WO2015118515A1

WO2015118515A1 - An improved process for the preparation of a non-nucleoside reverse transcriptase inhibitor

Info

Publication number: WO2015118515A1
Application number: PCT/IB2015/050994
Authority: WO
Inventors: Kondala Rao KOTA; Dhananjaya GUDLA; Srinivasa Rao ALA; Nishita MANNE
Original assignee: Discovery Intermediates Private Limited
Priority date: 2014-02-10
Filing date: 2015-02-10
Publication date: 2015-08-13

Abstract

The present invention relates to an improved process for the preparation of a non-nucleoside reverse transcriptase inhibitor. Specifically, the present invention relates to an improved process for the preparation of Efavirenz of Formula 1. The present invention also relates to a process for the preparation of compound of Formula 2, an intermediate used in the preparation of Efavirenz, wherein X is a halogen atom; X₁ is a leaving group.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF A NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR

Field of the Invention

The present invention relates to an improved process for the preparation of a non-nucleoside reverse transcriptase inhibitor. Specifically, the present invention relates to an improved process for the preparation of Efavirenz of Formula I.

Formula I

The present invention also relates to a process for the preparation of compound of Formula 2, an intermediate used in the preparation of Efavirenz.

Formula 2

wherein X is a halogen atom; X₁ is a leaving group.

Background of the Invention

Efavirenz, chemically known as (4S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4- (trifluoromethyl)-2H-3,l-benzoxazin-2-one, is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI). A number of compounds are effective in the treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system. Effective treatment through inhibition of HIV reverse transcriptase is known for non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. Efavirenz is efficacious against HIV reverse transcriptase resistance. Efavirenz is first disclosed in US patent 5,519,021 A and in EP patent 0 582 455 B 1. U.S.Pat. No. 5,519,021 discloses process for the preparation of Efavirenz which involves cyclisation of racemic mixture of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl- 1,1,1 -trifluoro- 3-butyn-2-ol of Formula II using Ι,Γ-carbonyldiimidazole as carbonyl delivering agent to give racemic Efavirenz. Further, resolution of the racemic Efavirenz is carried out using (-) camphanic acid chloride to yield optically pure Efavirenz. The process is shown in the

Formula II Formula I

Scheme I

U.S. Pat. No. 5,633,405 discloses another process for obtaining Efavirenz of Formula I which involves reaction of amino alcohol of Formula III with phosgene in a mixture of toluene and tetrahydrofuran as solvent and triethyl amine as a base to give a protected compound of Formula IV which on deprotection gives Efavirenz. The process is shown in the scheme-II given below:

Formula I I I Formula IV Formula I

Scheme II

U.S. Pat. No. 5,922,864 describes methods for cyclizing the compound of Formula II using chloroformates such as 4-nitrophenyl chloroformate, methyl chloroformate and ethyl chloroformate. These methods use 1.05 to 2 molar equivalents of chloroformates for cyclizing 1 mol of the compound of Formula II. U.S. Pat. No. 5,932,726 discloses a process for the preparation of Efavirenz of Formula I which involves reaction of the Efavirenz intermediate of Formula II with phosgene in a solvent such as heptane, toluene and tetrahydrofuran or mixtures thereof. The process is shown in the

Formula II Formula I

Scheme III

U.S. Pat. No. 5,952,528 discloses an efficient process for preparation of chiral amino alcohol by addition of n-butyl lithium and cyclopropylacetylene to a ketone of Formula V in presence of a chiral organozinc complex comprising of chiral additive and dialkyl zinc. Alternatively, the chiral amino alcohol is prepared by adding chloromagnesium complex of cyclopropylacetylene to the ketone of Formula V in presence of the chiral organozinc complex. The process is shown in the scheme-IV given below:

U.S. Pat. No. 6,147,210 discloses a process in which the desired benzoxazinone ring was obtained by reaction of compound of Formula VI in toluene/hexane mixture utilizing n-butyl lithium as base. The process is shown in the scheme-V given below:

Formula VI Formula I

Scheme V

U.S. Pat. No. 6,015,926 discloses a process for the preparation of Efavirenz of Formula I which involves reaction of amino alcohol with phosgene in methyl tert-butyl ether or toluene as solvent and aqueous potassium bicarbonate solution. The process is shown in the scheme - VI given belo

Formula II Formula I

Scheme VI

U.S. Pat. No. 6,114,569 discloses a process in which the benzoxazinone ring is formed by reaction of the carbamate derivative of an Efavirenz intermediate of Formula VII in the presence of an aqueous solution of a base in a solvent selected from the group consisting of MTBE, toluene, tetrahydrofuran, acetonitrile, dimethylacetamide, N-methylpyrrolidinone or mixtures thereof. The process is shown in the scheme-VII given below:

