FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR THE MANUFACTURE OF 2-(2-NITROANILINO)-5-METHYLTHIOPHENE-3-CARBONITRILE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention :

PROCESS FOR THE MANUFACTURE OF 2-(2-NITROANILINO)-5-METHYLTHIOPHENE-3-CARBONITRILE
FILED OF THE INVENTION
The present invention relates to an improved process for the manufacture of 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile of formula (II) comprising reacting 2-amino-5-methylthiophene-3-carbonitrile (III) with 2-fluoronitrobenzene (IV) in a solvent and in the presence of a cosolvent and a base. More particularly, this invention provides an improved, concise and industrially feasible process for producing highly pure compound (II) with substantially improved yield without any extraction and further recrystallization. The compound (II) is useful intermediate in the manufacture of Olanzapine of formula (I).
BACKGROUND OF THE INVENTION
2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine, also known by the name olanzapine is represented by the structural formula (I) below:
N^S^CH3 0)
Olanzapine is an antipsychotic agent that belongs to thienobenzodiazepine class. Olanzapine is an antagonist of D-l and D-2 dopamine receptors and also exhibits antimuscarinic and anticholinergic properties and antagonist activity at 5HT-2 receptor sites. Furthermore, olanzapine also acts as an antagonist of noradrenergic alpha-receptors. Olanzapine is therefore useful in treating psychotic conditions including schizophrenia and acute mania. Olanzapine can additionally be used in the treatment of mild anxiety states when administered at lower doses.


Olanzapine was described for the first time in the European patent EP 0454436. This patent also discloses the process for the preparation of compound of formula (II) comprising the reaction of 2-amino-5-methylthiophene-3-carbonitrile (III) & 2-fluoronitrobenzene (IV) in the presence of a base for example sodium hydride, in a solvent such as tetrahydrofuran or n-butyl lithium in tetrahydrofuran, or potassium carbonate or lithium hydroxide in dimethylsulphoxide or with a tetraalkylammonium salt in a two-phase system. Especially exemplified process as disclosed in stage-2 of example-1 of EP 0454436 Bl consist the reaction of compound (III) & (IV) in the presence of sodium hydride in dry tetrahydrofuran. The mixture was stirred at 25° C for 24 hours, poured onto cracked ice and extracted into dichloromethane. The combined extracts were washed with 2N hydrochloride acid, water, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the compound (II) with ~ 68% yield.
EP 454436 also describes the processes for preparing olanzapine using different intermediates including compound (II). One of the known procedures consists the reaction of 2-amino-5-methylthiophene-3-carbonitrile (III) & 2-fluoronitrobenzene (IV) in presence of a base, followed by simultaneous reduction and cyclization reaction of 2-(2-nitroanilino)-5-methylthiophen-3-carbonitrile with stannous chloride (SnC12) in an aqueous-alcoholic solution of hydrogen chloride followed by a reaction of thus formed 4-amino-2-methyl-10H-thieno[2,3- b][l,5]benzodiazepine with N-methylpiperazine in an organic solvent or solvents mixture such as anisole, toluene, dimethylformamide or dimethylsulphoxide, preferably at a temperature from 100°C to 150°C for about 20 hrs, to which excess water is added after the reaction is complete. The crude product is separated out and collected. The crude Olanzapine is then crystallized in acetonitrile and gives a crystalline form, which is designated as Form I in later patents.
WO 2004/094390 also discloses the preparation of compound (II) by reacting the compound (III) & (IV) in a polar aprotic solvent in the presence of a phase transfer catalyst. The work-up process for the isolation & purification of compound of formula (II) is same as disclosed in EP 0454436 Bl, except the reduction in the time of reaction, with 60% yield of (II).


