WO2007126889A1

WO2007126889A1 - Preparation of tegaserod acetate

Info

Publication number: WO2007126889A1
Application number: PCT/US2007/007681
Authority: WO
Inventors: Santiago Ini; Gustavo Frenkel; Amir Ehud
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2006-03-27
Filing date: 2007-03-27
Publication date: 2007-11-08

Abstract

Provided are processes for preparation of tegaserod acetate and tegaserod maleate.

Description

PREPARATION OFTEGASERODACETATE

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.

60/786,567, filed March 27, 2006. The contents of which are incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates to processes for preparing tegaserod acetate.

BACKGROUND OF THE INVENTION

Tegaserod maleate is an aminoguanidine indole 5HT4 agonist for the treatment of irritable bowel syndrome (IBS). Tegaserod maleate has the following structure:

According to the prescribing information (Physician's Desk Reference, 57^th Ed., at Page 2339), tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water.

Tegaserod maleate is disclosed in US Patent No. 5,510,353 and in its equivalent EP 0 505 322 (example 13). The '353 patent also discloses the preparation of tegaserod base by reacting indole-3-carbaldehyde and aminoguanidϊne in a protic solvent in the presence of inorganic or organic acid (example 2a describes the reaction in methanol and hydrochloric acid).

The literature (Buchheit K.H, et ah, J.Med.Chem., 1995, 38, 2331) describes a general method for the condensation of aminoguanidines with indole-3-carbaldehydes in methanol in the presence of HCl (pH 3-4). The product obtained may be converted to its hydrochloride salt by treatment of the methanolic solution with diethyl ether/HCl followed by recrystallization from methanol/diethylether. Tegaserod base prepared according to this general method is characterized solely by a melting point of 155 ⁰C (table 3 compound 5b). Additional Tegaserod maleate characterization was done by ¹H and ¹³C-NMR according to the literature (Jing J. et. al., Guangdong Weiliang Yuansu Kexue, 2002, 9/2, 51).

A salt of tegaserod is tegaserod acetate. Tegaserod acetate in solid state and processes for its preparation are disclosed in PCT publication No. WO 2005/058819. There is a need for a one pot process suitable for industrial scale that prepares tegaserod acetate from tegaserod base intermediates without isolation of tegaserod base as an intermediate.

SUMMARY OF THE INVENTION In one embodiment the present invention provides a process for preparing tegaserod acetate, comprising reacting N-amino-N'-pentylguanidine hydroiodide ("AGP-HI") and S-Methoxy-lH-indole-S-carbaldehyde ("MICHO") in an aqueous reaction mixture to obtain tegaserod base; extracting the tegaserod base with a water immiscible organic solvent to obtain a mixture and combining the mixture with acetic acid to obtain tegaserod acetate.

In one embodiment the present invention provides a process for preparing tegaserod acetate comprising reacting N-amino-N'-pentylguanidine hydroiodide ("AGP-HI"), S-Methoxy-lH-indole-S-carbaldehyde ("MICHO") and toluene to obtain a mixture containing tegaserod base; heating the mixture and combining the mixture with acetic acid to obtain tegaserod acetate.

In one embodiment the present invention provides a process for preparing tegaserod acetate comprising reacting N-amino-N'-pentylguanidine hydroiodide ("AGP-HI"), S-Methoxy-lH-indole-S-carbaldehyde ("MICHO") and methyl t-butyl ether to obtain a mixture containing tegaserod base; heating the mixture and combining the mixture with acetic acid to obtain tegaserod acetate.

In one embodiment the present invention provides a process for making tegaserod maleate by preparing tegaserod acetate as described above, and converting it to a tegaserod maleate.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "reduced pressure" refers to a pressure below one atmosphere. As used herein, the term "vacuum" refers to a pressure below about 50 mniHg, with about 30 mmHg or below being preferred.

The present invention provides, a process for the preparation of tegaserod acetate. The process is preferably a one pot process, wherein the tegaserod base is not isolated. The one pot process is ideal for use on industrial scale because it avoids isolation of tegaserod base as an intermediate.

This process comprises reacting N-amino-N'-pentylguanidine hydroiodide ("AGP-HI") and 5-Methoxy-lH-indole-3-carbaldehyde ("MICHO") in an aqueous reaction mixture to obtain tegaserod base; extracting the tegaserod base with a water immiscible organic solvent to obtain a mixture; and combining the mixture with acetic acid to obtain tegaserod acetate.

