WO2005107375A2

WO2005107375A2 - Process for the preparation of olanzapine form-i

Info

Publication number: WO2005107375A2
Application number: PCT/IN2005/000098
Authority: WO
Inventors: Satyanarayana Chava; Seeta Ramanjaneyulu Gorantla; Jyothi Basu Abbineni
Original assignee: Matrix Laboratories Ltd
Priority date: 2004-05-06
Filing date: 2005-04-04
Publication date: 2005-11-17
Also published as: AR050247A1; WO2005107375A3

Abstract

The present invention provides a reproducible, novel, commercially feasible process to obtain Olanzapine Form-I of substantial polymorphic purity with minimal number of steps using minimal number of solvents by condensation of 4-Aminomethyl-10H-thieno [2, 3-b] [1, 5] benzodiazepine hydrochloride with N-methyl piperazine followed by isolation of Olanzapine methylene chloride solvate and conversion of the same to Olanzapine Form-I.

Description

" Process for the preparation of Olanzapine Form-I "

Field of the Invention :

The present invention relates to a novel and advantageous process for the preparation of Olanzapine Form-I with polymorphic purity via Olanzapine methylene chloride solvate.

Background of the Invention :

Olanzapine, 2-methyl-4-(4-methyl piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine is useful for treatment of disorders of the central nervous system, for treating psychotic patients and mild anxiety is represented by the following structure.

Olanzapine US Patent no US 5,229,382 discloses the preparation of Olanzapine and its acid addition salts, having pharmaceutical properties, particularly in the treatment of disorders of the central nervous system. This patent does not refer to any specific polymorphic crystalline forms of Olanzapine. European Patent no EP 0733 635 Bl claims Form-II of Olanzapine but also states that this corresponds to Form-I of Olanzapine as claimed in US 5,229,382 based on the XRD 'd' values disclosed in the patent (table-1).

European Patent no EP 0 831 098 Bl discloses Form-II as the most stable anhydrous form of Olanzapine and further discloses that substantially pure Olanzapine Form-II can be prepared by drying of Olanzapine dihydrate.

European Patent no EP 0 733 634 Bl discloses methanol, ethanol, n-propanol solvates of Olanzapine and a process for the preparation of technical grade Olanzapine. US Patent no US 6,348,458 Bl discloses a series of crystalline polymoφhic forms of Olanzapine namely Form-Ill, Form-TV and Form-V and the process for their preparation from Olanzapine Form-I or Olanzapine Form-II. The 'd' values for these forms from their X-ray diffractograms are given in the table- 1.

PCT Publication WO 02/18390 discloses Olanzapine monohydrate-I and Olanzapine dehydrate-I and process for making these compounds. US Patent application 2002/ 086993 discloses new polymorphic Form-X and process for its preparation. . PCT publication WO 03/097650 discloses the process for preparation of Olanzapine Form-1 with contamination of 1% of other crystalline forms from mixed solvates of Olanzapine with chemical impurities less than 0.5%. The methylene chloride solvate as disclosed has 4 moles of Olanzapine, 1 mole of methylene chloride and 8 moles of water and characterized by the XRD and IR. The second mixed solvate disclosed is the DMSO - water solvate that contains 4 moles of Olanzapine, 1 mole of DMSO and 2 moles of water. The mixed solvates on crystallization from methylene chloride and drying under vacuum yield Olanzapine Form-I.

