AN IMPROVED PROCESS FOR INDUSTRIAL MANUFACTURE OF

NEVIRAPINE

FIELD OF THE INVENTION This relates to an improved cost-effective, environmental friendly, industrial method for manufacture of Nevirapine.

BACKGROUND OF THE INVENTION

Nevirapine of formula (I) chemically known as l l-cyclopropyl-5,ll-dihydro-4-methyl- 6H-dipyrido [3,2 b:2',3'-e] [1,4] diazepin-6-one, and belonging to the dipyridodiazepinone chemical class of compounds, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) useful in the treatment of patients affected by the Human Immunodeficiency Virus type-I (HIV-I).

Nevirapine binds directly to the reverse transcriptase and blocks the RNA-dependent and the DNA-dependent polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine (I) does not interfere with template or nucleoside triphosphates and is administered in combination with other anti-viral drugs such as didanosine, lamivudine, zalcitabine or zidovudine.

The synthesis of nevirapine was first disclosed in US Patent No. 5 366 972 and comprises of four steps as disclosed in Scheme-I.

/ Dioxane (II) (I") (V)

A < ^V1 > " «

Xylene

Scheme - 1: Method as disclosed in US Patent No 5 366 972 for the preparation of Nevirapine of formula (I)

The method disclosed in US Patent No. 5 366 972 for preparation of nevirapine of formula

(I) comprises the steps of: - i) reduction of 2-chloro-4-methyl-3-nitro pyridine (II) with stannic chloride employing acetic acid as a solvent to give 3-amino-2-chloro-4-methyl pyridine (III). The reaction is characterized by long reaction times of at least about 12 hours and utilizes a hazardous reagent like stannic chloride, which is difficult to handle on an industrial scale due to its fuming and corrosive nature. Further, the process is not environment friendly, since there is considerable load on the effluent treatment plant for removal of sludge material formed during work up. The preparation of compound (III) is the first step of the reaction, therefore, compound (III) has to be prepared in large quantity, and this proportionately creates a large volume of the sludge, which becomes difficult to remove on a commercial scale, ii) acylation of 3-amino-2-chloro-4-methyl pyridine (III) with 2-chloronicotinoyl chloride (IV) in the presence of a base like pyridine and in a mixture of solvents like cyclohexane and dioxane to yield 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3- pyridine carboxamide (V). The reaction employs a solvent like dioxane, which is highly toxic for inhalation (http://www.jtbaker.com/msds/ehglishhtml/d7552.htm), hence cannot be utilized on an industrial scale. Further, dioxane needs elaborate safety precautions during storage and handling in view of its explosive nature.

Further the yield of the compound of formula (V) obtained is only about 10%, which is very low for commercial utilization. Also, dioxane solvent present in the effluent if released into soil is difficult to remove as dioxane is not biodegradable, iii) reaction of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) with cyclopropyl amine (VI) to give 2-N'-cyclopropyl amino-N-(2-chloro-4-methyl-

3-ρyridinyi)-3-pyridine carboxamide (VII), iv) cyclization of 2-N'-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3-py ridine carboxamide of formula (VII) by employing a strong base like sodium hydride in dimethyl formamide as solvent to give nevirapine of formula (I). Further, this method mentions that isolation of nevirapine (I) involves quenching with water, which is quite dangerous, especially when a reagent like sodium hydride is used, as sodium hydride reacts violently and explosively with water and is highly flammable.

US 5,569,760 (assigned to Boheringer Ingelheim) discloses an improved method for preparing 2-N ' -cyclopropylamino-N-(2-chloro-4-methyl-3 -pyridinyl)-3 -pyridine carboxamide (VII) wherein the reaction of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3- pyridine carboxamide (V) with cyclopropyl amine (VI) is carried out in the presence of an oxide or hydroxide of an element of the second group of the periodic table and diglyme as solvent. Further, 2-N' -cyclopropylamino-N-(2-chloro-4-methyl-3 -pyridinyl)-3 -pyridine carboxamide (VII), thus formed is not isolated but is converted after removal of the inorganic base to nevirapine (I).

This method suffers from the following drawbacks: a) 2-N'-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3-py ridine carboxamide (VII) formed by reaction with cyclopropyl amine (VI) is not isolated, therefore, it is very likely that an impurity of formula (VIII) disclosed in US 5 569 760 and likely to be formed in this reaction will be carried forward to the final stage and would be isolated along with nevirapine of formula (T), thereby affecting its purity profile,

b) this method also utilizes a strong base like sodium hydride, which is difficult to handle on industrial scale and also requires stringent conditions like careful quenching with water.

US 6,680,383 (assigned to Boheringer Ingelheim) also describes a method as disclosed in Scheme-II for preparation of nevirapine from compound of formula (II). This process utilizes a costly base like sodium hexamethyl disilazane (HMDS) for achieving cyclization to give nevirapine (I).

Nevirapine (I)

Scheme-ll: Method as disclosed in US Patent No. 6 680 383 for the preparation of Nevirapine of formula (I)

The method disclosed in Scheme-II, is slightly different from that disclosed in Scheme-I, but this route also utilizes a fuming and costly base like sodium hexamethyl disilazane in the final step for preparation of nevirapine (I).