The reaction of AGP-HI with MICHO may be carried out under acidic or basic conditions. When the reaction is carried out under aqueous basic conditions, an organic or inorganic base may be used. The organic base is preferably a C3 to Cs alkyl amine such as trialkylamine (preferably triethylamine), or pyridine. The inorganic base may be an alkali/alkaline earth metal hydroxide or carbonate, preferably K₂CO₃, Na₂CO₃, NaHCO₃, NaOH, KOH, more preferably NaOH. The reaction is preferably carried out at a pH range of 7 to 14, more preferably of about 9 to 14. The temperature range during the reaction is preferably of about 5⁰C to reflux temperature. When a tertiary amine is used, the tertiary amine may also act as a solvent, thus, the reaction may be carried out in the presence of the tertiary amine in neat form, i.e. without the use of an additional solvent. When the reaction is carried out under acidic conditions water is added, and an organic or inorganic acid may be used. An organic acid such as p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, methanesulfonic acid, acetic acid or maleic acid may be used. In another embodiment, an inorganic acid such as HCl, HBr, H₃PO₄ or HaSO₄ may be used. The pH range during the reaction is preferably of 1 to 7, more preferably of about 3 to 4. The temperature range during the reaction is preferably of about 5⁰C to about reflux temperature of water. Before conversion to the acetate salt, a base may be used to neutralize the acid used in the process or to eliminate undesirable salts. In one embodiment, an aqueous solution of AGP-HI is combined with a mixture of MICHO and a solid base. Alkali and alkaline earth metal bases, such as potassium and sodium hydroxide may be used.

The tegaserod formed during the reaction can be extracted into a water immiscible organic solvent. Preferably, the water immiscible organic solvent is selected from the group consisting of: C3-C₇ esters, C4-₈ ethers and C₃-7 ketones. More preferably, the water immiscible organic solvent is a C₃-C₇ ester, most preferably ethyl acetate. In one embodiment, ethyl acetate is mixed with the tegaserod containing reaction mixture, after which tegaserod moves to the ethyl acetate. The reaction mixture may be stirred to accelerate the extraction process. The organic phase may then be washed with an aqueous solvent such as water to remove water mϊscible impurities. The organic phase may also be filtered to further remove impurities.

AGP-HI and MICHO may be reacted in the presence of water without an organic solvent. Optionally, AGP-HI and MICHO can be reacted in the presence of an organic solvent, preferably a Cβ-io aromatic hydrocarbon, a C₃-₅ alkyl ester, a C₂-S ether, C_1-S alkyl alcohol, acetonitrile and mixtures thereof.

Preferably, the AGP-HI and MICHO are reacted in a solvent selected form the group consisting of: a Cβ-io aromatic hydrocarbon, such as toluene; a C₃.₅ alkyl ester such as ethyl acetate; a C_4-8 ether, such as methyl t-butyl ether; a Ci_-8 alkyl alcohol such as ethanol; and acetonitrile.

Most preferably, the organic solvent is ethyl acetate. The ratio of ethyl acetate to MICHO is preferably about 9:1 to about 18:1 (volume/weight) Reacting AGP-HI and MICHO in the presence of an organic solvent may be followed by washing the reaction mixture with water, to reduce salt impurities. Further, the reaction mixture is combined with acetic acid.

Preferably the mixture is heated before combining with acetic acid. A suitable temperature range is about 40⁰C to about 65°C, more preferably about 6O⁰C.

The slurry resulting from combining of the mixture with acetic acid is preferably maintained at a temperature of about 40⁰C to about reflux temperature, more preferably about 60⁰C. The slurry is maintained so that a high yield of tegaserod acetate is obtained upon precipitation. Preferably, the slurry is maintained for about 1 hour to about 5 hours, more preferably about 3 hours.

Preferably, the slurry is cooled to precipitate the tegaserod acetate, more preferably, to about room temperature or less, even more preferably, the slurry is cooled to about 0⁰C to about 20⁰C, and most preferably about 10⁰C. The tegaserod acetate is subsequently recovered by any method known in the art, such as filtration. The filtrate may be further washed and dried. Drying can be carried out at reduced pressure and/or elevated tempeature. In one embodiment drying is carried out at a temperature of about 3O⁰C to about 40⁰C under vacuum.

Preferably, the tegaserod acetate thus obtained is in a crystalline form, characterized by X-ray powder diffraction reflections at about: 7.3, 8.7, 10.9 and 13.5 degrees two theta ± 0.2 degrees two theta.