PCT publication WO 03/091260 discloses Olanzapine crystalline Form-VI and process for its preparation by stirring the Olanzapine Form-I in a Ci - C₆ alkanol. The PCT publication WO 03/00693 discloses a process for preparation of Olanzapine Form-I by crystallization from a mixture of solvents containing iso propanol through solvates and a ^•novel polymorphic Form-A. The Olanzapine solvates disclosed are acetonitrile mixed solvate (acetonitrile-water mixed, acetonitrile/methylene chloride/water mixed solvate), iso-propanol solvate, methylene chloride solvate and characterized by their XRD and IR. It further discloses that the methylene chloride solvate exist in two forms (Form-IA, Form- IB) with different molar ratio between Olanzapine and methylene chloride. It further . discloses that the solvates may be used for preparation of anhydrous Olanzapine Form-I, II, III, rV, V, X, A or mixtures thereof. The methylene chloride solvate by grinding and optionally compression or grinding of any one of the methylene chloride solvate Olanzapine Form-I is obtained. For the preparation of all these solvates the starting material is Olanzapine. The prior art methods have constraints as they either start with Olanzapine for the preparation of Olanzapine Form-I or require the use of number of solvents. Moreover these methods lack consistency as Olanzapine prepared Form-I yielding Olanzapine Form-I which is often contaminated with other polymorphic forms/ hydrates / solvates. Table-l

Thus there is a need to provide a method that reproducibly produces Olanzapine Form-I that is of, substantial polymorphic purity.

Summary of the Invention :

The main object of the present invention is to provide the consistent process for preparation of Olanzapine Form-I of substantial polymorphic purity.

Another object of the present invention is to provide a process for preparation of Olanzapine Form-I with minimal number of steps

Yet another object of the present invention is to provide a process for the preparation of Olanzapine Form-I by using minimum number of solvents

The polymorphic purity of Olanzapine is > 98% of Olanzapine Form- 1.

Thus according to the present invention, 4-aminomethyl-10H-thieno[2,3-b] [1,5] benzo diazepine hydrochloride is condensed with N-methyl piperazine followed. by isolation of Olanzapine as Olanzapine methylene chloride solvate, purified, and converted to Olanzapine Form-I by treating Olanzapine methylene chloride solvate with iso-propanol as follows (Scheme - 1).

SCHEME-1

[2, 3-b][l, 5] benzodiazepine hydrochloride STEP -H:

Olanzapine MDC solvate Pure Olanzapine MDC solvate

STEP- m:

Pure Olanzapine MDC Solvate Olanzapine Form-I

Brief description of the drawings : Fig. 1 is the IR spectrum of the Olanzapine methylene chloride solvate Fig. 2 is the XRD of the Olanzapine methylene chloride solvate Fig. 3 is the IR absorption pattern of the Olanzapine Form-I Fig.4 is the XRD of the Olanzapine Form-I, made by the invented process (Example- 1) Detailed description of the Invention :

The essential features of the present invention for the preparation of Olanzapine Form-I with substantial polymorphic purity, which comprises of the following steps: - Reactiing 4-aminomethyl-10H-thieno[2,3-b][l,5]benzodiazepine hydrochloride with N-methyl piperazine in a mixture of Toluene and DMSO - Concentrating the reaction mass by distillation of solvents after the completion of reaction - Adding methylene chloride and water to the reaction mass - Separating the methylene chloride layer - Extracting the aqueous layer with methylene chloride - Washing the combined methylene chloride layer with water - Treating the methylene chloride layer with activated charcoal - Concentrating the reaction mass by distillation of methylene chloride - Cooling the residual mass to a temperature of -5 tq -15°C - Isolating and drying the formed Olanzapine methylene chloride solvate - Dissolving the Olanzapine methylene chloride solvate in methylene chloride - Removing the insolubles (if any) - Cooling the clear solution to temperature of 0°C to -50°C - Isolating and drying the pure Olanzapine methylene chloride solvate - Suspending the Olanzapine methylene chloride solvate in Iso-propanol - Mixing for 30 min to 2hrs at temperature of about 10 to 35°C - Isolating and drying the Olanzapine Form-I

