DESCRIPTION :

The present invention provides a one pot process for the preparation of olanzapine intermediate 5-methyl-2-(2-nitrophenylamino) thiophene-3-carbonitrile.

Olanzapine of the Formula I is chemically known as 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b][1,5]benzodiazepine. Olanzapine is indicated in the treatment of psychotic conditions including schizophrenia, schizophrenia-form diseases, and acute mania.

Several processes are known in the art for preparation of olanzapine such as U.S. Patent Nos. 7,329,747, U.S. Patent Applications 20060040921, 2006035887 and 2005159408.

The most common route of synthesis of olanzapine involves the use of a key intermediate 5-methyl-2-(2-nitrophenylamino) thiophene-3-carbonitrile (Formula II).

U.S. Patent No. 5,229,382; RE40,033; 5,627,178; 5,605,897; 6,008,216; 5,817,656; 5,817,655; 5,817,657; 5,627,178 and WIPO applications WO06/006180, WO04/094390, WO02/7105225 all discloses synthesis of olanzapine starting from key intermediate 5-methyl-2-(2-nitrophenylamino) thiophene-3-carbonitrile (Formula II).

The key intermediate, 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II) is prepared via a two step synthesis. The first step involves Gewald synthesis of 2-amino-5-methylthiophene-3-carbonitrile (Formula III) starting from propionaldehyde, sulfur and malononitrile. In the second step the 2-amino-5-methylthiophene-3-carbonitrile (Formula III) is condensed with 2-fluoronitro

benzene (Formula IV) to afford 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II).

The inventors while working on the improved commercial process for the preparation of Olanzapine have developed one pot synthesis of the key intermediate 5-methyl-2-(2-nitrophenylamino) thiophene-3-carbonitrile (Formula II). The process developed is very economical as the quantity of solvent required for the process is reduced drastically. Moreover, the time required for isolation of the intermediate is also saved. It was also found that the purity and yield of the final product is increased significantly.

In one aspect of the present invention, there is provided a process for the preparation of 5-methyl-2-(2-nitrophenylamino) thiophene-3-carbonitrile (Formula II) , a key intermediate for the synthesis of olanzapine.

The process includes steps of;

a) contacting malanonitrile, sulfur and propionaldehyde in one or more polar organic solvent in presence of a base,
b) adding 2-fluoronitrobenzene and an alkaline solution to the reaction mass of step a),
c) isolating 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II) from the reaction mass; and
d) converting the product obtained in step C) to olanzapine.

Generally, malanonitrile, sulfur and propionaldehyde are added in one or more polar organic solvent in presence of a base. After completion of reaction the reaction was concentrated. An alkaline solution is prepared separately by dissolving hydride or hydroxides of alkaline and alkaline earth metals in one or more organic solvents selected from the group of polar protic solvents. The prepared alkaline solution and 2-fluoronitrobenzene are added to the concentrated reaction mass. After completion of the reaction the compound of Formula II is isolated by addition of water into the reaction mass or vice versa.

The compound of Formula II thus obtained is subjected to reduction, cyclization and condensation with piperazine as per the teachings provided in the prior art like US 5,229,382, to afford olanzapine.

The base can be selected from the group of organic bases like triethylamine, dimethylamine, diethylamine, morpholine, piperazine or inorganic bases like sodium carbonate, sodium acetate, and ammonium acetate.

The alkaline, alkaline earth metals hydrides and hydroxide includes of sodium, potassium, sodium, lithium, aluminium, lithium aluminium metals.
The organic solvents selected from one or more group of polar protic solvents like C1-C4 alkanol or polar aprotic solvents like dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dioxane and dimethylacetamide or mixtures thereof.

Polar organic solvent can be selected from the group of polar protic solvents like C1-C4 alkanol or polar aprotic solvents like dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dioxane and dimethylacetamide or mixtures thereof.

The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Example 1:

5-Methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II)
A mixture of Sulphur (20.0 gm), DMF (15ml) and propionaldehyde (42.8 gm) was cooled followed by addition of triethylamine (39.7 gm) drop wise at 5-100C. The reaction mass was stirred for 45-60 min at 15-200C. A mixture of malononitrile and DMF (40.0 gm & 60.0 ml) charged into the reaction mixture drop wise at the same temperature. The reaction mass was stirred for 3-4 hrs. reaction mass was concentrated under vacuum at 45-500C (around 20%) (Mixture A). 2-Fluoro nitro benzene (83.3 gm) was taken in a solution of KOH (70.6 gm) in DMF (150 ml), and was charged into the reaction mass with stirring under nitrogen. 5-Methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II) was isolated from the reaction mass by the addition of chilled water. The isolated 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II) was purified from methanol.
Dry weight: 110.4 gm
HPLC Purity: > 99 %

Example 2: Conversion of 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II) to olanzapine:

a) 4-Amino-2-methyl-10H-thieno [2, 3-b][1,5]benzodiazepine hydrochloride

To the solution of 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (100 gm) in acetone (650 ml), Raney Nickel (25 g) was charged in hydrogenator at hydrogen pressure up to 100 psi at room temperature. After completion of reaction the reaction mixture was filtered and the solvent was removed. Residue obtained was dissolved in isopropyl alcohol (500 ml) and the reaction mixture heated was to 50- 55 C. To the reaction mixture hydrochloric acid (1 Lit, 6 N) was added and reaction mixture was heated to reflux for three hours. After completion of reaction the reaction mixture was cooled to 0- 5 C. Solid obtained was filtered, washed and dried.
Yield: 85 g
Purity: 99.77%

b) Olanzapine

To the solution of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine Hydrochloride(80 gm) in Dimethyl sulphoxide (400 ml) added 240 gm N-methyl piperazine and toluene(400 ml). The reaction mixture refluxed under stirring. After completion of reaction, reaction mixture is cooled and water (800 ml) was added. Reaction mixture was further stirred for 3 hr at below 200C. The precipitated product was filtered washed and recrystallised.
Yield = 70 gm
Purity: 99.80%

We Claim:

1. A process for the preparation of 5-methyl-2-(2-nitrophenylamino) thiophene-3- carbonitrile (Formula II) , a key intermediate for the synthesis of olanzapine, the process comprises of

a) contacting malanonitrile, sulfur and propionaldehyde in one or more polar organic solvent in presence of a base,
b) adding 2-fluoronitrobenzene and an alkaline solution to the reaction mass of step a),
c) isolating 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (Formula II) from the reaction mass; and
d) converting the product obtained in step C) to olanzapine.

2. The process as per claim 1, wherein the polar organic solvent is selected from the group of polar protic solvents like C1-C4 alkanol or polar aprotic solvents like dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dioxane and dimethylacetamide or mixtures thereof.

3. The process as per claim 2, wherein the polar organic solvent is dimethylformamide.

4. The process as per claim 1, wherein the base is selected from the group of organic bases like triethylamine, dimethylamine, diethylamine, morpholine, piperazine or inorganic bases like sodium carbonate, sodium acetate, ammonium acetate.

5. The process as per claim 4, wherein the base is triethylamine.

6. The process as per claim 1, wherein the alkaline solution prepared by dissolving hydrides and hydroxides of alkaline and alkaline earth metals like sodium, potassium, lithium, aluminium and lithium aluminium in one or more organic solvents.

7. The process as per claim 6, wherein the alkaline solution is prepared by dissolving potassium hydroxide in dimethylsulfoxide.

Dated this 7th day of October, 2008 For Wockhardt Limited

(Mandar Kodgule)
Authorized Signatory