FIELD OF THE INVENTION:

The present invention relates to an improved process for enhancing the optical purity of chiral alcohols compounds. The chiral alcohols are used in the preparation of HIV reverse transcriptase inhibitor such as Efavirenz.

BACKGROUND OF THE INVENTION:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as a part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded post exposure prophylaxis regimen to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission. Efavirenz (Formula-I) has chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1 -benzoxazin-2-one. U.S patent No. 5,519,021 discloses Efavirenz and related compounds along with the synthesis of Efavirenz. Journal references Angew Chem. Int. Ed. 1999 (5), 711-713, Journal of Organic Chemistry (JOC) 1998, 63(23), 8536-8543; Journal of Organic Chemistry 2003, 3, 754- 761 and Tetrahedron Letters volume 41, 2000, 3015-3019 and PCT application WO 0170707 describe various methods for the synthesis of Efavirenz. US 5952528 discloses a process for enhancing the optical purity of chiral alcohols compounds. IN 1453/CHE/2008 and IN 2146/CHE/2008 also discloses process for enhancing the optical purity of chiral alcohols compounds. Present invention provides an improved process for enhancing the optical purity of chiral alcohols compounds and further conversion into Efavirenz.

OBJECT AND SUMMARY OF THE INVENTION:

Main object of the present invention is to provide an improved process for enhancing the optical purity of 2R-[1-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline (alcohol Intermediate of Formula-II). Another object of the present invention is to provide further conversion of alcohol intermediate into Efavirenz.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for enhancing the optical purity of 2R-[ 1 -hydroxy-1 -trifluoromethyl-3-cyclopropylpropyn-2-y 1 ]-4-chloroaniline. The present invention also relates to further conversion of 2R-[1-hydroxy-1-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline into Efavirenz. The main aspect of the present invention is to provide an improved process for enhancing the optical purity of 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline comprising the steps of:

a) adding a carboxylic acid solution or solid to 2R-[ 1 -hydroxy-1 -trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline in an organic solvent,

b) stirring the slurry of the 2R-[ 1 -hydroxy-1 -trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt at 15-40 °C for about 1 to 10 hours,

c) cooling the reaction mass to 0-10°C and maintain for 2 to 10 hours,

d) filtering the reaction mass to isolate 2R-[1 -hydroxy- 1-trifluoromethy 1-3 -cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt,

e) optionally washing the obtained 2R-[1 -hydroxy-1 -trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt with organic solvent,

f) suspending the 2R-[1-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt in water and adjusting pH to 7.5 - 9.5, and

g) isolating 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline with enhanced optical purity.

In one embodiment, the carboxylic acid used in the present invention is selected from oxalic acid, tartaric acid, maleic acid, fumaric acid and succinic acid, preferably oxalic acid. In one more embodiment, the organic solvent used in the step-a is an alcoholic solvent. The alcoholic solvents are selected from methanol, ethanol, isopropanol or mixtures thereof. In one more embodiment, slurry of the 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt is stirred at a temperature of 15-40°C for about 1 hour to about 10 hours. The preferable temperature is 25-40°C. In another embodiment, the organic solvent used in the step-e is a hydrocarbon solvent, preferably hexane. In one more embodiment, acid addition salt of 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline is suspended in water and pH is adjusted to 7.5 to 9.5 with a suitable base selected from potassium hydroxide, sodium hydroxide or aq ammonia.

In another embodiment, the compound 2R-[l-hydroxy-l-trifIuoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline is prepared by following the prior art procedures for example disclosed in WO 2011000532, IN 262/CHE/2008, US 6015926, US 7439400, IN 2207/MUM/2008 and our Indian co-pending application IN 2095/CHE/2011 andIN4617/CHE/2011. The obtained 2R-[ 1 -hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4- chloroaniline with enhanced optical purity is converted into Efavirenz by following the prior art procedures for example disclosed in US 6015926, WO 2011000532 and US 20110071287. All patents, patent applications, and non-patent publications cited herein by reference should be considered in their entirety. The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Examples