Formula VII Formula I

R represents alkyl or aryl

Formula VI I can be isolated When

R represents alkyl

Scheme VII U.S. Appl. No. 2012/0264933 discloses a process for preparing chiral amino alcohol using an organometallic complex such as organozinc complex comprising the steps of: a) preparing salts of mixture of chiral additive and achiral additive with an inorganic base, b) adding metal halides such as zinc halides to the salts of mixture of chiral additive and achiral additive to obtain the chiral zincate complex, c) adding lithium or magnesium cyclopropylacetylide complex to the chiral zincate complex to obtain chiral organozinc alkyne complex and d) mixing ketone with the chiral organozinc complex. The process is shown in the scheme- VIII as iven below:

organozinc alkyne complex

Scheme VIII

Most of prior art processes involves solvents like tetrahydrofuran, which are prone to develop peroxides on storage and requires solvent purification for removing the peroxides. Further, the use of multiple solvents in the process not only increases the process cost but also increases the solvent inventory and reduces the possibility of obtaining a pure solvent for reuse when boiling points are close.

The cyclization methods described in the prior art for preparing Efavirenz have problems associated with the formation of by-products. Efavirenz of formula I isolated after the cyclization requires an additional step of purification for obtaining the desired form of the product. Further the use of reagents like ceric ammonium nitrate for deprotection of the nitrogen atom in the oxazinone ring drastically increases the load on the effluent treatment due to heavy metal contamination. Thus there is a need in the art for an improved process for the preparation of Efavirenz, which employs less expensive, easily available and environment friendly reagents.

Objective of the Invention

The main objective of the present invention is to provide cost-effective and commercially feasible process for the preparation of Efavirenz.

Another objective of the present invention is to provide a process for the preparation of Efavirenz which employs less expensive, easily available and environment friendly reagents.

Yet another objective of the present invention is to provide a process for the preparation of compound of Formula 2, an intermediate used in the preparation of Efavirenz.

Summary of the Invention

Accordingly, the present invention provides an improved process for the preparation of Efavirenz of compound of Formula

Formula I which comprises reacting the compound of Formula 2

Formula 2 wherein X is a halogen atom; Xi is a leaving group with 2,2,2-trifluoroethanol or ethyl trifluoro acetic acid followed by the reaction with cyclopropylacetylene in the presence of a grignard reagent to give Efavirenz of Formula I.

In another aspect, the present invention provides a process for the preparation of Efavirenz of compound of formula I, which comprises the steps of:

i. reacting the compound of Formula 2,

Formula 2

wherein X is a halogen atom; Xi is a leaving group with 2,2,2-trifluoroethanol or ethyl trifluoroacetate to obtain a compound of Formula 3,

Formula 3

X-\ is a leaving group

ii. reacting the compound of Formula 3 with cyclopropylacetylene in the presence of a grignard reagent to give Efavirenz of formula I.

In yet another aspect, the present invention provides a process for the preparation of compound of formula 2, which comprises the steps:

i. acylating 4-chloroaniline of compound of Formula 4,

Formula 4 with a condensing agent to give compound of Formula 5,

Formula 5

Xi is a leaving gp

ii. halogenating the compound of formula 5 to give compound of formula 2,

Detailed Description of the Invention

In an embodiment of the present invention, halogen atom X is selected from chloro, bromo, iodo and the like.

In another embodiment of the present invention, leaving group Xi is selected from chloro, bromo, iodo, mesyl, tosyl, imidazolyl, cyclohexyl, methyl, ethyl, phenyl and the like.

In yet another embodiment of the present invention, the acylation takes place in the presence of a condensating agent selected from Ν,Ν'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), phosgene, dimethylcarbonate, diphenylcarbonate, or di- (paranitrophenyl)carbonate and the like.

In yet another embodiment of the present invention, the halogenation is carried out using suitable halogenating reagents for the preparation of corresponding bromides or chlorides include for example NBS, Br₂/acetic acid, HBr/acetic acid, NCS, and S0₂C1₂. The reaction is carried out in a solvent selected from MDC, EDC and the like.

In yet another embodiment of the present invention, the Grignard reagent used in step (b) is selected from RMgX wherein R is methyl, ethyl, isopropyl, vinyl, phenyl, allyl and the like and X is a halogen atom selected from chloro, bromo, fluoro and iodo.

In yet another embodiment of the present invention, the intermediate of Formula 3 is isolated from the reaction mixture before reacting with cyclopropylacetylene.

In yet another embodiment of the present invention, the intermediate of Formula 3 is reacted with cyclopropylacetylene without isolation for maintaining the chirality. In yet another embodiment of the present invention, the chiral reagent is selected from (1R, 2S)pyrrolidynyl norephedrine. In yet another embodiment the solvents used in the present invention are selected from THF, diethyl ether, toluene, hexane, cyclohexane, methyl cyclopropyl hexane, MTBE, ethyl acetate, benzene, methanol, ethanol, acetonitrile, MDC, EDC, DMF, DMSO and the like.

In yet another embodiment the temperature at which the reactions are carried out ranges from -78 to 120°C.

