Process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropdxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one and intermediate used in said process

Patent metadata

Field	Value
Publication number	US-9340518-B2
Application number	US-201314422167-A
Country	US
Kind code	B2
Filing date	Aug 15, 2013
Priority date	Aug 17, 2012
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

The present invention relates to a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one and to the new intermediate (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde used in this process. (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one is described in WO 2005/054215 to act as an immunosuppressive agent. The present invention further also relates to a new process for the preparation of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde.

First claim

The invention claimed is:

1. A process for the preparation of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1):

which process comprises reacting 3-chloro-4-hydroxybenzaldehyde with (R)-3-chloro-1,2-propanediol and isolating the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde by crystallisation.

2. The process according to claim 1 , wherein the reaction of 3-chloro-4-hydroxybenzaldehyde with (R)-3-chloro-1,2-propanediol is performed in the presence of the base potassium tert-butoxide and the solvent n-propanol, at elevated temperatures.

3. The process according to claim 1 , wherein the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1) is crystallised in water plus a co-solvent.

4. The process according to claim 3 , wherein the co-solvent is n-propanol.

5. The process according to claim 1 , further comprising reacting the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one to form (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (2):

6. The process according to claim 5 , wherein 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one is prepared by reacting o-tolyl-iso-thiocyanate with n-propylamine followed by reaction with bromo-acetyl bromide and the base pyridine, wherein no isolation and/or purification of intermediates occurs and wherein the obtained 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one is not isolated and/or purified before the reaction with (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1).

7. The process according to claim 6 , wherein (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1) is reacted with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one in the presence of the solvent ethanol and the base sodium acetate, at elevated temperatures.

8. The process according to claim 5 , characterised in that (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1) is isolated by a single crystallisation before the reaction with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one.

9. The process according to claim 5 , wherein in a first isolation step the obtained compound (2) is isolated by crystallisation.

10. The process according to claim 9 , wherein the compound (2) obtained after the first isolation step is in the crystalline form characterised by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 10.5°, 11.1°, 11.4°, 13.6°, 13.9°, 16.3°, 20.8°, 22.2°, 23.4°, 24.1°, 25.7°, 27.7°, 27.9°, 28.7°, and 29.3°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ=1.5406 Å) and stripping of the Kα2 component and wherein the accuracy of the 2θ values is in the range of +/−0.2°.

11. The process according to claim 9 , wherein the obtained crystalline compound (2) is further purified by one or more recrystallisation steps.

12. The compound (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form.

13. The crystalline form according to claim 12 , characterised by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 7.3°, 9.7°, 12.7°, 13.3°, 19.6°, 22.1°, 27.9°, and 28.5°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ=1.5406 Å) and stripping of the Kα2 component and wherein the accuracy of the 2θ values is in the range of +/−0.2°.

14. The crystalline form according to claim 12 , which has a melting point of about 94° C. as determined by differential scanning calorimetry.

15. A crystalline form of the compound (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde obtainable by:
i) adding potassium tert-butoxide (118 g, 1.20 eq.) to n-propanol (963 mL) followed by 3-chloro-4-hydroxybenzaldehyde (137 g, 1.00 eq.);
ii) adding to the mixture (R)-3-chloro-1,2-propanediol (126 g, 1.30 eq.), heating the suspension to 90° C. and stirring it at this temperature for 17 h;
iii) distilling off the solvent (500 mL) at 120° C. external temperature and reduced pressure;
iv) adding water (1.1 L) and removing solvent (500 mL) by distillation;
v) cooling the turbid solution to 20° C. and stirring for one hour to obtain a white suspension;
vi) adding water (500 mL) and cooling the suspension to 10° C.;
vii) filtering the suspension and washing the resulting filter cake with water (500 mL); and
viii) drying the product at 50° C. and reduced pressure.

16. The crystalline form according to claim 15 , which has a melting point of about 94° C. as determined by differential scanning calorimetry.

17. A process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one comprising the process according to claim 1 .

18. The crystalline form according to claim 13 , which has a melting point of about 94° C. as determined by differential scanning calorimetry.

Assignees

• Actelion Pharmaceuticals Ltd
• Actelion Pharmaceuticals Ltd

Inventors

• Herse Christelle

Classifications

• C07C45/64 Primary

  by introduction of functional groups containing oxygen only in singly bound form · CPC title

• C07C45/71 Primary

  being hydroxy groups · CPC title

• C07D277/54 Primary

  Nitrogen and either oxygen or sulfur atoms · CPC title

• C07C47/575

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C45/81

  by change in the physical state, e.g. crystallisation · CPC title