Also, the method disclosed in US 6 680 383 utilizes a very toxic and hazardous raw material like 2-halo-3-cyano pyridine of formula (IX), which would be difficult to handle on a large scale due to its high toxicity, since compound (IX) contains a cyano functional group.

In view of the above shortcomings, there is a need for a method for preparing nevirapine (T), which would not only make the process safe and environment friendly, but also would be simple and cost-effective for commercial utilization.

Further, it should be noted that since nevirapine (I) has a market potential of Euro 310 million dollars (sales worldwide for the year 2001; (http://www.pjbpubs.com/pharmaprojects/sample therapy.htm). Therefore, it becomes more worthwhile and pertinent to develop a simple process, which is not only cost- effective, but also environment friendly.

The present inventors have prepared nevirapine of formula (I), by a simple process, which circumvents the utilization of hazardous reagents like stannic chloride, sodium hydride, pyridine and dioxane.

OBJECT OF THE INVENTION

An object of the invention is to provide a cost-effective industrial process for the manufacture of nevirapine, which utilizes a single solvent as reaction medium.

Another object of the invention is to provide a simple process, which utilizes reagents that are comparatively safer, easy to handle, environmentally friendly and reduces the load on effluent treatment plant.

SUMMARY OF THE INVENTION

An aspect of the invention relates to a cost-effective method for the preparation of 3- amino-2-chloro-4-methyl pyridine of formula (III), which comprises reduction of 2- chloro-4-methyl-3-nitro pyridine of formula (II) with iron powder in the presence of an acid, either organic or inorganic.

Another aspect of the invention relates to an alternate method for preparing 3-amino-2- chloro-4-methyl pyridine of formula (III) which comprises reduction of 2-chloro-4- methyl-3-nitro pyridine of formula (II) with sodium dithionite utilizing an organic solvent as a solvent.

A further aspect of the invention relates to use of safer environmental friendly reagents like a carbonate of an alkali metal as base and an alkyl acetate or an aromatic hydrocarbon as solvent for preparation of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (V) avoiding the use of hazardous solvents like dioxane and pyridine.

Yet another aspect of the invention relates to preparation of nevirapine of formula (I) comprising cyclization of 2-N'-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3- pyridine carboxamide of formula (VII) in the presence of a alkali metal alkoxide and in an inert organic solvent followed by neutralization with an acid and isolation of nevirapine of formula (I) by crystallization from an organic solvent.

Yet a further aspect of the invention relates to the utilization of a single solvent for the preparation of nevirapine of formula (I) in step-II, step-III, and step-IV thereby providing a cost-effective process.

Advantages of the invention:

The instant invention overcomes the following shortcomings with respect to prior art, i) avoids use of stannic chloride for reduction of the nitro group in the first step for preparation of compound of formula (III), ii) aqueous medium is used during the process of the invention and use of organic solvent is avoided during the preparation of 2-chloro-4-methyl-3-amino pyridine of formula (III), making the process cost effective and reduced load on effluent treatment; iii) circumvents utilization of pyridine and dioxane in the second step for preparation of compound of formula (V), iv) obviates the utilization of strong bases like sodium hexamethyl disilazane and sodium hydride used in prior art, for preparation of nevirapine of formula (I), thereby making the process safe, cost-effective and environment friendly, v) avoids load on the effluent treatment plant, vi) does not utilize dioxane as solvent, thereby making the process environment friendly, vii) providing a process, which utilizes toluene as solvent in Step-II, Step-III, and Step-IV. The advantages accrued therefore, would be low inventory of solvents, easy recovery and recycling of toluene. These factors, make the process of the instant invention more cost-effective, viii) providing an Active Pharmaceutical Ingredient, with acceptable limits of impurity profile.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, nevirapine of formula (I) is obtained by the method as disclosed in Scheme-Ill.

Iron powder and acetic acid / aqueous mineral acid sodium dithionite soα ⁱ um cutmon ⁱ t ^β

alkali metal alkoxide refluxed in toluene

Scheme - III: Method for preparation of Nevirapine of formula (I) as per the present invention.

Step-I:

First Method: Reduction with Iron powder in acetic acid

The first step relates to reduction of 2-chloro-4-methyl-3-nitro pyridine of formula (II) to give 3-amino-2-chloro-4-methyl pyridine of formula (III). The reduction of the nitro group is achieved by utilizing cheap and readily available raw materials like iron and an acid as compared to stannic chloride employed in prior art.

The acids are selected from organic or inorganic acids. The organic acid is preferably acetic acid while the inorganic acid is selected from the group comprising of hydrochloric acid, sulphuric acid, orthophosphoric acid etc.

2-Chloro-4-methyl-3 -nitro pyridine of formula (II) is added to acetic acid and stirred at a temperature ranging from 50 ⁰ C-110 ⁰ C, but preferably between a temperature of 65 ⁰ C and 85°C.

The volume of acetic acid employed for the reaction is between 5 volumes to 15 volumes per gram of compound of formula (II)

Iron powder is added to the mixture and stirred at the same temperature for duration of 3 - 8 hours. The preferred time duration is between 4.5 hours and 7.0 hours.