WO 2006/006180 also discloses the process for the preparation of compound (II) by reacting compound (III) & (IV) in the presence of potassium hydroxide, in acetonitrile at 0-10°C for 3 hour. The solid is isolated by addition of water and crystallized from water-methanol mixture to provide (II) with the over all yield of 74%.
Bioorganic & Medicinal Chemistry Letter, Vol. 7, No. 1, pp. 25-30, 1197 also discloses the process for the preparation of compound (II) in Scheme-1 on page no. 27 but with poor yield.
Russian Journal of Bioorganic Chemistry, Vol. 31, No. 4 2005, pp. 378-382, describes the process for the preparation of compound (II) with very low yield (23%).
Zhongguo Yiyao Gongye Zazhi (2001), 32(9) discloses the process for the preparation of compound of formula (II) by reacting the compound (III) &(IV) in DMF in the presence of lithium hydroxide with 70% yield, however the isolation of final material requires extraction of reaction mass with dichloromethane after distillation and followed by ethanol purification.
Moreover, it has also been observed when reaction of compound of formula (III) & (IV) is carried out in the presence of polar protic solvent like DMSO & weak base like K2C03, the Nitro-dimer impurity (herein referred to as "impurity A") is formed in the range of 5-20% depends upon the reaction conditions and molar ratio of compound (III) & (IV). The formation of this Nitro-dimer impurity may be the presence of weak base like K2C03 because potassium carbonate in the presence of polar protic solvent decreases the nucleophilicity of compound (III). Once dimer impurity is formed, it remains unreacted in the next stage of reaction, which ultimately reduce the yield of overall reaction. Furthermore, this dimer-impurity is very difficult to remove from the compound of formula (II) even after multiple purifications and hence in the subsequent stage of olanzapine, it is must to remove this dimer impurity to enhance the purity of olanzapine by crystallization or any other means, which ultimately reduce the overall yield of the synthesis of olanzapine.

N02 CLN

It is perceptible from the above mentioned prior art that according to the known process for the preparation of compound (II), there are more than one or more underlying problems associated with each of the processes like long time for reaction, isolation of compound (II) required extraction by chlorinated solvent like chloroform or dichloromethane, residue or crude material required further crystallization by using alcohol or alcohol-water mixture to obtain required purity of the compound (II), use of phase transfer catalyst, use of corrosive and expensive agent like n-butyllithium and low yield.
Hence, there is a demand for an improved, cost effective, commercially viable and suitable for large scale-up process for the preparation of compound (II) having high purity and substantially improved yield, which is key, intermediate for preparation of olanzapine.
The present invention discloses a process for the preparation of compound (II), which is key intermediate of olanzapine, which solves the problems associated with the prior art and provides a simple, efficient and cost effective method for production of compound (II), suitable for plant scale.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of compound (II) comprising the following steps;
a) adding the compound (III) to compound (IV) in a solvent and in the presence of a cosolvent and a base; and

.NO,

(IN)

(IV)

b) stirring for sufficient time; and
c) isolating the compound (II).
,NCL


CN
H3C

~NH
(ID

Another embodiment of the present invention is to provide the highly pure compound (II) in substantially improved yield.
Yet another embodiment of the present invention is to provide the compound (II) having purity greater than 99%.


Yet another embodiment of the present invention is to provide an improved process for the compound (II) in substantially improved yield, which is higher than 88%.
Another embodiment of the present invention is to provide an improved process to prepare highly pure compound (II) in substantially improved yield, wherein the process is substantially devoid of any extraction and/or crystallization step by using organic solvent.
Yet another embodiment of the present invention is to provide the improved process for the preparation of compound (II), which is cost effective, commercially viable & industrially feasible.
In another embodiment, the present invention provides a process for the preparation of olanzapine (I) comprising the following steps;
a) adding the compound (III) to compound (IV) in a solvent and in the presence of a cosolvent and a base; and

CN
H3C^S^~NH2 (Ml)

(IV)

-NO,

b) stirring for sufficient time; and
c) isolating the compound (II).


d) converting the compound (II) into the olanzapine by any known method.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates X-ray diffraction pattern of olanzapine Form I prepare according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The term "highly pure" compound (II) refers to the compound (II) having purity greater than 99%.
The term "substantially improved yield" refers to the compound (II) obtained according to the present invention in yield higher than 88%.
The term "cosolvent" used herein refers a second solvent added to the original solvent during chemical processing, generally in small concentrations than solvent, to form a mixture that has greatly enhanced solvent powers due to synergism.

