This patent application claims priority from Indian Patent application bearing number 1244/CHE/2009 dated May 29, 2009.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of formula-III.
CH3 0

Formula-III

The present invention also relates to an improved process for the preparation of Nevirapine using the intermediate of formula-III.

BACKGROUND OF THE INVENTION

Nevirapine is used to treat HIV-I infection caused by human immunodeficiency virus, type-1. Nevirapine works by HIV-1 reverse transcriptase inhibition. Nevirapine is marketed as tablets under brand name VIRAMUNE.

Nevirapine is chemically known as 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-one having the chemical structure of formula I.

Formula I

Nevirapine is first known in US 5,366,972 wherein 3-amino-2-chloro-4-methylpyridine of formula-A is condensed with 2-chloronicotinoyl chloride of formula-B in the presence of p to give 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide of formula-ll, which is reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of formula-III, which is cyclized in the presence of sodium hydride to give Nevirapine of Formula I.

The disadvantage of the above process is the use of excess cyclopropylamine, which results in generation of pressure, and it is difficult to handle in commercial scale.

Moreover, the reaction is carried at higher temperature, resulting in decomposition of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide. Further, with the above process undesirable side products are obtained during the reaction, which makes the product impure and it needs number of purification steps in different solvents or mixture of solvents to get the desire quality of the final product.

US 5,569,760 discloses a process for the preparation of Nevirapine, which comprises the reaction of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide with cyclopropylamine in the presence of a neutralizing agent, which is an oxide or hydroxide of an element of the second main or second subgroup of the periodic table, preferably calcium oxide is used. According to this process handling of calcium oxide is difficult due to its highly hygroscopic nature.

WO 2008142528 application claims process for the preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of I, wherein 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyhdine carboxamide of is reacted with cyclopropylamine in the presence of potassium fluoride or trisodiumphosphate dodecahydrate and solvent. Compound of formula-III thus obtained is further subjected to cyclization to get Nevirapine. According to this process, handling potassium fluoride in the plant level requires more safety precautions.

Now we have found that condensation of cyclopropyl amine with 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of using the simple and readily available reagent such as dipotassium hydrogen phosphate, N-methyl morpholine, potassium acetate, triethanol amine, aluminium oxide (basic), calcium carbonate, sodium bicarbonate, pyridine, triethyl amine, molecular sieves(3A), cuprous iodide or diisopropylethyl amine preferably dipotassium hydrogen phosphate.

OBJECT AND SUMMARY OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of I, which comprises: a) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide of with cyclopropylamine in the presence of a reagent in a solvent to get compound of I.

Another object of the present invention, is to provide an improved process for the preparation of Nevirapine of formula-I, which comprises: a) reacting 2-chloro-N-(2-
chloro-4-

methyl-3-pyridinyl)-3-pyridinecarboxamide of , with cyclopropylamine in the presence of a reagent in a solvent, b) cyclizing the compound of I in a solvent and c) isolating Nevirapine of formula-l.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of Formula III. The present invention also relates to a process for the preparation of Nevirapine using intermediate of I.

One embodiment of the present invention is to provide an improved process for the preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of I, which comprising the steps of:

a) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of

with cyclopropyl amine in the presence of a reagent such as dipotassium hydrogen phosphate, N-methyl morpholine, potassium acetate, triethanol amine, aluminium oxide (basic), calcium carbonate, sodium bicarbonate, pyridine, triethyl amine or diisopropylethylamine in a solvent, and

b) isolating the compound of I.

According to the present invention cyclopropyl amine, 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of , reagent and solvent are heated to reflux in autoclave for about 12-20 hrs and then cooled to 80-110°C. The reaction mass is filtered and washed with the solvent at about 70-95°C. The filtrate thus obtained is cooled to 20-40°C and then to 0-5°C and isolated the compound of formula-II by filtration.