The amount of iron in moles, utilized for the reaction was between 1.0 mole and 5.0 moles per mole of 2-chloro-4-methyl-3 -nitro pyridine of formula (II).

The amount of iron in moles, utilized for the reaction was preferably between 2.0 moles and 3.5 moles per mole of 2-chloro-4-methyl-3-nitro pyridine of formula (II).

After completion of the reaction, the mixture is concentrated and the residue diluted with water.

An organic solvent selected from the group comprising of a chlorinated hydrocarbon, alkyl ester, aromatic hydrocarbon, aliphatic hydrocarbon etc. The preferred organic solvent is an alkyl ester, which was added to the reaction mixture.

The alkyl ester was selected from the group comprising of ethyl acetate, methyl acetate, propyl acetate, isobutyl acetate. The preferred alkyl ester is ethyl acetate.

The pH of the mixture was adjusted with an inorganic base selected from the group comprising of bicarbonates, carbonates or hydroxides of alkali or alkaline earth metals.

The preferred inorganic base was the carbonate of an alkali metal selected from sodium carbonate, or potassium carbonate.

The preferred inorganic base was sodium carbonate.

The amount of sodium carbonate utilized in moles for adjusting the pH of the reaction mixture was between 2.5 moles and 6.0 moles of sodium carbonate per mole of compound (II).

The mixture was stirred and the aqueous layer separated. The organic layer after optional treatment with activated charcoal was concentrated at reduced pressure to provide 3- amino-2-chloro-4-methyl pyridine of formula (III) which had the desired HPLC purity.

The present inventors state that reduction of 2-chloro-4-methyl-3-nitro pyridine of formula

(II) is also achieved in a very convenient and efficient manner, when the reduction is carried out with iron and a mineral acid in an aqueous medium or an organic solvent.

2-Chloro-4-methyl-3-nitro pyridine of formula (II) is added to water or an organic solvent and stirred at an ambient temperature.

The organic solvent is selected from the group comprising of an alcohol comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol, tertiary butanol etc or mixtures thereof. The preferred alcohol is methanol.

The volume of water or methanol employed for the reaction was between 5 volumes to 20 volumes of water per gram of compound of formula (II).

The mineral acid selected from the group comprising of orthophosphoric acid, hydrochloric acid and sulfuric acid was added to the reaction mixture. The preferred mineral acid was orthophsphoric acid.

The mixture is heated to a temperature ranging from 50 ⁰ C-I lO ⁰ C, but preferably between 65 ⁰ C and 85°C.

The amount of iron in moles utilized for the reaction was between 1.0 mole and 5.0 moles per mole of 2-chloro-4-methyl-3-nitro pyridine of formula (II).

The preferred amount of iron in moles utilized for the reaction was between 2.0 moles and 3.5 moles per mole of 2-chloro-4-methyl-3-nitro pyridine of formula (II).

The reaction mixture is cooled to ambient temperature, an organic solvent was added to the reaction mixture and stirred.

An organic solvent selected from the group comprising of chlorinated hydrocarbons, esters, and aromatic hydrocarbons added was added to the reaction mixture.

The organic solvent was preferably an ester selected from the group comprising of ethyl acetate, methyl acetate, propyl acetate and isobutyl acetate. 3-Amino-2-chloro-4-methyl pyridine of formula (III) thus obtained was converted to 2-chloro-N-(2-chloro-4-methyl-3- pyridinyl)-3 -pyridine carboxamide of formula (V) by reaction with nicotinoyl chloride of formula (IV).

The advantage of this method lies in utilizing iron and a mineral acid like orthophosphoric acid in an aqueous medium and the ease of work up, due to the absence of any sludge during the isolation of compound (III). The absence of any sludge formation during workup, reduces the load on effluent treatment significantly, thereby making the process

environment friendly and industrially viable. The process also becomes cost-effective, since the time required for each batch run reduces significantly.

Step-I:

Second Method: Reduction of nitro group with sodium dithionite in an organic solvent

This is an alternate method for reduction of nitro group, which comprises reduction of 2- chloro-3-nitro-4-methyl pyridine of formula (II) with sodium dithionite in an organic solvent to give 3-amino-2-chloro-4-methyl pyridine of formula (III).

The organic solvent is selected from the group comprising of an alcohol, ether, alkyl acetate etc. The preferred organic solvent is an alcohol.

The alcohol is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, secondary butanol, tertiary butanol etc and mixtures thereof.

The preferred alcohol is methanol.

2-Chloro-3-nitro-4-methyl pyridine of formula (II) is added to methanol and heated to a temperature between 65 ⁰ C and 80 ⁰ C. The preferred temperature range is between 7O ⁰ C and 8O ⁰ C.

A freshly prepared solution of sodium dithionite in water was added to the reaction mixture.

The reaction mixture was heated between 70 ⁰ C and 80 ⁰ C for 1 hour and cooled to ambient temperature.

The reaction mixture was extracted with an organic solvent selected from the group comprising of alkyl esters, aromatic hydrocarbon, chlorinated hydrocarbon etc.

The preferred organic solvent is an alkyl ester.

The alkyl ester is selected from the group comprising of ethyl acetate, methyl acetate, butyl acetate isopropyl acetate etc.

