WO2006025065A1

WO2006025065A1 - A process for the preparation of anhydrous olanzopine hydrochloride of form-1

Info

Publication number: WO2006025065A1
Application number: PCT/IN2004/000270
Authority: WO
Inventors: Venkat Reddy Alla; Kameswara Rao Vyakaranam; Venugopala Reddy Marella; Aruna Kumari Sirigiri; Sreenivasa Reddy Bodapati; Ranadheer Reddy Billa
Original assignee: Lee Pharma Private Limited
Priority date: 2004-08-31
Filing date: 2004-08-31
Publication date: 2006-03-09

Abstract

Malononitrile is reacted with Propionaldehyde in presence of Sulphur Powder and Triethylamine in N,N-dimethlyformamide to give 5-Amino-4-Cyano-2-Methyl Thiophene. 2-fluoronitrobenzene is condensed with 5-Amino-4-Cyano-2-Methyl Thiophene in Isopropyl alcohol and Potassium Hydroxide powder give 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene. Reduction of 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene with Stannous Chloride and Hydrochloric acid in Isopropyl Alcohol and followed by cyclization to get 4-Amino-2-Methyl-10H-Thieno [2,3,-b][1,5] Benzodiazepine . Condensation of 4-amino-2-methyl-10H-Thieno [2,3,-b][1,5] Benzodiazepine and N-methyl Piperazine in presence of Dimethyl Sulfoxide and Toluene gives Olanzapine Technical grade. In anhydrous form. Recrystallization of the Technical grade anhydrous Olanzapine in Dichloromethane gives anhydrous Olanzapine hydrochloride of Form-I.

Description

A PROCESS FOR THE PREPARATION OF ANHYDROUS OLANZAPINE HYDROCHLORIDE OF FORM - 1.

FIELD OF INVENTION:

The invention pertains to the process of obtaining Olanzapine hydrochloride of Form-I, having a novel process of preparation resulting in anhydrous.

BACKGROUND OF THE INVENTION:

Olanzapine hydrochloride is commonly known as Olanzapine and its chemical name is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b][1 ,5] benzodiazepine.

Currently there are many drugs available for the treatment of disorders of the central nervous system. Amongst these drugs is a category known as antipsychotics for treating serious mental conditions such as schizophrenia and schizophreniform illnesses.

The great majority of drugs available for treatment of schizophrenia are prone to produce extra pyramidal side effects when used at dosages that yield a beneficial effect on the symptoms of the disease. The severity of adverse events and/or lack of efficacy in a considerable number of patients frequently results in poor compliance or termination of treatment.

Ofanzapine,2-methyl-4- (4-methyl-l-piperazinyl)-IOH-thieno- [2, 3b][1 , 5] benzodiazepine is a potent antipsychotic agent. Olanzapine free base or its hydrochloride salt is an active ingredient of pharmaceutical preparations used in the treatment of disorders of the central nervous system. PRIOR ART:

Some of the patents have described this process of preparation, which no¬ where are related to the process herein described in producing anhydrous Olanzapine hydrochloride of Form-I.

Olanzapine was described for the first time in the European Patent EP 0454436BI. One of the methods for preparation of Olanzapine is based on condensation of 4-amine-2-methyl-10H- thieno [2,3-b][1 , 5] benzodiazepine with N-methylpiperazine carried out in dimethylsulfoxide and toluene. At the final stage of the reaction water is added in order to isolate the product. The crude product thus obtained is crystallized from acetonitrile.

In the second method Olanzapine is obtained by cyclization of l-{[2- aminoaniline)-5- methylthiophen-3-yl] carbonyl}-4-methylpiperazine carried out in N-methylpiperazine and anisole. The crude Olanzapine is isolated by treating the reaction mixture with ammonia, isopropanol and ethyl acetate and finally purified. Purification is performed by column chromatography with the use of Florisil eluted with ethyl acetate and the product is further crystallized from acetonitrile. Both methods claimed in EP 0454436BI lead to obtain Olanzapine in a pure crystalline form which is identified by the same melting point, NMR spectrum (IH andl3C) and mass spectrum.

The Patent No. US 5,229,382 describes the first polymorph of Olanzapine hydrochloride called Form I which has been described to be metastable and not suitable for commercial use in pharmaceutical formulations such as tablets due to its color, which changes over time on exposure to air.

In the patent EP 07336335 B1, a more stable second polymorph of Olanzapine is claimed. Olanzapine polymorphic Form Il is obtained by suspending crude Olanzapine in ethyl acetate in anhydrous conditions and crystallization from this solution. The existing of two different polymorphs has been confirmed by X-ray powder diffraction patterns characterized by different interplanar spacing d and relative intensities l/lo.