The Olanzapine methylene chloride solvate obtained is anhydrous, having the methylene chloride content of about 11 - 14 % w/w. The molar ratio of Olanzapine and methylene chloride in Olanzapine methylene chloride solvate is 2: 1. The required 4-aminomethyl-10H-thieno [2, 3-b] [1, 5] benzodiazepine hydrochloride is prepared by method described in prior art. Reaction of 4-aminomethyl-lOH-thieno [2, 3-b] [1, 5] benzodiazepine hydrochloride with N-methyl piperazine is carried out at temperature 115°C to 120°C in toluene, DMSO in the ratio about 1: 1 to 5:1 for 4 - 8 hrs. The total volume of solvent with respect to 4-aminomethyl-10H-thieno [2, 3-b] [1, 5] benzo diazepine hydrochloride during the reaction varies from 6 volumes to 12 volumes. After completion of reaction, the reaction mass volume is reduced to one-third volume to half volume by removal of solvents under reduced pressure at temperature below 95°C. About 5 volumes to 15 volumes of methylene chloride, 2 volumes to 6 volumes of water are added to the reaction mass at 20°C - 35°C. The layers are allowed to settle and the organic layer is separated. The aqueous layer is extracted with methylene chloride and the combined organic layer is washed with water and treated with carbon. The carbon treated filtrate is concentrated to about 3 volumes to 10 volumes with respect to 4-amino methyl-lOH- thieno[2,3-b][l,5]benzodiazepine hydrochloride, preferably 3 volumes to 6 volumes under reduced pressure at temperature initially at 20°C to 35°C, preferably at 25°C - 30°C and finally at - 15°C to 0°C. The Olanzapine methylene chloride solvate is filtered and dried at temperature at 20°C to 30°C under vacuum for 1 to 8 hrs preferably 1 to 4 hrs.

Olanzapine methylene chloride solvate is dissolved in 4 to 12 volumes preferably 4 volumes to 6 volumes of methylene chloride, removed the insolubles and the clear solution is cooled to -50°C to 0°C. The pure Olanzapine methylene chloride solvate is filtered and dried at 20°C to 35°C under reduced pressure for about 1 to 12 hrs preferably for about 2 to 6 hrs.

Pure Olanzapine methylene chloride solvate is suspended in 2 to 6 volumes of Iso- propanol, preferably about 2 to 4 volumes, mixed for about 10 minutes to 120 minutes preferably about 30 minutes to 60 minutes at temperature of 10°C - 30°C preferably at 20 - 25°C under inert atmosphere. The solid is isolated, dried at temperature at 40°C to 60°C preferably at 45°C to 55°C for about 12 to 24 hrs to obtain Olanzapine Form-I with substantial polymorphic purity. The invention is now illustrated with non-limiting examples

Example-l:

Step-1: Preparation of Olanzapine methylene chloride solvate

50 g (0.188moles) of 4-aminomethyl-10H-thieno[2,3-b][l,5]benzodiazepine hydrochloride is suspended in 225 ml of toluene, 225 ml of DMSO and 87.5g ( 0.875 moles, 4.65 mole equiv.) of N-methyl piperazine is added. The temperature of the reaction mass is raised and maintained at reflux temperature for 6 hrs. 300 ml of solvent is distilled off under reduced pressure at temperature below 90°C. The reaction mass is cooled to room temperature, added 400 ml of methylene chloride and 200 ml of water. The reaction mass is allowed to settle for 10 minutes and the layers are separated. The aqueous layer is extracted twice with 200 ml of methylene chloride, combined the total organic layer and washed with 200 ml of water twice. The organic layer is treated with carbon, filtered and the clear filtrate is concentrated to a volume of 100 ml initially at room temperature and finally at temperature of 0°C under reduced pressure. The solid is filtered, washed with 50 ml of pre-cooled methylene chloride and dried at 25°C to 30°C for 2 hrs under reduced pressure.

The dry wt of Olanzapine methylene chloride solvate is 40 g (59.8 % yield). Moisture content by KF is 0.3 %, Methylene chloride content is 13.5%.

Step-2: Purification of Olanzapine methylene chloride solvate:

40 g of Olanzapine methylene chloride solvate is dissolved in 240 ml of methylene chloride by mixing at 32°C to 35°C for 30 min. The insolubles are filtered off and the clear filtrate is cooled and maintained at - 40°C for 1 hr. The solid is filtered and dried at 25°C to 30°C for 6 hrs under reduced pressure. The dry weight of pure Olanzapine methylene chloride solvate is 32 g (80%). Methylene chloride content is 12.6%.