Example-1: Process for the preparation of 2R-[l-hydroxy-l-trifIuoromethyI-3- cycIopropylpropyn-2-yl]-4-ch!oroaniline Toluene (80 ml), Sodium hydride (44 g), and Tetrahydrofuran (120 ml) were mixed at a temperature of 30 °C. The reaction mass was cooled to 0-5° C and a solution of trifluoroethanol (38.4 g) in Tetrahydrofuran (40 ml) was added. To this, a solution of (1R, 2S)-N-Pyrrolidinyl Norephedrine (117.1) in toluene was added slowly. To this anhydrous Zinc acetate (131.4 g) was added and the temperature was raised to room temperature. In another flask a mixture of THF (22.4 ml) and Cyclo Propyl Acetylene (31.6g) was added to n-Butyl Magnesium Chloride (58.9 g) and stirred for an hour. The obtained Grignard solution was slowly added to above reaction mixture. The reaction mixture was cooled and a solution of 4-Chloro-2-trifluoro acetyl aniline (prepared by adding sodium hydroxide to 100 g of 4-Chloro-2-trifluroacetyl aniline hydrochloride hydrate) in THF was added at the temperature of 0-5 °C. The reaction mass was maintained at a temperature of 16 °C and toluene was added.

The reaction mass was cooled to 15 °C and the product was quenched with Citric acid solution. The aqueous layer was separated for the recovery of (1R, 2S)-N-Pyrrolidinyl Norephedrine. The organic layer was charged with water and distilled completely under vacuum. To this Isopropyl alcohol (300 ml) was added and temperature was raised to 37 °C. To this Oxalic acid dihydrate (54.4 g) was added. The obtained solution is stirred for one hour at 25-30 °C. The reaction mass was cooled to 0-10 °C and maintained for 2 hrs. The precipitated material was filtered and washed with washed with hexane. The obtained 2R-[l-hydroxy-l-trifiuoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline oxalate was suspended in water (500 ml) at 25-35°C. The reaction mass pH was adjusted to 7.5-9.5 with potassium hydroxide solution. The reaction mass was stirred for 1 hr at 25-35°C. The product was filtered and washed with water. The wet material was dried at 45-55 °C to get 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline.

ExampIe-2: Process for the preparation of 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yI]-4-chloroaniline Sodium hydride (44 g) was charged into a mixture of toluene (80 ml) and tetrahydrofuran (120 ml) at 28 + 3 °C and stirred at same temperature for 10 - 20 min. Reaction mass was cooled to 2 + 2 °C. To this a solution of 2,2,2-trifluoroethanol in tetrahydrofuran (38.4 g in 40 ml) was slowly added over a period of 2-4 hours and stirred at same temperature for 25 - 35 min. To this a solution of (1R, 2S)-N-Pyrrolidinyl Norephedrine (117.1 g) in toluene was slowly added at below 5 °C over a period of 3-5 hrs. The temperature of reaction mass was slowly raised to 28 + 3 °C with nitrogen purging and stirred at same temperature for 60 min. Reaction mass was cooled to 2 + 2 °C and to this Zinc acetate (131.4 g) was added. The resulting reaction mass was stirred at 2 + 2 °C for 30 min, temperature was slowly raised to 28 + 3 °C and stirred at same temperature for 1 hour.. In another flask a mixture of tetrahydrofuran (22.4 ml) and Cyclo Propyl Acetylene (31.6g) was added to n-Butyl Magnesium Chloride (58.9 g) and stirred for an hour. The obtained Grignard solution was slowly added to above reaction mixture.