In one embodiment, the present invention provides a process for the preparation of compound (II) comprising the following steps;
a) adding the compound (III) to compound (IV) in a solvent and in the presence of a cosolvent and a base; and

(HI)

b) stirring for sufficient time; and
c) isolating the compound (II).

In step a), the compound (III) is added to the compound (IV) in a solvent and in presence of a cosolvent and base. In preferred embodiment, the solvent for the reaction is selected from the group consisting of acetonitrile, isopropyl alcohol and tetrahydrofuran. Acetonitrile is the most preferable solvent for the reaction. The cosolvent is preferably selected from the group consisting of dimethylformamide, dimethylsulfoxide, dimethylacetamide, and N-methyl pyrolidone. The most preferable cosolvent is dimethylformamide.

In step a), the ratio of solvent and cosolvent can be in a range, which is suitable for the reaction, preferred ratio of solvent and cosolvent can be 4:1 (v/v) to 8:1 (v/v), the more preferred ratio of solvent and cosolvent is 6:1 to 8:1 (v/v). In the presence of a cosolvent, the compound (III) is almost entirely converted into the compound (II).
The base used in step (a), according to the present invention is strong base selected from the group consisting of potassium hydroxide, sodium hydroxide, sodium hydride, potassium tertiary butoxide and sodium methoxide. Potassium hydroxide is more preferred base for the present invention.
In step (a), generally the base is taken in almost half volume of solvent at any suitable temperature, preferably at 25°C-35°, then stir the reaction mixture at the same temperature for sufficient time and cool the reaction mass below -5°C. The prepared mixture is added with 2-fluoronitrobenzene (IV) with maintaining the temp at below -5°C preferably between -5°C to -20°, followed by the addition of cosolvent with maintaining the temp i.e. below -5°C. Then the solution of 2-amino-5-methylthiophene-3-carbonitrile (III) in rest of the volume of solvent is added to the above solution of compound (IV) over a period of 2-4 hrs at the temperature below -5°C. After the completion of addition, temperature of the reaction mixture is raised to 10-15°C and the reaction is maintained for sufficient time at the same temperature. Once the reaction has proceeded to completeness, it can be checked by using any known analytical method i.e. TLC or HPLC.
In step b), isolation of the compound (II) includes filtration, washing and drying of the isolated product at appropriate condition wherein filtration should preferably be carried out after the formation of precipitates in step b). Preferably once the reaction has completed it can be taken for further work-up. Isolation compound (II) can be done by the adding ice water to the reaction mass and stir the reaction mass for sufficient time to allow the complete isolation of compound (II). After filtering the compound (II), it can be optionally washed with water and dried at 20 ~ 80°C, preferably at 50 ~ 60°C, for 10 ~ 18 hours.
The compound of formula (II) is further converted into the olanzapine (I) by any known method reported in prior art such as mentioned in EP 0454436.

