WO2009053993A2

WO2009053993A2 - Process for preparation of novel salt of voriconazole oxalate form-c

Info

Publication number: WO2009053993A2
Application number: PCT/IN2007/000562
Authority: WO
Inventors: Venkat Reddy Alla; Jaganmohan G; Aruna Kumari Sirigiri; Raghu Mithra Alla; Sreenivasa Reddy Bodapati
Original assignee: Lee Pharma Limited
Priority date: 2007-10-22
Filing date: 2007-12-03
Publication date: 2009-04-30
Also published as: WO2009053993A3

Abstract

The invention relates to the process of obtaining novel polymorphic form of voriconazole. Voriconozole has the chemical name (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2-4-triazol-yl)-butan-2-ol represented as Formula (1).

Description

Process for the preparation of novel salt of Voriconazole oxalate form C

Introduction to the invention:

The invention relates to the process of obtaining novel polymorphic form of Voriconazole. Voriconazole has the chemical name (2R, 3S)-2-(2,4-difluorophenyl)-3- (5-fluoiOpyrimidin-4-yl)-l-(lH-l,2,4-triazol-yl)-butan-2-ol represented as Formula (I)

Back ground and prior art:

Voriconazole exhibits excellent antifungal activity against a wide range of yeasts and filamentous fungi as demonstrated by in vitro and in vivo infection models. Voriconazole has excellent activity in vitro against Aspergillus species, shows efficacy in vivo models of aspergillosis and has demonstrated efficacy in both acute and chronic aspergillosis, with few observed side effects. Depending on the results of future clinical trials, this drug promises to become an important new agent in the treatment of invasive infections due to Aspergillus and other life- threatening fungal infections.

US patent No.s 5,278,175 & 5,567,817 & EP patent No.s EP0440372 & EP0440372A1: Disclose Voriconazole its pharmaceutically acceptable salts, pharmaceutical composition comprising Voriconazole and their use in the treatment of fungal infections. The process includes the reaction of 1 -(2,4-difluoro phenyl)-2- (lH-l,2,4-triazol-l-yl) ethanone with di iso propyl amide and in tetra hydro furan medium to yield 3-(4-chloro-5-fluoro pyrimidin-6-yl)-2- (2,4-difluoro phenyl)-l- (lH-l,2,4-triazol-l-yl) butan-2-ol. The enantiomeric pair (2R,3S & 2S,3R) on hydrogenation with 10% pd/c catalyst in presence of ethanol and sodium acetate followed by resolution with lR(-)-10- Camphor sulfonic acid in methanol gives a corresponding camphor sulfonate salt which on hydrolysis with aqueous sodium bicarbonate solution gives Voriconazole. US 6,586,594 : Discloses a process for the preparation of Voriconazole which comprises condensing l-(2,4-difluoro phenyl)-2-(lH-l,2,4-triazol-l-yl ethanone with 6-(l- bromo ethyl)- 2,4- dichloro-5- fluoro pyrimidine in presence of Zinc powder, Lead powder and Iodine in tetra hydro furan medium gives corresponding derivative which on reduction with 10 % pd/c catalyst followed by resolution with R(-) -10- camphor sulfonic acid and isolated in Isopropanol resulted in the formation of Voriconazole later on identified this crystalline form as a form B.

WO 2006/065726 : Discloses the process for the preparation of crystalline form A and B as well as its amorphous form of Voriconazole. In this patent, (2R,3S/2S, 3R)-3- (4-chloro-5- fluoro pyrimidin-6-yl) -2(2,4- difluoro phenyl -1- (lH-l,2,4-triazol-l- yl)butan-2- ol on reduction with Raney nickel in presence of methanol and Sodium acetate it gives corresponding derivative which on resolution with ΙR(-) -10- camphor sulfonic acid in presence of Acetone and Methanol gives corresponding camphor sulfonate salt which on hydrolysis with Aqueous Sodium carbonate in presence of Methylene dichloride solvent and isolated in Iso propanol resulted the formation of crystalline form B. The same patent also describes the crystalline form B by isolation from acetone and water mixture, acetonitrile, methanol and amorphous form is isolated by crystallizing from Methanol, Methylene dichloride solvent.

WO 9706160: Discloses the preparation of triazoles by organometalic addition. This invention relates to process for the preparation of Voriconazole acid addition salts like Hydrochloride, Hydro bromide, Hydro iodide, sulfate, Nitrate, methane sulfonate , Para toluene sulfonate ,Benzene sulfonate, Camphor sulfonate and 3-Bromo camphor sulfonate.