The IR and XRD are given in figs 1 & 2.

Step-3: Conversion of Olanzapine methylene chloride solvate to Olanzapine Form-I :

30 g of Olanzapine methylene chloride solvate pure is suspended in 60 ml iso-propanol and mixed for 1 hr at 20°C to 25°C under nitrogen atmosphere. The slurry is filtered, washed with 10 ml of pre-cooled iso-propanol and dried at 50°C to 55°C for 18 hrs.

The dry weight of Olanzapine Form-I is 21 g (79.5 %)

The IR and the XRD are presented in figs. 3 & 4.

Claims

We claim:

1. A process for the preparation of crystalline Olanzapine Form-I from 4-aminomethyl- lOH-thieno [2,3-b][l,5]benzodiazepine hydrochloride via Olanzapine methylene chloride solvate with substantial polymorphic purity comprising a. Reactiing 4-amiήomethyl-10H-thieno[2,3-b][l,5]benzodiazepine hydrochloride with N-methyl piperazine in a mixture of Toluene and DMSO b. Concentrating the reaction mass by distillation of solvents after the completion of reaction c. Adding methylene chloride and water to the reaction mass d. Separating the methylene chloride layer e. Extracting the aqueous layer with methylene chloride f. Washing the combined methylene chloride layer with water g. Treating the methylene chloride layer with activated charcoal h. Concentrating the reaction mass by distillation of methylene chloride i. Cooling the residual mass to a temperature of -5 to -15°C j. Isolating and drying the formed Olanzapine methylene chloride solvate k. Dissolving the Olanzapine methylene chloride solvate in methylene chloride 1. Removing the insolubles (if any) m. Cooling the clear solution to temperature of 0°C to -50°C n. Isolating and drying the pure Olanzapine methylene chloride solvate o. Suspending the Olanzapine methylene chloride solvate in Iso-propanol p. Mixing for 30 min to 2hrs at temperature of about 10 to 35°C q. Isolating and drying the Olanzapine Form-I

2. A process as claimed in claim 1 a), wherein the toluene-DMSO ratio is about 1 :1 to about 5:1 and the total volume of solvent is 6 volumes to 12 volumes with respect to 4- aminomethyl-lOH-thieno [2,3-b][l,5]benzodiazepine hydrochloride

3. A process as claimed in claim 1 b), wherein the concentration of reaction mass is one third to half volume of the original volume

4. A process as clamed in claim 1 c), wherein the addition of methylene chloride is 5 volumes to 15 volumes with respect to 4-aminomethyl- 1 OH-thieno [2,3-b] [1 ,5] benzodiazepine hydrochloride

5. A process as claimed in claim 1 h), wherein the concentration of organic layer is 3 volumes to 10 volumes

6. A process as claimed in claim 1 h) & 5, wherein the concentration of organic layer is at temperature initially at 20°C to 35°C, preferably at 25°C to 30°C and finally at -15°C to 0°C

7. A process as claimed in claim 1 j), wherein the drying of Olanzapine methylene chloride solvate is for 1 hr to 12 hrs, preferably 1 to 6 hrs and at temperature of 20°C to 35°C under reduced pressure

8. A process as claimed in claim 1 n), wherein the drying of Olanzapine methylene chloride solvate pure is for 1 hr to 12 hrs, preferably 4 hrs to 8 hrs and at temperature of 20°C to 35°C under reduced pressure

9. A process as claimed in claim 1 o), wherein the employed iso-propanol is 2 volumes to 6 volumes, preferably 2 volumes to 4 volumes with respect to Olanzapine methylene chloride solvate

10. A process as claimed in claim 1 q), wherein the drying of Olanzapine Form-I is at temperature of 40°C to 60°C, preferably at 45°C - 55°C and the drying time is about 12 hours to 24 hours.