According to the present invention the solvent selected from aromatic hydrocarbons, such as benzene, toluene, o-xylene, ethers, such as tetrahydrofuran, 1,4-dioxane, glycoldimethyl ether, diethyleneglycoldimethyl ether, chlorobenzene or pyridine, alcohols such as methanol, ethanol, isopropanol, dipolar aprotic solvents, such as dimethylformamide, l,3-dimethyl-2-imidazolidinone, l,3-dimethyltetrahydro-2(IH)- pyrimidinone or sulfolane.

Another embodiment of the present invention provides an improved process for the preparation of Nevirapine of formula-I,

which comprising the steps of:

a) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of formula-II

Formula-II

with cyclopropyl amine in the presence of a reagent such as dipotassium hydrogen phosphate, N-methyl morpholine, potassium acetate, triethanol amine, aluminium oxide (basic), calcium carbonate, sodium bicarbonate, pyridine, molecular sieves(3A), cuprous iodide, triethyl amine or diisopropylethylamine in a solvent to get compound of formula-III,

Formula-III

b) cyclizing the compound of formula-III in the presence of a base in a solvent, and

c) isolating Nevirapine of formula-I.

According to the present invention the mixture of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of formula-II, cyclopropyl amine, reagent and solvent are heated to reflux in autoclave for about 12-20 hrs and then cooled to 70-95°C. The reaction mass is filtered, the filtrate thus obtained is cooled to 20-40°C and then to 0-5°C.

The obtained solid is isolated as compound of formula-III by filtration. This compound of formula-III is dissolved in solvent and added to a base in a solvent at reflux temperature. The reaction mass is stirred at the same temperature for about 2-4 hrs, cooled to ambient temperature and then cooled to 5-15°C. The pH of the reaction mixture is adjusted to about 7.0-7.5 with an acid and the obtained Nevirapine of formula-l is isolated by filtration.

According to the present invention the solvent selected from aromatic hydrocarbons, such as benzene, toluene, o-xylene, ethers, such as tetrahydrofuran, 1,4-dioxane, glycoldimethyl ether, diethyleneglycoldimethyl ether, chlorobenzene or pyridine, alcohols such as methanol, ethanol, isopropanol, dipolar aprotic solvents, such as dimethylformamide, l,3-dimethyl-2-imidazolidinone, l,3-dimethyltetrahydro-2(IH)- pyrimidinone or sulfolane.

According to present invention, the base used for the cyclization is selected from sodium hydride, lithium hydride, potassium hydrides or n-butyl lithium and solvent is selected from o-xylene, toluene, benzene, tetrahydrofuran, 1,4-dioxane, glycoldimethyl ether, diethylene glycoldimethyl ether, triethyleneglycoldimethyl ether, dimethylformamide, N-methyl-2-pyrrolidinone, pyridine, anisole, sulfolane, dimethylsulfone or mixtures thereof
Yet another embodiment of the present invention is to provide a process for the purification of Nevirapine of formula-l which comprising the steps of:

a) dissolving Nevirapine in a solvent at reflux temperature,

b) cooling the solution of step a), and

c) isolating the Nevirapine of formula-I.

According to the present invention Nevirapine of formula-l is suspended in ethyl acetate and the temperature is raised to reflux to get a clear solution treated with carbon, cooled to 20-40°C and then to 0-5°C. The obtained solid is isolated by filtration.

According to the present invention 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of formula-ll is prepared as per the process disclosed in US 5,366,972.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1:

A) Preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide:

2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (50g), dipotassium hydrogen phosphate (67.8g, 2.19 mole eq), cyclopropylamine (40g, 3.96 mole eq) were suspended in o-xylene (250ml) and heated to 140-150°C in autoclave for 14-18 hrs. Then the reaction mass was cooled to 90-100°C, filtered and washed with o-xylene (100ml).

The filtrate was washed with purified water (150ml X 2) at 80-85°C. The reaction mass was distilled under vacuum at below 105°C to remove half of the xylene and then cooled to 25-35°C and to 0-5°C. The crystallized product was filtered, washed with o-xylene (25ml) and dried at 85-100° C. Dry weight: 50 gm (93.46% on theory).

B) Preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide:

2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (50g), dipotassium hydrogen phosphate (33.90 g, 1.10 mole eq), cyclopropylamine (20.21 g, 2.0 mole eq) were suspended in o-xylene (250ml) and heated to 140-150°C in autoclave for 14-18 hrs. The reaction mass was cooled to 90-100°C, filtered and washed with o-xylene (100ml). The filtrate was washed with purified water (150ml X 2) at 80-85°C. The organic phase was distilled under vacuum at below 105°C to remove half of the xylene. The reaction mass was cooled to 25-35°C and to 0-5°C to crystallize out the product. The crystallized product was filtered, washed with o-xylene (25ml) and dried at 85-100°C. Dry weight: 51gm (95.33% on theory)

EXAMPLE 2:

Preparation of Nevirapine:

Sodium hydride (9.0g) was suspended in o-xylene (180ml) at 25-30°C under nitrogen atmosphere and slowly heated to 130-135°C. N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide (22.5g) was dissolved in o-xylene and dimethyl formamide (5.0g) at 80-90°C was added to the above suspension over a period of 2-3 hours at 130-135°C and stirred for 3 hours. The reaction mixture was cooled to 25-35°C and methanol was added to the reaction mixture slowly at 25-35°C under nitrogen atmosphere. The reaction mass was stirred for 15 minutes and cooled to 10°C. Purified water was added to the reaction mixture and stirred for 30 min. The pH of the reaction mixture was adjusted to 7.0-7.3 using cone, hydrochloric acid below 25°C. The reaction mass was stirred for 30 minutes and cooled to 5-10°C and maintained for 30 min. The product obtained was filtered, washed with pure water, suck dried and dried at 85-95°C under reduced pressure. Dry weight: 19.35gm (86.0% on theory)

EXAMPLE 3:

Purification of Nevirapine:

Nevirapine (7.0g) was suspended in ethyl acetate (55.0ml). The temperature was raised to reflux to obtain a clear solution. Activated carbon (1.5g) was added to the solution and maintained at reflux for about 30 minutes and filtered the mass. The filtrate was cooled to 0-5°C and maintained for 30 minutes, filtered, suck dried and dried the compound at 85-95°C. Dry weight: 6.5gm (93.0% on theory)

We Claim:

1. An improved process for preparing N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of formula-III,

Formula-III which comprising the steps of:

a) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of formula-II,

Formula-II

with cyclopropyl amine in the presence of dipotassium hydrogen phosphate in a solvent,

b) isolating compound of formula-III.

2. The process according to claim 1, wherein said solvent is selected from toluene, o-xylene, benzene, tetrahydrofuran, 1,4-dioxane, chlorobenzene, dimethylformamide or sulfolane.

3. An improved process for preparing Nevirapine of formula-l,

which comprising the steps of:

a) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of formula-II

Formula-II

with cyclopropyl amine in the presence of dipotassium hydrogen phosphate in a solvent to get N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide of formula-III,

Formula-III

b) cyclizing the compound of formula-III in the presence of a base in a solvent, and

c) isolating Nevirapine of formula-l.

4. The process according to claim 3, wherein said solvent used for condensation in step a)
is selected from toluene, benzene, o-xylene, tetrahydrofuran, 1,4-dioxane, chlorobenzene, dimethylformamide or sulfolane.

5. The process according to claim 3, wherein said base used for cyclization in step c) is selected from sodium hydride, lithium hydride, potassium hydride or n-butyl lithium.

6. The process according to claim 3, wherein said solvent used for cyclization in step

c) is selected from toluene, o-xylene, benzene, tetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methyl-2-pyrrolidinone, sulfolane or dimethylsulfone.

7. A process for the purification of Nevirapine which comprising the steps of:

a) dissolving Nevirapine in a solvent at reflux temperature,

b) cooling the solution of step a), and

c) isolating pure Nevirapine.

8. The process according to claim 7, wherein the solvent is ethylacetate.