The preferred alkyl ester is ethyl acetate.

The organic layer was separated after extraction and concentrated under reduced pressure and cooled. The compound of formula (III), which solidified on cooling, had the desired HPLC purity.

The compound of formula (III) obtained by both the methods was carried forward as such to Step-II, without isolation.

It is pertinent to note that reduction of nitro group with sodium dithionite is more facile and takes place in only one hour as compared to 12 hours with stannic chloride. Furthermore, this method reduces the load on effluent treatment as there is no formation of a sludge that is usually encountered, when stannic chloride is employed as the reducing agent.

This step comprises acylation of 3-amino-2-chloro-4-methyl pyridine of formula (III) with 2-chloro nicotinic acid activated as 2-chloro nicotinoyl chloride (IV) in the presence of inert organic solvents or mixtures thereof to give 2-chloro-N-(2-chloro-4-methyl-3- pyridinyl)-3 -pyridine carboxamide of formula (V) .

The improvement in this step lies in the replacement of a toxic and hazardous solvent like dioxane and an organic base such as pyridine employed in prior art methods, which is detrimental for human health and safety. This improvement makes the process safe and environment friendly as compared to prior art methods.

2-Chloronicotinoyl chloride of formula (IV) is prepared utilizing thionyl chloride and dimethyl formamide with toluene as solvent.

The acid chloride of formula (FV) was dissolved in an organic solvent after removal of toluene under reduced pressure.

The organic solvent was selected from the group comprising of a chlorinated solvent, aromatic hydrocarbon, alkyl ester etc. The preferred organic solvent is an alkyl ester and/or aromatic hydrocarbon.

The alkyl ester was selected from the group comprising of ethyl acetate, methyl acetate, propyl acetate, isobutyl acetate etc. The preferred alkyl ester is ethyl acetate.

The aromatic hydrocarbon is selected from the group comprising of benzene, toluene, xylene, cumene etc. The preferred aromatic hydrocarbon is toluene.

2-Chloronicotinoyl chloride of formula (FV) was treated with 3-amino-2-chloro-4-methyl pyridine of formula (III) dissolved in an alkyl acetate and /or aromatic hydrocarbon in the presence of a base.

An inorganic or an organic base was added to the reaction mixture.

It should be noted that if toluene is utilized for the acylation method in step-II, then the method would be more cost effective since only one solvent viz. toluene, would be utilized for step-II, step-III, and step-IV.

The inorganic bases were selected from the group comprising of bicarbonates, carbonates, hydroxides of alkali or alkaline earth metals and/or alkoxides of alkali metals but preferably carbonates of alkali metals.

The organic base was selected from the group comprising of triethyl amine, n-propyl amine, tri-n-butyl amine, N,N-dimethyl aniline etc

The preferred organic base was N,N-dimethyl aniline. N,N-dimethyl aniline is less hazardous as compared to dioxane, which is highly flammable and has a tendency to explode in addition to being carcinogenic.

However, the present inventors, have noted that utilization of organic bases such as triethyl amine, pyridine etc. gave high impurity formation (about 40%), which is not at all desirable, when a commercially valuable compound of formula (I) is required with good purity profile.

But among the organic bases when N,N-dimethyl aniline was utilized, the impurity formation was within pharmacopeial limits, with yields around 89-95% as compared to yields of around 65%.

The amount in moles of N,N-dimethyl aniline employed was between 1.10 moles and 1.50 moles per mole of compound of formula (III).

Hence, it would be evident that the Step-II is specifically dependent on the type of base employed. Inorganic bases give much better results as compared to organic bases in terms of yield, purity of compound (V), and impurity profile.

The carbonates of alkali metals were selected from the group of sodium carbonate, potassium carbonate. The preferred inorganic base is potassium carbonate.

The amount in moles of potassium carbonate added to the reaction mixture is between

1.75 moles and 4.0 moles per gram mole of compound of formula (VI).

The mixture was refluxed for duration of between 12 to 16 hours, when an inorganic base like potassium carbonate was used, while the reaction was at around ambient temperature for 1-2 hours, when an organic base like N,N-dimethyl aniline was used.

After the reaction was over, the solvent was distilled under reduced pressure and the residue was diluted with water, mixture filtered between 5°C and 30 ⁰ C and dried at 50- 6O ⁰ C.

Alternately, the compound of formula (V) was isolated by adjusting the pH of the reaction mixture with 10% sodium carbonate solution to pH 7.0 and 7.5. The product of formula (V) separating out after stirring for 60-120 minutes at ambient temperature was filtered and washed with toluene

The HPLC purity of the compound of formula (IV) thus isolated was found to be according to the desired specification.

Step-III:

This step relates to the reaction of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) with cyclopropyl amine (VI) to give 2-N'-cyclopropylamino-N-(2- chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide of formula (VII).

In this step, 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (V) and cyclopropyl amine (VI) are added to an autoclave followed by addition of an inert organic solvent and heated between 12O ⁰ C and 13O ⁰ C for duration of between 19 to 22 hours.

The reaction in the autoclave was carried out in the pressure range of 12 to 25 psi.