The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
Example-l
Preparation of 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile
Potassium hydroxide (45.59 gm) in acetonitrile (200 ml) was taken under nitrogen atmosphere at 25°C to 35°C and stirred the reaction mass for 10 minutes. Cooled the reaction mass to -15°C to -10°C and added with 2-fluoronitrobenzene (53.6 gm) at -15°C to -10°C, followed by addition with DMF (50 ml). A solution of 2-amino-5-methylthiophene-3-carbonitrile (50 gm) in acetonitrile (175 ml) was added over a period of 2-2.5 hrs at -15°C to -10°C. The reaction mass was then maintained for 3 hrs at 10°C-15°C with stirring and then chilled R.O. water (1.25 lit.) was added at 5°C-15°C and stirred for 2 hrs. The obtained solid mass was filtered off and washed with R.O. water and dried under vacuum at 60°C for 12-18 hrs to obtain the title compound (86.0 gm) (Yield = 91.68% & Purity = 99.42%).
Example-2
Preparation of 4-amino-2-methyl-10H-thieno[2,3-b]|l,5] benzodiazepine hydrochloride
To a stirred solution of concentrated HCL (1250 ml) & water (1250 ml) was added stannous chloride dihydrate (717.9 gm) at 25°C-35°C. At the same temperature the solution of 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (250 gm) in isopropyl alcohol (1250 ml) was added. The mixture was stirred under reflux for 2 hrs at 80°C-90°C, slowly cooled to 25°C-30°C and stirred for 30 minutes and finally maintained it to 10-15°C with continuous stirring for 1 hrs. The obtained mass was filtered off and washed with 2 x 150 ml of dilute HC1 solution (1:1) (Cone. HC1: R.O. water) and followed by washing with 2 x 250 ml of R.O. water and suck dry well. The obtained wet cake was charged in acetone (500 ml) and stirred for 1 hrs. at room temperature, followed by cooling it to 0°C-5°C and stirred for another 1 hrs. The obtained mass was filtered and

washed with 2 x 62.5 ml. of pre-chilled acetone and dried under vacuum at 60°C for 12 hrs to obtain the title compound (186.0 gm).
Example-3
Preparation of 2-methyl-10-(4-methyl-l-piperazinyl)-4H-thieno[2,3-b] [1,5] benzodiazepine
4-amino-2-methyl-10H-thieno[2,3-b][l,5]benzodiazepine hydrochloride (175 gm) was refluxed in a mixture of N-methylpiperazine (527.6 gm), dimethylsulphoxide (875 ml) and toluene (875 ml) under a nitrogen atmosphere for 6 hours at 120°C-130°C. The mixture was cooled to 50°C-60°C, water (875 mL) added over a period of 1 hrs. and the reaction mass was further cooled to 25°C-30°C and maintained for 1 hrs. Again cooled down it to 10°C-15°C, the obtained mass was filtered and washed with 2 x 175 ml of R.O. water. The wet cake was charged to 1750 ml of R.O. water, heated it to 55°C-60°C and filtered the wet-cake followed by washing with 2 x 175 ml of R.O. water and used the wet-cake (213 gm) without any treatment for next stage.
Example-4
Preparation of olanzapine Form-I
Olanzapine crude (100 gm) was dissolved in MDC (1500 ml) by heating the reaction mass at 28° to 30°C. Add the molecular sieve (50 mg) and stirred the reaction mass for 20 to 30 minutes. Filtered the reaction mass through hyflowbed and washed filter bed with 3X100 ml of MDC. The obtained filtrate was added with aluminum oxide (20 gm) and stirred the reaction mass for 20 minute at 28° to 30°C. Filtered the reaction mass through hyflowbed and washed filter bed with 3X100 ml of MDC. The methylene chloride was removed by distillation under vacuum up to 450-500 ml and remaining residual mass was seeded with olanzapine Form I (2-4 gm) and maintained the reaction mass at 10°C-12°C for 1 hr. Then distilled out the methylene chloride under vacuum up to 250-300 ml. Cooled down the reaction mass to 0°C-5°C and maintained for 2-2.5 hrs and filtered the mass under nitrogen atmosphere. Dried the material under vacuum at 25-30° for 8 hrs and 40-45° for 12 hrs to obtain Form-I of olanzapine (weight = 50 gm).

Abstract:
The present invention relates to an improved process for the manufacture of 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile of formula (II) comprising the reaction of 2-amino-5-methylthiophene-3-carbonitrile (III) & 2-fluoronitrobenzene (IV) in a solvent and in the presence of a cosolvent and a base without any extraction and further recrystallization. The compound of formula (II) is useful intermediate in the manufacture of Olanzapine of formula (I).