipitating Compound 9 from the solution to form solid Compound 9,
(i) further comprising quenching the solution comprising Compound 9 with water to form a solution comprising a compound of Compound 9,
(j) further comprising adding toluene to the solution comprising Compound 9 and washing with water,
(k) further comprising distilling a solution comprising Compound 9 by vacuum distillation,
(l) wherein Compound 9 is precipitated with an alkane selected from pentane, hexane, heptane, and octane, or
(m) wherein the solution comprising Compound 9 or the solid Compound 9 is free of THF or THF residues.

13. The process of claim 1 , further comprising lithiating 3-bromothioanisole with a lithiating agent followed by performing a coupling between 3-lithium thioanisole and 1-propyl-4-piperidone to form the hydrochloride salt of Compound 9 or a solution comprising the hydrochloride salt of Compound 9 and using a vacuum distillation to obtain a composition comprising the hydrochloride salt Compound 9 wherein the composition comprises less than 1% w/w.

14. A process for preparing pridopidine hydrochloride from pridopidine free base comprising
a) obtaining solid pridopidine free base,
b) dissolving solid pridopidine free base in an alcohol to form a solution,
c) filtering the solution, and
d) adding to the solution a mixture of hydrochloric acid and an alcohol which is the same as the alcohol in which the pridopidine base is dissolved in step (b) to precipitate pridopidine hydrochloride.

15. The process of claim 2 , wherein the alkane is n-heptane.

16. The process of claim 3 , wherein in step (c) the strong base is NaOH which is added until the pH of the solution is pH 11-14.

17. The process of claim 5 , wherein
(a) the amount of the reduction catalyst is 8%-10% w/w,
(b) the catalyst is a JM type 402 catalyst,
(c), the catalytic reduction is complete in 0.5-1 hour, and/or
(d) the predetermined reduction temperature is 30-40° C.

18. The process of

Assignees

• Barel Offir
• Lidor Hadas Ramy
• Gottesfeld Ronen
• Mizrahi Orel Yosef
• Bergh Anders Olof Ingemar
• Nguyen Ba Vu
• Teva Pharmaceuticals Int Gmbh

Inventors

• Barel Offir
• Lidor-Hadas Ramy
• Gottesfeld Ronen
• Mizrahi Orel Yosef
• Bergh Anders Olof Ingemar
• Nguyen Ba-Vu

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D211/24 Primary

  by sulfur atoms to which a second hetero atom is attached · CPC title