The reaction mass was cooled to 0 °C and to this a solution of 4-chloro-2-trifluoro acetyl aniline base solution (prepared from 100 g of the corresponding hydrochloride salt and dissolving in a mixture of Toluene + tetrahydrofuran) was slowly added at 2 + 4 °C. The reaction mass temperature was slowly raised to 14 - 18 °C and maintained at same temperature for 3 hours. The progress of the reaction mass was monitored by HPLC. The reaction mass was cooled to 15 °C and the product was quenched with Citric acid solution. The aqueous layer was separated for the recovery of (1R, 2S)-N-Pyrrolidinyl Norephedrine. The organic layer was charged with water and distilled completely under vacuum. To this Isopropyl alcohol (300 ml) was added and temperature was raised to 37 °C. To this Oxalic acid dihydrate (54.4 g) was added. The obtained solution was stirred for one hour at 25-30 °C. The reaction mass was cooled to 0-10 °C and maintained for 2 hrs. The precipitated material was filtered and washed with washed with hexane. The obtained 2R-[ 1 -hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline oxalate was suspended in water (500 ml) at 25-35°C. The reaction mass pH was adjusted to 7.5-9.5 with potassium hydroxide solution. The reaction mass was stirred for 1 hour at 25-35°C. The product was filtered and washed with water. The wet material was dried at 45-55 °C to get 2R-[ 1 -hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline.

Example-3: Process for the preparation of 2R-[l-hydroxy-I-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline 2,2,2-Trifluoroethanol (21.2 g) was added to a mixture of (1R, 2S)-N-Pyrrolidinyl Norephedrine (108.7 g) in toluene at 28 + 3 °C under nitrogen atmosphere and cooled the reaction mass temperature to 2 + 2 °C. To this Diethyl Zinc solution (50 g on 100 % basis) was slowly charged and reaction mass temperature was raised to 28 + 2 °C. The reaction mass temperature was cooled to 2 + 2 °C and a solution of Cyclopropyl acetylene Grignard complex (prepared on reaction with n-Butyl Magnesium chloride using 31.6 g of Cyclopropyl acetylene) was added. To this 4-chloro-2-trifluoro acetyl aniline base (prepared from 100 g of corresponding hydrochloride salt) was added and temperature was raised to 25 + 2 °C. The reaction mass was cooled to 15 °C and the product was quenched with Citric acid solution.

The bottom aqueous layer was separated and resulting organic layer was washed with water. The final organic layer was distilled off completely under vacuum at below 60 °C. To this Isopropyl alcohol (250 ml) was added and temperature was raised to 37 °C. To this Oxalic acid dihydrate (54.4 g) was added. The obtained solution is stirred for one hour at 25-30 °C. The obtained reaction mass was further cooled to 3 + 2 °C and stirred at same temperature for 2 hrs. The obtained solid was filtered, washed with hexane and suck dried. The wet solid obtained was suspended in water and pH of the solution was adjusted to 7.5 - 9.5 using aqueous potassium hydroxide solution. The resulting heterogeneous mass was stirred at 30 + 5 °C for 30 min. The obtained solid was filtered, washed with water followed by aqueous methanol solution and suck dried. The wet material was dried at 50 + 5 °C to get 2R-[1-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline.

We Claim:

1. An improved process for enhancing the optical purity of 2R-[1-hydroxy-1- trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline comprising the steps of:

a) adding a carboxylic acid solution or solid to 2R-[ 1-hydroxy-1-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline in an organic solvent,

b) stirring the slurry of the 2R-[1 -hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt at 15-40°C for about 1 to 10 hours,

c) cooling the reaction mass to 0-10°C and maintain for 2 to 10 hours,

d) filtering the reaction mass to isolate 2R-[1 -hydroxy-1-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt,

e) optionally washing the obtained 2R-[1-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt with organic solvent,

f) suspending the 2R-[1-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline acid addition salt in water and adjusting pH to 7.5 -9.5 using a base, and

g) isolating 2R-[ 1 -hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline with enhanced optical purity.

2. The process according to claim 1, wherein the carboxylic acid is selected from oxalic acid, tartaric acid, maleic acid, fumaric acid and succinic acid.

3. The process according to claim 1, wherein the organic solvent used in the step-a is an alcoholic solvent.

4. The process according to claim 3, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol or mixtures thereof.

5. The process according to claim 1, wherein the organic solvent used in the step-e is a hydrocarbon solvent.

6. The process according to claim 5, wherein the hydrocarbon solvent is hexane.

7. The process according to claim 1, wherein the base used for the pH adjustment in step-f is selected from potassium hydroxide, sodium hydroxide or aq ammonia.

8. The process according to claim 1,wherein obtained 2R-[l-hydroxy-l-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline is further converted into Efavirenz.