There is always a need for newer routes of synthesis of commercially important pharmaceutically active compounds. Regulatory authorities internationally desire to have all possible polymorphic forms of a new drug substance identified prior to approval of a product containing the drug. However, as is well known in the art, the existence of polymorphic forms of any given compound cannot be predicted, and there is no standard procedure for proceeding to make a previously unknown polymorphic form. Even after a polymorph has been identified, there is no possibility of predicting whether any additional forms will ever be discovered. There is thus also a need to prepare and identify different crystalline and amorphous forms of such compounds. Consequently, it would be a significant contribution to the art to provide newer and improved processes for the synthesis of a commercially important compound such as Voriconazole & its different polymorphic forms. Summary of the invention:

The present invention relates to processes for the preparation of Voriconazole and its polymorph.

The invention also relates to novel crystalline form C of Voriconazole.

The process for preparation of Voriconazole oxalate salt of form C comprises the steps: a) Suspending Voriconazole crystalline form B in suitable solvent, b) Addition of an acid at a suitable temperature, c) Cooling the reaction mass and isolation of the solid, d) Drying the solid. Detailed description of the invention:

In one aspect, the invention provides a process for the preparation of Voriconazole and its novel salts and its different polymorphic form comprising steps of: Step (1) :

Resolution of racemic compound (2R,3S/2S,3R) -2- (2,4- difluoro phenyl) -3- (5-fluoro pyrimidin-4-yl) -l-(lH-l,2,4-triazol-l yl) butan-2-ol with a suitable chirally active acid such as IR- (-) -10- camphor sulfonic acid, solvents that can be used for this process is acetone, methanol or their mixture and thus Voriconazole camphor sulfonate salt is crystallized.

Step (2):

Methylenedichloride lsopropyl ether

Involves hydrolysis of Voriconazole camphor sulfonate in a mixture of solvent, such as water and Dichloro methane and in the presence of base such as Sodium hydroxide, layers are separated and extracted with Dichloro methane solvent. Solvent is removed by distillation under reduced pressure at below 40⁰C. The obtained crude Voriconazole is crystallized from Iso propyl ether to get pure Voriconazole crystalline form B.

The crystalline form B of Voriconazole is characterized by its XRD pattern in accordance with that shown in Fig (1). The most characteristic peaks are located at about 6.9, 12.6, 13.8, 14.8, 15.9, 16.5, 17.4, 19.8, 21.2, 22.5, 23.3, 26.1 & 27.8± 0.2 degrees two theta

The crystalline form B of Voriconazole is also characterized by its DSC curve having an endotherm at about 132° C that shown in fig (2)

The crystalline form B is also characterized by an infrared spectrum in accordance with that show in fig (3) Step (3):

Oxalic acid

Involves the conversion of Voriconazole crystalline form B to its pharmaceutically acceptable salts such as oxalate in to its novel polymorph form C

a) Suspending Voriconazole crystalline form B in suitable solvent preferably

Ethyl acetate or Toluene b) Adding Oxalic acid at 20-25° C c) Cooling the reaction mass to 0-5 C d) Isolation of the obtained solid e) Drying the solid at 60-65° C

The crystalline form C of Voriconazole oxalate is characterized by its XRD pattern as shown in fig (4). The most characterized peaks are located at about

10.07, 11.82, 12.78, 15.43, 17.21, 18.45, 19.46, 20.03, 20.85, 21.32, 23.35, 26.09, 26.53, 27.95,

28.22

The crystalline form C of Voriconazole oxalate is also characterized by DSC fig (5) curve having an endotherm at about 152° C.

Examples

Example 1 :

Preparation of (2R,3S)-2- (2,4- difluoro phenyl )-3- (5- fluoro pyrimidin -4-yl )-l- (1H-1,2,4- triazol- 1 - yl) butan-2-ol-R (-) - 10-camphor sulfonate salt.

250 gm of (2R,3S)-2- (2,4-difluoro phenyl) -3- (5-fluoro pyrimidin -4-yl) -1- (lH-l,2,4-triazol-l- yl) butane -2-ol was charged into a flask having 1.5 Lt of acetone 165 gm of R-(-) -10- camphor sulfonic dissolved in 500 ml of methanol was added and heated to about 50 - 55° C maintained for 10-15 min at 50 -55° C. the reaction mass was cooled to 15 -20° C and maintained for 2-3 hr. The separated solid was filtered and washed with 25 ml of acetone. Solid was dried filtered under vacuum of about 650 mm/Hg for about 8 hrs to yield 160 gm of the title compound. Further purification in acetone and methanol mixture (3:1) and heated to 50-55° C and maintained for 10-15 min. Then the reaction mass was cooled to 20-25° C and maintained for over night. The solid separated was filtered and washed with 25 ml of acetone. The obtained solid was dried at

70 -75° C for about 10 hi- to yield 130 gm of title compound as a pure crystalline solid. Example 2 :

