FIELD OF INVENTION:

The invention relates to a novel process for the preparation of 2-methyl-4i/-3-thia-4, 9-diazabenzo[f]azulen-10-ylamine hydrochloride of Formula I,
an useful intermediate in the preparation of Olanzapine.

BACKGROUND OF INVENTION:

Olanzapine, 2-methyl-4- (4-methyl-l-piperazinyl)- 10H- 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. It is used in the treatment of Schizophrenia and Bipolar disorder.

2-methyl-4/f-3-thia-4,9-diazabenzo[/]azulen-10-ylamine hydrochloride of Formula I is an important intermediate in the preparation of Olanzapine. Several processes are known in the literature for the preparation of this intermediate.

Olanzapine was described for the first time in the European Patent EP 0 454 436 Bl. In EP 0 454 436 there are number of disclosed processes for olanzapine preparation. One of the known procedures consists in reduction and cyclization reaction of 2- (2-nitroanilino)-5-methylthiophen-3- carbonitrile with stannous chloride SnCl2 in an aqueous-alcoholic solution of hydrogen chloride, followed by a reaction of thus formed 2-methyl-4H-3-thia-4, 9-diazabenzo[f]azulen-10-ylamine hydrochloride with N- methylpiperazine in an organic solvent such as anisole, toluene, dimethylformamide or dimethylsulphoxide (DMSO), preferably at a temperature from 100 to 150°C, to produce olanzapine. The reaction scheme is shown below.

The main disadvantage of the prior-art process is generation of impurities which have to be removed by repeated crystallizations that has adverse effect on the process efficiency.

Another known procedure consists reaction of methyl-2-amino-5-methylthiophene-3-carboxylate with l-fluoro-2-nitrobenzene in presence of sodium hydride and tetrahydrofuran to form methyl -5-methyl-2-(2nitrophenylamino)thiophene-3-carboxylate. Reduction step was carried out in presence of palladium carbon to form methyl-2-(2-aminophenylamino)-5-methylthiophene-3-carboxylate which is shown in the following scheme.

SCHEME II
Palladium is very costly and highly pyrophoric. It is always advantageous to perform the nitro reduction without using palladium. Hence, inventors thought of developing alternatives for this reduction.
The present invention discloses an efficient method for the preparation of 2-methyl-4H-3-thia-4, 9-diazabenzo[f]azulen-10-ylamine hydrochloride of Formula I through novel reducing agent.

OBJECTIVE OF INVENTION;

An object of the present invention is to provide a process for the preparation of 2-methyl-4H-3-thia-4, 9-diazabenzo[f]azulen-10-ylamine hydrochloride of Formula I.

SUMMARY OF THE INVENTION:
The present invention discloses a novel and efficient method for the preparation of 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-ylamine hydrochloride of Formula I,

Formula I
which comprises:
reduction of compound of formula II,
Formula II
with sodium hydrosulfite (sodium dithionite or hydrose) in a suitable organic solvent and water followed by cyclization under acidic conditions to give compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION;
The present invention describes a novel reduction process of 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile compound of formula II for the preparation of 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-ylamine hydrochloride compound of formula I, which is an useful intermediate in the preparation of Olanzapine.

5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile compound of formula II is reacted with reducing agent in presence of an organic solvent and water at a temperature of 25-35 °C. Sodium hydrosulfite (commonly known as sodium dithionite or hydrose) is used as reducing agent which is added slowly to the mixture of 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile compound of formula II, organic solvent and water at 25-35 °C for 30 minutes. Organic solvent is selected from lower alcohols such as methanol, ethanol, propanol or ketones such as acetone, dimethyl ketone, propanone, methyl ketone or ethers such as 1,4-dioxane, THF or dipolar aprotic solvents such as DMF, DMA, DMSO and the like, more preferably methanol, acetone or DMF. After the completion of addition, the reaction mass is heated to reflux temperature and the reaction is maintained for about 2 hours at reflux.

After the completion of the reaction, the contents were cooled to 25-35 °C and 35% Hydrochloric acid was added with stirring for about 30 minutes. Then the reaction mixture was heated to reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. The reaction mass is allowed to cool to 30 °C and was stirred for about 30 minutes which is further cooled to 0-5 °C and is maintained for 1 hour. The obtained solid is filtered and washed with water to obtain compound of formula I.

We have surprisingly found that compound of formula I can be prepared in good yield and high purity by reduction of compound of formula II with sodium hydrosulfite.

EXAMPLES:
Preparation of 2-methyI-4H-3-thia-4,9-diazabenzo[f]azulen-10-yIamine
hydrochloride (I):

Example-1:
Methanol (150 mL), water (300 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (50 g) were stirred into a flask and the mixture was stirred to 25-35 °C for 15 minutes. Sodium hydrosulfite (200 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 2 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and 35% Hydrochloric acid (250 mL) was added with stirring for about 30 minutes. Then the reaction mixture maintained at reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. After the reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 30 minutes. The reaction mass was further cooled to 0-5 °C and maintained for 1 hour. The obtained solid was filtered and was washed with water (100 mL) to yield 48.6 gm of title compound.

