Process for preparing pridopidine

Patent metadata

Field	Value
Publication number	US-2017022158-A1
Application number	US-201615217683-A
Country	US
Kind code	A1
Filing date	Jul 22, 2016
Priority date	Jul 22, 2015
Publication date	Jan 26, 2017
Grant date	—

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

1 . Pridopidine base in a solid form.

2 . A composition comprising the pridopidine base of claim 1 .

3 . A composition comprising the pridopidine base of claim 1 , wherein the composition is free of isopropyl alcohol.

4 . The composition of claim 2 , wherein the composition is free of chloride or free of pridopidine hydrochloride.

5 . (canceled)

6 . A process for preparing solid pridopidine base comprising
a) obtaining a solution comprising pridopidine base, and b) precipitating pridopidine base from the solution to form solid pridopidine base.

7 . The process of claim 6 further comprising precipitating pridopidine base with a volume of one or more alkanes, preferably wherein the alkane is n-heptane.

8 . (canceled)

9 . The process of claim 6 ,
(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, preferably NaOH, more preferably wherein the strong base is added until the pH of the solution is pH 8-14, pH 11-14 or about pH 13, (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.

10 - 15 . (canceled)

16 . The process of claim 6 , 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% or less than 0.15% 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 or about 1:2 and/or (c) precipitating pridopidine base after the vacuum distillation and forming the pridopidine base.

17 - 20 . (canceled)

21 . The process of claim 6 , 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, 5%-15% w/w, 5%-12% w/w, 8%-10% w/w, about 10% w/w or about 8% w/w,
(c) the catalytic reduction is complete in 0.1-20 hours, 0.1-10 hours, 0.1-5 hours, 0.5-5 hours, 0.5-1 hour or about 50 minutes,
(d) wherein the predetermined reduction temperature is 5-60° C., 30-50° C., 40-50° C., 36-50° C. or about 40° C.,
(e) the predetermined reduction temperature is 0-39° C., 0-35° C., 0-30° C., 10-30° C., or 20-30° C.,
(f) the pridopidine base formed is free of pridopidinium,
(g) the catalyst is a JM type 402 catalyst and the amount of the JM type 402 catalyst present is 8%-10% w/w,
(h) the reaction is complete after 0.1-2 hours, 0.1-1 hours, about 1 hour or about 50 minutes, or
(i) Compound 8 formed is free of Compound 1.

22 - 30 . (canceled)

31 . The process of claim 21 , (a) further comprising dissolving Compound 8 in water (b) further comprising mixing Compound 8 with a weak acid, preferably formic acid.

32 - 33 . (canceled)

34 . The process of claim 21 , wherein the process further comprises cold addition to prevent the formation of pridopidinium.

35 . The process of claim 6 , 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., 35-38° C. or 35-55° C.,
(b) the catalytic oxidizing agent is a tungsten oxidizing agent, preferably sodium tungstate, or
(c) wherein the oxidant is a peroxide, preferably sodium peroxide.

36 - 40 . (canceled)

41 . The process of claim 35 , further comprising (a) adding the oxidant in two batches, a first batch and a second batch and optionally adding the first batch of oxidant, followed by adding the second batch of oxidant after the accumulated heat is released.

42 - 43 . (canceled)

44 . The process of claim 6 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%, 50-95%, or 50-95%,
(b) wherein the amount of strong acid is 1.5-4.5 equivalents, 1.8-4.0 equivalents, 1.8-3.0 equivalents, 1.0-2.0 equivalents, 1.8-2.5, or about 2.0 equivalents,
(c) the amount of time is 1-22 hours, 2-5 hours, or about 3.5 hours,
(d) wherein the temperature is below 118° C., 90° C., below 83° C., below 80° C., below 70° C., between 57° C. and 80° C., or about 70° 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%, 95-99.4%, 98.9-99.7%, or 98.9-99.4%, or
(i) the yield of the step of dehydrating Compound 9 is 20-95%, 50-95%, or 50-95%.

45 - 53 . (canceled)

54 . The process of claim 9 , further comprising lithiating 3-bromothioanisole with a lithiating agent using a continuous flow reactor to obtain 3-lithium thioanisole.

55 . The process of claim 54 ,
(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, 2.8-14 seconds, 7-14 seconds, 4-10 seconds, or about 5.6 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, 10-480 seconds, 8-15 seconds, or about 8 seconds, (e) wherein the lithiation of 3-bromothioanisole and/or the coupling is performed at a temperature of between 15° C. and −100° C., between −5° C. and −100° C., between −40° C. and −100° C., between −60° C. and −100° C., between −60° C. and −80° C., between −80° C. to −100° C., between 15° C. and −25° C., between 15° C. and −10° C., between 5° C. and −5° C., between 0° C. and 10° C., between 2° C. and 8° C., about 0° C. or about −5° 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 alkylithi

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