The present invention also provides a method for making tegaserod maleate by preparing tegaserod acetate as described above, and converting it to a tegaserod maleate.

The conversion may be performed according to any method known in the art, such as combining with maleic acid, with or without the presence of an organic solvent.

The obtained tegaserod maleate may be in any crystalline and/or amorphous form.

EXAMPLES

Instruments: X-Ray powder diffraction data were obtained using by method known in the art using 5 a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 A was used. A round aluminum sample holder with zero background was used. AU peak positions are within kθ.2 degrees two theta.

Example 1 — Preparation of Tegaserod acetate

Preparation of Tegaserod base

To a mixture of AGP-HI (434.4 g) in 1158 mL of water was added 5-MICHO (180 g) followed by NaOH (130 g, 47%) and stirred 40⁰C. After 60 hours, 2140 mL of ethyl acetate was added and the mixture was stirred for an additional 1.5 hours. After phase separation the organic phase was washed with water (670 ml), and filtrated under vacuum to give a clear solution of TGS Base. Preparation of Tegaserod acetate 536 gr of a solution of TGS-base (obtained in Example 1) was heated to 60⁰C and acetic acid (100 ml) was added, and the reaction mixture stirred at the same temperature for an additional three hours. The mixture was cooled to 10⁰C, kept under stirring at the same temperature for 2.5 hrs and then filtered under vacuum. The wet product was washed twice with.65 ml of ethyl acetate and dried in a vacuum oven at 45°C for 12 hours to give 84.2% of the product.

Example 2 — Preparation of TGS Acetate in toluene

536 gr of a solution of TGS-base in toluene is heated to 60⁰C and acetic acid (100 ml) is added, and stirred for 3 hours. The mixture is cooled to 10⁰C, kept under stirring at the same temperature for 2.5 hrs and then filtered under vacuum. The wet product is washed twice with 65 ml of toluene and dried in a vacuum oven at 45°C for 12 hours.

Example 3 — Preparation of TGS Acetate in MTBE 536 gr of a solution of TGS-base in MTBE is heated to 60⁰C and acetic acid (100 ml) is added, and stirred for 3 hours. The mixture is cooled to 10⁰C, kept under stirring at the same temperature for 2.5 hrs and then filtered under vacuum. The wet product is washed twice with 65 ml of toluene and dried in a vacuum oven at 45°C for 12 hours. Example 4: Preparation of Tegaserod maleate from Tegaserod acetate

Maleic acid is added to a mixture of tegaserod acetate in a solvent (or without) at room temperature. The mixture is stirred till the conversion to tegaserod maleate and filtered and washed with a solvent. The mixture may be dried on vacuum oven at 45°C for 15 hours.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

Claims

What is claimed is:

1. A process for preparing tegaserod acetate, comprising reacting N-amino-N'- pentylguanidine hydroiodide ("AGP-HI") and 5-Methoxy-lH-indole-3- carbaldehyde ("MICHO") in an aqueous reaction mixture to obtain tegaserod base; extracting the tegaserod base with a water immiscible organic solvent to obtain a mixture and combining the mixture with acetic acid to obtain tegaserod acetate.

2. The process of claim 1, wherein the tegaserod base is not isolated.

3. The process any one of claims 1 or 2, wherein the reaction between AGP-HI and MICHO is carried out under acidic or basic pH.

4. The process of claim 3, wherein the pH is higher than about 7.

5. The process of claim 4, wherein the base is a C₃ to Cs alkyl amine.

6. The process of claim 5, wherein the base is triethylamine.

7. The process of claim 6, wherein the tritethylamine is a neat reagent.

8. The process of claim 3, wherein the base is an alkali/alkaline earth metal hydroxide or carbonate.

9. The process of claim 3, wherein the base is K₂CO₃, Na₂CO₃, NaHCO₃, NaOH, KOH or pyridine.

10. The process of claim 9, wherein the base is NaOH.

11. The process of any of the preceding claims, wherein the temperature range during the reaction between AGP-HI and MICHO is of about 5⁰C to about reflux temperature.

12. The process of claim 3 or 11, wherein the pH range is about less than 7.

13. The process of claim 12, wherein the acid is p-toluensulfonic acid, pyridinium p- toluenesulfonic acid, methanesulfonic acid, acetic acid or maleic acid.