The inert organic solvent is selected from the group comprising of aromatic hydrocarbon, aliphatic hydrocarbon etc. The preferred organic solvent is an aromatic hydrocarbon.

The aromatic hydrocarbon is selected from the group comprising of benzene, toluene, xylene. The preferred aromatic hydrocarbon was toluene.

The volume of toluene added to the mixture is between 4.0 volumes to 10.0 volumes per gram of compound (V).

The amount in moles of cyclopropyl amine (VI) utilized for the reaction is between 2.0 moles to 5.0 moles per gram mole of compound (V).

The reaction mixture was heated between 120 ⁰ C and 13O ⁰ C but preferably between 125 ⁰ C and 13O ⁰ C.

After completion of the reaction, the mixture is cooled to ambient temperature and washed with water.

The aqueous layer is separated and extracted with an organic solvent.

The organic solvent is selected from the group comprising of an aromatic hydrocarbon, chlorinated hydrocarbon, an alkyl ester etc. The preferred solvent is an alkyl ester and/or an aromatic hydrocarbon.

The alkyl ester is selected from the group comprising of methyl acetate, ethyl acetate, propyl acetate. The preferred alkyl ester is ethyl acetate.

The volume of ethyl acetate added is between 1-3 volumes per gram of compound of formula (V).

The organic layers were combined and concentrated under reduced pressure to obtain compound of formula (VII), which had purity according to specification.

Step-IV;

This step relates to a method for cyclization of N-(2-chloro-4-methyl-3-pyridinyl)-2- cyclopropylamino)-3 -pyridine carboxamide of formula (VII) to give nevirapine of formula (I)-

The present inventors have found that alkoxides of alkali metals such as sodium and potassium are quite effective for cyclization of N-(2-chloro-4-methyl-3-pyridinyl)-2- cyclopropylamino)-3-pyridinecarboxamide of formula (II).

The alcohols selected for preparation of the alkoxides are selected from methanol, ethanol, tertiary butanol etc and mixtures thereof.. The preferred alcohol is tertiary butanol.

The alkali metals are selected from the group comprising of lithium, sodium or potassium. The preferred alkali metal is potassium.

The metal alkoxides are selected from the group comprising of sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide etc. The preferred metal alkoxide is potassium tertiary butoxide.

The amount in moles of the metal alkoxide utilized for the reaction is between 2.0 mole and 5.0 moles per mole of the compound of formula (VII).

The solvent is selected from the group comprising of ethers, aromatic hydrocarbon, chlorinated hydrocarbon, aliphatic hydrocarbon etc. The preferred solvent is ether and/or an aromatic hydrocarbon.

The aromatic hydrocarbon is selected from the group comprising of toluene, xylene, cumene etc. The preferred aromatic hydrocarbon is toluene.

The ether is selected from the group comprising of 1,2-dimethoxy ethane, methoxyethanol, diglyme etc. The preferred ether solvent is diglyme.

The volume of toluene or diglyme utilized for the cyclization reaction was between 3.0 volumes and 20 volumes per gram of compound of formula (VII).

The reaction mixture is refluxed for duration of 2.5 to 5.0 hours, but preferably for 3.0 to 4.0 hours for completion of reaction.

Reaction mixture is cooled between -10 ⁰ C and +15°C. The preferred temperature is between 0 ⁰ C and 10 ⁰ C.

The biphasic mixture was neutralized between pH 6.0 and 7.0 with an inorganic or organic acid.

The inorganic acid is selected from the group comprising of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc. The preferred inorganic acid is sulfuric acid.

The organic acid is selected from the group comprising of acetic acid, propionic acid, formic acid, oxalic acid, pivalic acid etc. The preferred organic acid is acetic acid.

The amount of acetic acid employed for neutralization of the biphasic mixture is between 0.60 volume and 1.2 volumes per gram of compound of formula (VII). After pH adjustment, the reaction mixture is quenched with water.

When ether like diglyme was employed as solvent, the amount of water employed for quenching the reaction mixture was between 40 volumes and 60 volumes of water per gram of compound of formula (II) .

In case of an aromatic hydrocarbon like toluene as solvent, the amount of water employed for quenching the reaction mixture was between 2 volumes and 10 volumes of water per gram of compound of formula (II).

Nevirapine of formula (I) separating out during neutralization and quenching with water of the biphasic mixture, is then filtered and dried.

Nevirapine of formula (I) is then recrystallised from an organic solvent selected from the group comprising of an aromatic hydrocarbon, aliphatic hydrocarbon, chlorinated hydrocarbon, alkyl esters etc.

The chlorinated hydrocarbon is selected from the group comprising of dichloromethane, ethylene dichloride, chloroform. The preferred solvent is ethylene dichloride.

The solvent for recrystallization can be any solvent other than a chlorinated solvent.

Nevirapine of formula (I) is added to ethylene dichloride and refluxed between 60 ⁰ C -

70 ⁰ C till clear solution is obtained.

The mixture after optional charcoal treatment is partially concentrated under reduced pressure and cooled between 5°C and 1O ⁰ C.

The mixture is filtered and dried at 100 ⁰ C -110 ⁰ C.

Nevirapine of formula (I) thus obtained has the desired purity, which is as per pharmacopoeial specifications.