The drawback of the methods described above is that they require the use of different solvents at the subsequent steps of isolation and purification of technically grade Olanzapine. Moreover, these methods are rather difficult to repeat and often do not lead to obtaining the required polymorphic form.

For example, following the procedure of Preparation 1 of European Patent EP 0828494, comprising suspending the crude Olanzapine in a very small amount of Methylene chloride, filtration off the precipitate, then its maceration with Methylene chloride and drying, the obtaining of crystalline Form Il solvate with Methylene chloride is declared in the said patent. However, the X- ray powder diffraction pattern of the product matches with that of Olanzapine Form Il as claimed in EP 733635BI.

On the other hand, in EP 0828494, preparation methods were given for a polymorph defined by the Applicant as Olanzapine Form I, by crystallization of crude Olanzapine from acetone (Preparation 5), tetrahydrofuran (Preparation 6), ethyl acetate (Preparation 7), t-butanol (Preparation 8) and by transforming Form I in toluene.

In WO03097650 it is described that the use of any solvent such as acetonitrile, tetrahydrofuran, acetone, toluene or ethyl acetate for crystallization of crude Olanzapine always results in crystalline Form II, identified by X-ray powder diffraction patterns described in EP 0733635. The only one solvent enabling to obtain polymorphic Form I of Olanzapine by crystallization of crude Olanzapine or of its crystalline Form Il is methylene chloride.

Independently, the use of methylene chloride to crystallize Olanzapine in Form I mono- and dihydrate has been described in International Patent Application WO 02/18390. Moreover, the attempts to reproduce the methods known from the art for isolation and purification of Olanzapine obtained by the reaction of a molar excess of N-methylpiperazine and 4-amine-2-methyl-IOH-thieno [2,3- b] [1 , 5] benzodiazepine in organic solvent, e.g. dimethylsulfoxide, and subsequent addition of water and alcohol, show that the obtained product contains usually 10-15% of impurities. Triple crystallization from different solvents is required to remove these impurities and to obtain Olanzapine of pharmaceutical grade which is again hydrate.

In US 6251895 the invention describes the novel Dihydrate of D 2- Methyl thieno benzodiazepine and a formulation thereafter. Applicants claim that 2-methyl - 4-(4-methyl-1-piperazinyl)-10H-thieno[2,3 b]- [1 ,5]-benzodiazepine exists as 2 different dehydrate forms which are distinguishable by XRD

In US 5229382 invention describes the preparation of Olanzapine and does not describe or mention any of the Forms. It only relates to another property of the Compound and the formulations corresponding to it.

Thus, according to all of the teachings of the above mentioned and many others patents and patent applications, the typical methods for preparation of Olanzapine of technical grade comprise the condensation of 6-fold molar excess of N-methylpiperazine with 4-amine-2-methyl-10H-thieno- [2, 3-b] [I₁ 5] benzodiazepine hydrochloride in an organic solvent, e. g. dimethylsulfoxide, to which alcohol and excess of water is added after the reaction is completed, to remove unreacted substrates and impurities. The product is separated in a form of solvate with alcohol. Depending on the method used for the purification of technical grade Olanzapine, pharmaceutical grade of Olanzapine Hydrochloride is obtained. Using different methods of crystallization, Olanzapine Hydrochloride Form I in hydrated form is described. OBJECTS OF THE INVENTION:

The following shortcomings were observed in using the methods described earlier for the preparation of Olanzapine hydrochloride.

i) The Olanzapine Hydrochloride Form I prepared in any of the known processes is hydrate, ii) The patents and publications available have described the method of preparation of Olanzapine Hydrochloride Form I only.

As above discussed the shortcomings of the earlier inventions, the present invention has achieved all of the above and are treated as the advantages of the invention.

The primary objective of this invention is to develop a better method of preparation for anhydrous Olanzapine hydrochloride of form -1. Further objective of the invention is to develop a stable compound of Olanzapine Hydrochloride Form -1 in anhydrous form.

The above and other objects and advantages will be clear from the following description of the preferred embodiment.

Since the polymorphic Form 1 of Olanzapine hydrochloride is reported in hydrated form only, a need is felt to produce an anhydrous material of Form I. This aim was accomplished according to the present invention by developing a method for preparation of essentially pure Olanzapine polymorphic Form I, in which the Olanzapine thus obtained is anhydrous.