Preparation of (2R,3S) -2- (2,4-difluoro phenyl)-3-(5-fluoro pyrimidin-4- yl) -1- (1H-1,2,4- triazol-1-yl) butan-2-ol (Voriconazole crystalline form B)

100 gm of (2R,3S) -2-(2,4-difluoro phenyl) -3- (5- fluoro pyrimidin-4-yl) -1- (lH-l,2,4-triaozol -

1- yl) butan-2- ol-R (-) -10- camphor sulfonate salt was charged in to flask containing 300 ml water and 500 ml of Dichloro methane. Reaction mass P^H was adjusted to 11.0-12.0 with 10 %

Sodium hydroxide solution at 25 -30° C. Stirred for 20 min. The aqueous layer is separated and extracted with Dichloro methane (100 ml X 3) combined Organic layer was washed out with

DM. Water (300 ml X 3). The solvent was evaporated under reduced pressure. Iso propyl ether

(50 ml) was added and redistill off solvent to remove traces of dichloro methane. Again Iso propyl ether (250 ml) was added and maintained for 1 hr at 25-30° C. The obtained solid material is filtered and washed with Isopropyl ether (50 ml). Dried the material at 70-75° C for about 10 hr to yield 60 gm of Voriconazole crystalline form B.

Example 3:

Preparation of (2R,3S)-2- (2,4- difluoro phenyl)-3- (5- fluoro pyrimidin-4-yl) -1- (1H-1,2,4- triazol-1-yl) butan-2-ol oxalate (Voriconazole oxalate crystalline form C)

25 gm of Voriconazole crystalline form B and 140 ml of Ethyl acetate was charged in to a round bottom flask. 8.7 gm of Oxalic acid was charged in to the reaction mass and maintained for 1 hr at 20-25° C. Then the reaction mass was cooled to 0-5° C and maintained for 1 hr at 0-5° C. Then the obtained solid was filtered and washed with 25 ml of Ethyl acetate. The material was dried at 60-65° C for about 10 hr to yield title compound as a Voriconazole oxalate crystalline form C.

Example 4:

Alternative preparation of Voriconazole oxalate crystalline form C 25 gm of Voriconazole crystalline form B and 250 ml of Toluene was taken in to a round bottom flask. 8.7 gm of Oxalic acid was dissolved 50 ml of DM Water was added to the reaction mass and maintained for 2-3 hrs at 25 -30° C. The obtained solid was filtered and wash with 25 ml of Toluene. The material was dried at 60 -65° C for about 10 hr to yield title compound as a Voriconazole crystalline form C.

Claims

Claims:

1. A crystalline polymorph of Voriconazole oxalate salt of form C having substantially the same X-ray diffraction pattern as shown in fig (4), characterized by peaks located at about 10.07, 11.82, 12.78, 15.43, 17.21, 18.45, 19.46, 20.03, 20.85, 21.32, 23.35, 26.09, 26.53, 27.95, 28.22.

2. A crystalline polymorph of Voriconazole Oxalate salt of form C according to claim 1, further is characterized by DSC as shown in fig (5), exhibiting an endotherm at 152 degrees Celsius.

3. The process for preparation of Voriconazole Oxalate salt of form C comprises the steps: a) Suspending Voriconazole crystalline form B in suitable solvent, b) Addition of an acid at a suitable temperature, c) Cooling the reaction mass and isolation of the solid, d) Drying the solid

4. The process for preparation of Voriconazole oxalate salt of form C according to claim 3, wherein the Voriconazole oxalate salt is prepared from Voriconazole form B.

5. The process for preparation of Voriconazole oxalate salt of form C according to claim 3, wherein the Voriconazole Form B is obtained by crystallization from Isopropyl ether.

6. The process for preparation of Voriconazole oxalate salt of form C according to claim 3, wherein the Voriconazole form B is characterized by X-ray diffraction pattern comprising peaks about 6.9, 12.6, 13.8, 14.8, 15.9, 16.5, 17.4, 19.8, 21.2, 22.5, 23.3, 26.1 & 27.8± 0.2 degrees two theta. (fig 1)

7. The process for preparation of Voriconazole oxalate salt of form C according to claim 3, wherein the suspension of crystalline form B is in suitable solvent.

8. The process for preparation of Voriconazole oxalate salt of form C according to claim

7, wherein the suitable solvent is preferably, as ethyl acetate or toluene.

9. The process for preparation of Voriconazole oxalate salt of form C according to claim 3, wherein, the acid being added is oxalic acid and specifically at a temperature of 20- 25 degrees Celsius.

10. The process for preparation of Voriconazole oxalate salt of form C according to claim

3, wherein after the addition is done the reaction mass is cooled to 0-5 degrees Celsius 11. The process for preparation of Voriconazole oxalate salt of form C according to claim

3, wherein the drying is done at a temperature of 60-65 degrees Celsius and drying time is 10 hours.