The invention can be further illustrated by the following examples, which however, should not be construed as limiting the scope of the invention.

Example-1 : Preparation of 3-Aniino-2-chloro-4-methyl pyridine of formula (III)

First method: Reduction with Iron in acetic acid.

2-Chloro-3-nitro-4-methylpyridine (II; lOOOgm, 5.75moles), was dissolved in acetic acid

(10 litres) and heated to 70 ⁰ C -8O ⁰ C. Iron (750gm, 13.42moles) was added and the temperature maintained at 70 ⁰ C to 8O ⁰ C. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residual mass was diluted with water (5 litres). The pH of the aqueous layer was adjusted between 8.0-8.5 by addition of aqueous sodium carbonate solution and organic layer was separated. The aqueous layer was washed with ethyl acetate (2 litres). The organic layer after optional charcoal treatment was concentrated under reduced pressure to give 3-Amino-2-chloro-4-methyl pyridine of formula (III).

Yield: 750gm %Yield: 90.79% HPLC purity: 99.25%.

Example-2: Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III)

Second method: Reduction with sodium dithionite

2-Chloro-3-nitro-4-methylpyridine (II; lOOgm, 0.575moles), was dissolved in methanol (1000 ml) and heated to 70°C-80°C. Sodium dithionite (300gm, 1.725moles) dissolved in water (1000 ml) was added gradually to the reaction mixture and the temperature maintained at 70 ⁰ C to 8O ⁰ C. After completion of reaction, the reaction mixture was concentrated under reduced pressure, residue extracted with ethyl acetate (1000 ml) and the separated organic layer was then concentrated under reduced pressure to give 3-

Amino-2-chloro-4-methyl pyridine of formula (III). Yield: 60gm % Yield: 72.60%

HPLC purity: 99.25%.

Example-3: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) [utilizing ethyl acetate as solvent during acylation]

2-Chloro nicotinic acid (1.33kg; 8.44moles) was added to toluene (S.Olitres) and thionyl chloride (0.75 litres; 10.42 moles) and dimethyl formamide (100ml; 0.18moles) were added and the mixture refluxed at 80°C-90°C till completion of reaction. The reaction mixture was concentrated under reduced pressure and cooled between 25°C and 30 ⁰ C. Ethyl acetate (8.0 litres) was added to the mixture followed by potassium carbonate (2.0kg; 15.15 moles). 3-Amino-2-chloro-4-methyl pyridine of formula (IιI).was dissolved in ethyl acetate and added to the acid chloride (IV). The mixture was refluxed at 75°C to 8O ⁰ C for 14 hours. The reaction mixture was concentrated after completion of the reaction and water (5.0 litres) was added. The reaction mass was cooled between 10-15 ⁰ C, filtered and dried between 60 ⁰ C and 70 ⁰ C under reduced pressure..

Yield: 1.73 kg. % Yield: 87.80%. HPLC Purity: 99.9%.

Example-4: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) [utilizing toluene as solvent and potassium carbonate as inorganic base during acylation]

2-Chloro nicotinic acid (1.33kg; 8.44moles) was added to toluene (5.01itres) and thionyl chloride (0.75 litres; 10.42 moles) and dimethyl formamide (100ml; 0.18moles) were added and the mixture refluxed at 80 ⁰ C -9O ⁰ C till completion of reaction. The reaction

mixture was concentrated under reduced pressure and cooled between 25°C and 30 ⁰ C. Toluene (8.0 litres) was added to the residue containing compound (IV), followed by addition of potassium carbonate (2.0kg; 15.15 moles). 3-Amino-2-chloro-4-methyl pyridine of formula (III) dissolved in toluene was added to the acid chloride (IV). The mixture was refluxed at 75 ⁰ C to 80 ⁰ C for 14 hours. The reaction mixture was concentrated after completion of the reaction and quenched with water (5.0 litres). The reaction mass was cooled between 10-15 ⁰ C and filtered.

Yield: 1.73 kg. % Yield: 87.80%. HPLC Purity: 99.9%.

Example-5: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) [utilizing toluene as solvent during acylation and triethyl amine as organic base]

2-Chloro nicotinic acid (1.33kg; 8.44moles) was added to toluene (5.01itres) and thionyl chloride (0.75 litres; 10.42 moles) and dimethyl formamide (100ml; 0.18moles) were added and the mixture refluxed at 80 ⁰ C -9O ⁰ C till completion of reaction. The reaction mixture was concentrated under reduced pressure. Toluene (8.0 litres) was added to the mixture. 3-Amino-2-chloro-4-methyl pyridine of formula (III) dissolved in toluene was added to the acid chloride (IV) and triethyl amine was added to the reaction mixture to adjust pH. The mixture was stirred at 25 ⁰ C to 32°C. Impurity formation up to 30-40% was formed in the reaction mixture, therefore, the reaction was not worked up for isolation of compound (V).