Example-2:
Methanol (150 mL), water (300 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (50 g) were stirred in a flask at 25-35 °C for 15 minutes. Sodium hydrosulfite (165 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 2 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and precipitated product was filtered. 30% Hydrochloric acid (250 mL) was added to the wet material. The reaction mixture maintained at reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. After the reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 30 minutes. The reaction mass was further cooled to 0-5 °C and maintained for 1 hour. The obtained solid hydrochloride salt was filtered and washed with water (100 mL) to yield 49 gm of title compound.

Example-3:
Ethanol (30 mL), water (60 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (10 g) were mixed in a flask and stirred at 25-35 °C for 15 minutes. Sodium hydrosulfite (33 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 5 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and filtered. 30% Hydrochloric acid (50 mL) was added to the wet material. The reaction mixture maintained at reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. After the reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 30 minutes. The reaction mass was further cooled to. 0-5 °C and maintained for 1 hour. The obtained solid was filtered and was washed with water (20 mL) to yield 7.8 gm of title compound.

Example-4:
Isopropyl alcohol (30 mL), water (60 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (10 g) were mixed in a flask at 25-35 °C for 15 minutes. Sodium hydrosulfite (33 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 12 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and filtered. 30% Hydrochloric acid (100 mL) was added to the wet material. The reaction mixture maintained at reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. After the reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 1 h 30 minutes. The reaction mass was further cooled to 0-5 °C and maintained for 3 hours. The obtained solid was filtered and was washed with water (30 mL) to yield 7.2 gm of title compound.

Example-5:
Acetone (30 mL), water (60 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (lOg) were stirred into a flask and the mixture was stirred to 25-35°C for 15 minutes. Sodium hydrosulfite (33 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 12 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and filtered. 30% Hydrochloric acid (50 mL) was added to the wet material. The reaction mixture maintained at reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. After the cyclisation reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 30 minutes. The reaction mass was further cooled to 0-5 °C and maintained for 1 hour.

The obtained solid was filtered and was washed with water (10 mL) to yield 6.5 gm of title compound.

Example-6:
1,4-Dioxane (30 mL), water (60 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (lOg) were stirred into a flask and the mixture was stirred to 25-35°C for 15 minutes. Sodium hydrosulfite (33 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 12 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and filtered. 30% Hydrochloric acid (50 mL) was added to the wet material. The reaction mixture maintained at reflux temperature for about 2 hours 15 minutes and completion of reaction was determined by thin layer chromatography. After the reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 1 hour 20 minutes. The reaction mass was further cooled to 0-5 °C and maintained for 1 hour. The obtained solid was filtered and was washed with water (50 mL) to yield 8 gm of title compound.

Example-7:
DMF (30 mL), water (60 mL) and 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbonitrile (lOg) were stirred into a flask and the mixture was stirred to 25-35°C for 15 minutes. Sodium hydrosulfite (33 g) was slowly added at the same temperature during 30 minutes. After the completion of addition, the mass was heated to reflux temperature. The reaction was maintained for about 2 hours at reflux. The completion of reaction was monitored by thin layer chromatography. After the completion of the reaction, the contents were cooled to 25-35 °C and filtered. 30% Hydrochloric acid (50 mL) was added to the wet material. The reaction mixture maintained at reflux temperature for about 2 hours and reaction completion was determined using thin layer chromatography. After the reaction was completed, the mass was allowed to cool to 30 °C and was stirred for about 30 minutes. The reaction mass was further cooled to 0-5 °C and maintained for 1 hour. The obtained solid was filtered and was washed with water (20 mL) to yield 8.2 gm of title compound.

CLAIMS:

1. A process for the preparation of compound of formula I, by reduction of compound of formula II,

with sodium hydrosulfite in the presence of an organic solvent and water followed by cyclization under acidic conditions to give compound of formula I.

2. The process according to claim 1, wherein an organic solvent selected from lower alcohols, ketones, dipolar aprotic solvent and ethers.

3. The process according to claim 2, wherein lower alcohol selected from methanol, ethanol or propanol.

4. The process according to claim 2, wherein ketone selected from acetone, dimethyl ketone, propanone or methyl ketone.

5. The process according to claim 2, wherein ether selected from 1,4-dioxane or THF.

6. The process according to claim 2, wherein dipolar aprotic solvent selected from DMF, DMA, DMSO and the like.

7. The process according to claim 2, wherein organic solvent is more preferably methanol.

8. The process according to claim 1, wherein said reaction was carried out at a temperature ranging from 15-45 °C, preferably 20-40 °C.

9. Use of compound of formula I obtained as per claim 1, in the conversion to Olanzapine.