14. The process of claim 12, wherein the acid is HCl, HBr, H₃PO₄ or H₂SO₄.

15. The process of any one of claims 1-3 or 11, wherein an aqueous solution of AGP- HI is combined with a mixture of MICHO and a solid base.

16. The process of any of the preceding claims, wherein the water immiscible organic solvent is selected from the group consisting of: C₃-C₇ esters, C_3-8 ethers, and C_3-7 ketones.

17. The process of any of the preceding claims, wherein the water immiscible organic solvent is a C₃-C₇ ester.

18. The process of claim 17, wherein the solvent is ethyl acetate.

19. The process of claim 18, wherein the ethyl acetate is mixed with the tegaserod containing reaction mixture, after which tegaserod moves to the ethyl acetate.

20. The process of any of the preceding claims, wherein the AGP-HI and MICHO are reacted in the presence of an organic solvent.

21. The process of claim 20, wherein the solvent is selected from the group consisitng ofC₆-io aromatic hydrocarbons, C_3-5 alkyl ester, C₂-₈ ether, Ci-s alkyl alcohols, acetonitrile and mixtures thereof

22. The process of claim 21, wherein the solvent is a C₆-_Io aromatic hydrocarbon.

23. The process of claim 21, wherein the solvent is toluene.

24. The process of claim 21, wherein the solvent is a C₃.₅ alkyl ester.

25. The process of claim 21, wherein the solvent is ethyl acetate.

26. The process of claim 25, wherein the ratio of ethyl acetate to MICHO is about 9:1 to about 18:1 (volume/weight).

27. The process of claim 21, wherein the solvent is a C2-₈ ether.

28. The process of claim 21, wherein the solvent is methyl t-butyl ether.

29. The process of claim 21, wherein the solvent is a Ci-g alkyl alcohol.

30. The process of claim 21, wherein the solvent is ethanol.

31. The process of claim 1, wherein the aqueous reaction comprises water.

32. The process of claim 21, wherein the solvent is acetonitrile.

33. The process of any of the preceding claims, wherein the mixture is heated before addition of acetic acid.

34. The process of claim 33, wherein the temperature range is about 40⁰C to about 65°C.

35. The process of any of the preceding claims, wherein the combining of the mixture with acetic acid results in a slurry which is maintained at a temperature of about 40⁰C to about reflux temperature.

36. The process of claim 35, wherein the slurry is maintained for about 1 hour to about 5 hours.

37. The process of claim 35, wherein the slurry is cooled to precipitate the tegaserod acetate.

38. The process of any of the preceding claims, wherein the slurry is cooled to about room temperature or less.

39. The process of claim 39, wherein the slurry is cooled to about 0⁰C to about 20⁰C.

40. The process of any of the preceding claims, further comprising drying at a temperature of about 3O⁰C to about 4O⁰C.

41. The process of any of the preceding claims, wherein the tegaserod acetate recovered is in a crystalline form, characterized by X-ray powder diffraction reflections at about: 7.3, 8.7, 10.9 and 13.5 degrees two theta ± 0.2 degrees two theta.

42. A process for preparing tegaserod acetate comprising reacting N-amino-N'- pentylguanidine hydroiodide ("AGP-HI") and 5-Methoxy-lH-indole-3- carbaldehyde ("MICHO") in an aqueous reaction mixture to obtain tegaserod base; extracting the tegaserod base with ethyl acetate; separating the ethyl acetate from the aqueous reaction mixture; filtering the ethyl acetate to obtain a solution; heating the solution and combining the solution with acetic acid to obtain tegaserod acetate.

43. A process for preparing tegaserod acetate comprising reacting N-amino-N'- pentylguanidine hydroiodide ("AGP-HI"), S-Methoxy-lH-indoIe-3-carbaldehyde ("MICHO") and toluene to obtain a mixture containing tegaserod base; heating the mixture and combining the mixture with acetic acid to obtain tegaserod acetate.

44. A process for preparing tegaserod acetate comprising reacting N-amino-N'- pentylguanidine hydroiodide ("AGP-HI"), 5-Methoxy-lH-indole-3-carbaldehyde ("MICHO") and methyl t-butyl ether to obtain a mixture containing tegaserod base; heating the mixture and combining the mixture with acetic acid to obtain

^• tegaserod acetate.

45. A method for preparing tegaserod maleate comprising preparing tegaserod acetate according to any of the preceding claims, and converting the tegaserod acetate to tegaserod maleate.

46. A one pot process for preparing tegaserod acetate.