Example 6: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (V) [utilizing toluene as solvent during acylation and pyridine as organic base]

2-Chloro nicotinic acid (41.5gms; 0.263moles) was added to toluene (125ml) and thionyl chloride (19ml; 0.26moles) and dimethyl formamide (2.5ml; 0.005moles) were added and the mixture refluxed at 80 ⁰ C -90 ⁰ C till completion of reaction. The reaction mixture was concentrated under reduced pressure and the residue diluted with dioxane (55ml). Pyridine (62.5ml; 0.77moles) was added to a mixture of 3-Amino-2-chloro-4-methyl pyridine of formula (111) stirred in cyclohexane (62.5ml). The acid chloride (IV) mixture in dioxane,

was added to the mixture containing (III) and stirred for 2.5 hours at 25°C to 32°C. TLC monitoring of the reaction mixture showed lot of impurities. The solid separating out was filtered washed with cyclohexane. Compound (V) was dissolved in acetone (300ml), refiuxed, and concentrated to 50ml. The mixture was cooled between 5 and 10 ⁰ C, filtered and dried.

Yield: 32gms % Yield: 64.9%.

Example 7: Preparation of 2-N'-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridinyl)-3- pyridine carboxamide (VII)

2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (III; 1.0 kg; 3.5587 moles) was added to toluene (6.0 litres) in an autoclave. Cyclopropyl amine (0.813 kg; 14.23 moles) was added and the mixture heated between 125 ⁰ C and 130 ⁰ C at a pressure of 15 psi for 21 hours. After completion of the reaction, the reaction mixture was cooled between 25°C and 3O ⁰ C and washed with distilled water. The aqueous layer was separated and extracted with ethyl acetate (2.0 litres). The ethyl acetate layer was separated, combined with the toluene layer and concentrated under reduced pressure.

Yield: 0.857 kg. % Yield: 79.64%.

HPLC Purity: 98.14%.

Example 8: a) Preparation of Nevirapine of formula (I) (diglyme as solvent)

N-(2-Chloro-4-methyl-3 -pyridinyl)-2-cyclopropylamino)-3 -pyridine carboxamide of formula (VII; 1.0 kg; 3.305moles) was stirred in diglyme (10 litres) and potassium tertiary butoxide (1.48 kg; 13.188 moles) was then added to the mixture, which was then heated between 100 ⁰ C and 110 ⁰ C for 90 minutes. After completion of the reaction, the mixture was cooled between 5°C and 10 ⁰ C, the pH of the mixture adjusted between 6.0 and 7.0 by the addition of acetic acid, diluted with chilled water (50 litres) and the nevirapine (I) separating out was filtered. The compound of formula (I) was dried.

b) Recrystallization of Nevirapine of formula (I). Nevirapine (obtained from example 8a) was added to ethylene chloride (24 litres) and refiuxed for 30 minutes at 60 ⁰ C - 70 ⁰ C. The mixture after optional charcoal treatment was

concentrated partially and filtered at 5 ⁰ C-IO ⁰ C. The wet solid was dried at 100-110 ⁰ C for 24 hours.

Yield: 0.73 kg % Yield: 83.39% HPLC Purity: 99.92%.

Example 9: a) Preparation of Nevirapine of formula (I) (toluene as solvent)

N-(2-chloro-4-methyl-3-pyridinyl)-2-cyclopropylamino)-3-pyri dine carboxamide of formula (VII; 1.0 kg) was stirred in toluene (10 litres) and potassium tertiary butoxide (1.48 kg; 13.188 moles) was then added to the mixture, which was then heated between 100 ⁰ C and HO ⁰ C for 180-210 minutes. After completion of the reaction, the mixture was cooled between 5°C and 1O ⁰ C the pH of the mixture adjusted between 6.0 and 7.0 by the addition of sulfuric acid and then diluted with water (5 litres) and again the pH was adjusted between pH 1-2 by addition of sulfuric acid. Nevirapine (I) separating out was filtered. The compound of formula (I) was dried.

b) Recrystallization of Nevirapine of formula (I). Nevirapine (obtained from example 9a) was added to ethylene chloride (24 litres) and refluxed for 30 minutes at 60 ⁰ C - 70 ⁰ C. The mixture after optional charcoal treatment was concentrated partially and filtered at 5 ⁰ C-IO ⁰ C. The wet solid was dried at 100-110 ⁰ C for 24 hours.

Yield: 0.70 kg % Yield: 79.96%

HPLC Purity: 99.92%.

Example 10: Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III)

First method: Reduction of 2-chloro-3-nitro-4-methyl pyridine with Iron and phosphoric acid in an aqueous medium.

2-Chloro-3-nitro-4-methylpyridine (II; 2000gm, 11.59moles), was suspended in water (20 litres). Orthophosphoric acid (4.545kg; 46,36 moles ) was added to the mixture and heated between 70°C-80°C. Iron (1813 gms, 32.45moles) was added and the temperature maintained at 70 ⁰ C to 80 ⁰ C. The reaction mixture was monitored by thin layered chromatography and after completion of reaction; the reaction mixture was cooled to ambient temperature. Ethyl acetate was added to the reaction mixture and stirred. The

organic layer was separated and concentrated. Cyclohexane (3.116 kg) was added to the residue with stirring and the resulting mixture after stirring at 10-15 ⁰ C for 60 minutes was filtered, washed with cyclohexane and dried to give 3-Amino-2-chloro-4-methyl pyridine of formula (III). Yield: 15 OOgms to 1600gms %Yield: 90.7 to 96.8% HPLC purity: 99%.