The foregoing description is outlined rather broadly preferred and alternatively featured of the present invention so that those skilled in the art may better understand the detailed description of the invention that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed concept and specific embodiment as a basis for carrying out the same purposes of the present invention. Those skilled in the art should realize such equivalent conception do not depart from the spirit and scope of the invention in its broadest sense.

SUMMARY OF THE INVENTION:

Considering the need for developing a process for the manufacture of Olanzapine hydrochloride , it was imperative to find an alternative method to get a product of anhydrous Olanzapine hydrochloride of Form - 1.

The brief summary of the invention can be described in the last stage which results in preparation of anhydrous Olanzapine hydrochloride of Form- 1.

Stage of Olanzapine Form-I

Recrystallization of Technical grade Olanzapine in Dichloromethane gives Olanzapine Form-I.

DESCRIPTION OF THE INVENTION

Now the invention will describe in detail with reference to the chemical drawings herein provided for easy reference to overcome the shortcomings of the prior art available with the same process, and this invention was made.

This invention describes an improved method for the preparation of Olanzapine Hydrochloride of form I

By the reaction of Malononitrile with Propionaldehyde in presence of Sulphur Powder and Triethylamine in N,N-dimethlyformamide to give 5-Amino-4- Cyano-2-Methyl Thiophene as per the procedure described in EP0454436A1

2-fIuoronitrobenzene is condensed with 5-Amino-4-Cyano-2-Methyl Thiophene in lsopropyl alcohol and Potassium Hydroxide powder give A- cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene.

Reduction of 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene with Stannous Chloride and Hydrochloric acid in lsopropyl Alcohol and followed by cyclization to get 4-Amino-2-Methyl-10H-Thieno [2,3,-b][1 ,5] Benzodiazepine using the same procedure as described in EP 0454436A1 but using lsopropyl alcohol in place of Ethanol

12.3-*j

Condensation of 4-amino-2-methyl-10H-Thieno [2,3,-t>][1 ,5] Benzodiazepine and N-methyl Piperazine in presence of Dimethyl Sulfoxide and Toluene gives Olanzapine Technical grade as described in EP 0454436A1.

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DESCRIPTION OF THE PREFERRED EMBODIMENT:

Recrystallization of Technical grade Olanzapine in Dichloromethane gives Olanzapine Form-I. is carried out according to the procedure described below.

Olanzapine Hydrochloride (Technical grade) (1 Kg) is dissolved in Methylene Dichloride (7 Lit) at reflux temperature. The resultant clear solution is then treated with activated carbon(100 gms) and stirred for 1 hour at reflux temperature. It is then filtered and the clear filtrate is collected into a separate vessel. It is then slowly cooled to ambient temperature. The mass is stirred for 1 hour at room temperature and then further cooled to 0° C. it si kept under stirring at 0° C for 3 hours. The separated solid is filtered and washed with chilled Methylene dichloride. The product obtained is dried at 40° C till constant weight appears. The material thus obtained is taken into the vessel and treated with methanol (1.2 Lit) to make a slurry. The slurry was stirred for 30 minutes and filtered. The solid is washed with methanol (20 ml), the product is dried at 60° C till constant weight.

It will be understood that the aforesaid description is only illustrative of the present invention and is not intended that the present invention is limited thereto. Many other specific embodiments of the present invention will be apparent to one skilled in the art from the foregoing disclosure. Any substitution, alteration or modification of the present invention which come within the scope of claims are to which the present invention is readily susceptible without departing from the spirit of invention.

Characterization of the Olanzapine as prepared aforesaid is taken as follows;

For Elucidation of Structure of Olanzapine Form-I was investigated by the following techniques. Its structure is confirmed by the Elemental analysis, Ultra-violet spectrophotometer, Infrared absorption spectrophotometer, Proton nuclear magnetic resonance spectrophotometer, Carbon magnetic resonance spectrophotometer and mass spectrophotometer. Details of the test methods used, and results obtained are given below.

Upon X - Ray Diffraction the values are equalized with the stabilized values and can be compared with the earlier reported values. Below is the comparison of d-values of Form-I produced by the inventor and reported values.

The XRD spectrum was shown in next page.

Claims

CLAIMS: We claim,

01. A process for the preparation of Olanzapine hydrochloride of form- 1 by,

a) re-crystallization of Technical grade Olanzapine in Dichloromethane to give Olanzapine Form - 1.

02. A process for the preparation of Olanzapine hydrochloride of form- I as claimed in claim 1 , wherein the resultant product is anhydrous.

03. A product as resulted through the process claimed and described in the present invention and obtained as anhydrous Olanzapine hydrochloride.