Example 11: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (V) [utilizing toluene as solvent and N,N-dimethyl aniline as organic base during acylation]

2-Chloro nicotinic acid (165.75gms; 1.057moles) was added to toluene (542gms) and thionyl chloride (56.40gms; 0.477moles) and dimethyl formamide (5.9gms; 0.080moles) were added and the mixture refluxed at 80°C-90°C till completion of reaction. The reaction mixture was concentrated under reduced pressure and the residue diluted with toluene (542gms). 3-Amino-2-chloro-4-methyl pyridine (125gms; 0.877moles) of formula (III) was added to the mixture containing compound of formula (IV) at ambient temperature followed by addition of N,N-dimethyl aniline (127.12gms; 1.05moles). The reaction mixture was stirred for 2.5 hours at 25 ⁰ C to 4O ⁰ C. After completion of reaction, the reaction mixture was cooled to ambient temperature and neutralized with 10% sodium carbonate solution to pH 7.0 to 7.5. The solid separating out was filtered, washed with toluene and dried. Yield: 220-230 gms % Yield: 89-93%. Purity: 99%

Example 12: Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III)

First method: Reduction of 2-chloro-3-nitro-4-methyl pyridine with Iron and hydrochloric acid in an aqueous medium.

2-Chloro-3-nitro-4-methylpyridine (II; lOOgm, 0.579moles), was suspended in methanol (1000 ml). Hydrochloric acid (550ml; 15.06 moles ) was added to the mixture and heated to 65°C. Iron (195gms, 3.49moles) was added and the temperature maintained at 65°C. The reaction mixture was monitored by thin layered chromatography and after completion of reaction; the reaction mixture was cooled to ambient temperature. Ethyl acetate was

added to the reaction mixture and stirred. The organic layer was separated and concentrated. 3-Amino-2-chloro-4-methyl pyridine of formula (III) thus obtained was dried.

Yield: 74.4gms~79.9gms %Yield: 90.1-96.7% HPLC purity: 99%.

Example 13: Recrystallization of Nevirapine of formula (I) Nevirapine (15gms; obtained from example 9a) was added to methanol (510 ml) and refluxed for 30 minutes at 6O ⁰ C - 7O ⁰ C. The mixture after optional charcoal treatment was cooled between 5 ⁰ C-IO ⁰ C and filtered. The wet solid was dried at 100-110 ⁰ C for 24 hours.

Yield: 11.2 gms % Yield: 74.67% HPLC Purity: 99,89%. Melting point: 245-247°C

Example 14: Recrystallization of Nevirapine of formula (I) Nevirapine (15gms; obtained from example 9a) was added to isopropanol (660 ml) and refluxed for 30 minutes. The mixture after optional charcoal treatment was cooled between 0°C-5°C and filtered. The wet solid was dried at 100-11O ⁰ C for 24 hours.

Yield: 11.3 gms % Yield: 75.33% HPLC Purity: 99.63%. Melting point: 245-247°C.

Example 15: Recrystallization of Nevirapine of formula (I)

Nevirapine (5 gms; obtained from example 9a) was added to nitromethane (165 ml) and heated between 75°C-80°C for 30 minutes. The mixture after optional charcoal treatment was cooled between 0 ⁰ C-IO ⁰ C and filtered. The wet solid was dried at 100-110 ⁰ C for 24 hours.

Yield: 2.0 gms % Yield: 40%

HPLC Purity: 99.20%. Melting point: 245-247°C

Example 16: Recrystallization of Nevirapine of formula (I)

Nevirapine (lOgms; obtained from example 9a) was added to chloroform (200 ml) and refluxed for 30 minutes. The mixture after optional charcoal treatment was concentrated and a mixture of chloroform (10ml) and methylene dichloride (50ml) was added at ambient temperature and filtered. The wet solid was dried at 100-110 ⁰ C for 24 hours. Yield: 6.9gms % Yield: 69%

ADVANTAGES OF THE INVENTION:

The instant invention overcomes the following shortcomings with respect to prior art, 1. avoids use of stannic chloride for reduction of the nitro group in the first step for preparation of compound of formula (III),

2. aqueous medium is used during the process of the invention and use of organic solvent is avoided during the preparation of 2-chloro-4-methyl-3-amino pyridine of formula (III), making the process cost effective and reduced load on effluent treatment;

3. circumvents utilization of pyridine and dioxane in the second step for preparation of compound of formula (V),

4. obviates the utilization of strong bases like sodium hexamethyl disilazane and sodium hydride used in prior art, for preparation of nevirapine of formula (I), thereby making the process safe, cost-effective and environment friendly,

5. avoids load on the effluent treatment plant,

6. does not utilize dioxane as solvent, thereby making the process environment friendly,

7. providing a process, which utilizes toluene as solvent in Step-II, Step-Ill, and Step- IV. The advantages accrued therefore, would be low inventory of solvents, easy recovery and recycling of toluene. These factors, make the process of the instant invention more cost-effective,

8. providing an Active Pharmaceutical Ingredient, with acceptable limits of impurity profile.