In yet another embodiment the pressure at which the reactions are carried out in the present invention is atmospheric pressure.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES Example 1

Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:

4-Chloroaniline (1 mmol) was added to solution of aqueous NaOH (1.15 mmol in 1.2 times of water) in toluene (4 vol.). The reaction mixture was cooled to 15°C and add pivaloylchloride (1.2 equiv.) slowly by maintaining the temperature below 40°C. The reaction was maintained between 25-35°C for 1 h. After completion of the reaction, it was cooled to - 10°C for 2 h, filtered, washed with 10% aqueous methanol to afford 98% of N-(4- chlorophenyl)pivalamide .

Step 2: Synthesis of N-(2-bromo-4-chlorophenyl)pivalamide from N-(4- chlorophenyl)pivalamide:

Bromine (1.2 mmol) was added dropwise to a solution of N-(4-chlorophenyl)pivalamide (1 mmol) in acetic acid (2 vol.) at room temperature. The reaction was stirred at the same temperature for lh. After completion of the reaction the reaction mixture was poured into crushed ice to get precipitate. The precipitate was filtered and washed with water to yield 90% N-(2-bromo-4-chlorophenyl)pivalamide.

Step 3: Synthesis of l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone hydrochloride from N-(2-bromo-4-chlorophenyl)pivalamide:

Isopropylmagnesium bromide (2 mmol) was added to a solution of N-(2-bromo-4- chlorophenyl)pivalamide (1 mmol) in THF (4 vol.) at -20 °C under inert atmosphere. The reaction mixture was maintained at -20°C for 1 h. Then ethyltrifluoroacetate (1.4 mmol) was added at the same temperature. After complete addition the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml) and extracted with MTBE (2X50 ml). The organic layer was separated and washed with water and dried. The crude compound was added to a mixture of acetic acid (4 vol.) and HC1 (2 vol.) and slowly heated to 75°C and stirred for 4 h at the same temperature. The reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate (1 vol.) to afford 40% of the title compound.

Example 2

Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:

Step 2: Synthesis of N-(2-bromo-4-chlorophenyl)pivalamide from N-(4- chlorophenyl)pivalamide :

Bromine (1.2 mmol) was added dropwise to a solution of N-(4-chlorophenyl)pivalamide (1 mmol) in acetic acid (2 vol.) at room temperature. The reaction was stirred at the same temperature for lh. After completion of the reaction the reaction mixture was poured into crushed ice to get precipitate. The precipitate was filtered and washed with water to yield 90% N-(2-bromo-4-chlorophenyl)pivalamide. Step 3: Synthesis of l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone hydrochloride from N-(2-bromo-4-chlorophenyl)pivalamide:

Isopropylmagnesium bromide (2 mmol) was added to a solution of N-(2-bromo-4- chlorophenyl) pivalamide (1 mmol) & lithium chloride (0.25mmol) in THF (4 vol.) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to - 15°C. Then ethyltrifluoroacetate (1.4 mmol) was added at -15°C. After complete addition the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml) and extracted with MTBE (2X50 ml). The organic layer was separated and washed with water and dried. The crude compound was added to a mixture of acetic acid (4 vol.) and HC1 (2 vol.) and slowly heated to 75°C and stirred for 4 h at the same temperature. The reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate (1 vol.) to afford 40% of the title compound. Example 3

Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:

Bromine (1.2 mmol) was added dropwise to a solution of N-(4-chlorophenyl)pivalamide (1 mmol) in acetic acid (2 vol.) at room temperature. The reaction was stirred at the same temperature for lh. After completion of the reaction the reaction mixture was poured into crushed ice to get precipitate. The precipitate was filtered and washed with water to yield 90% N- (2-bromo -4-chlorophenyl)pivalamide .

Step 3: Synthesis of l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone hydrochloride from N-(2-bromo-4-chlorophenyl)pivalamide: Sodium metal (2.5 mmol) was added to a solution of N-(2-bromo-4-chlorophenyl) pivalamide (1 mmol) & lithium chloride (0.25mmol) in THF (4 vol.) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to -15°C. Then ethyltrifluoro acetate (1.4 mmol) was added at -15°C. After complete addition the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml) and extracted with MTBE (2X50 ml). The organic layer was separated and washed with water and dried. The crude compound was added to a mixture of acetic acid (4 vol.) and HC1 (2 vol.) and slowly heated to 75°C and stirred for 4 h at the same temperature. The reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate (1 vol.) to afford 40% of the title compound.

Example 4

Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:

4-Chloroaniline (1 mmol) was added to solution of aqueous NaOH (1.15 mmol in 1.2 times of water) in toluene (4 vol.). The reaction mixture was cooled to 15°C and add pivaloylchloride (1.2 equiv.) slowly by maintaining the temperature below 40°C. The reaction was maintained between 25-35°C for 1 h. After completion of the reaction, it was cooled to - 10°C for 2 h, filtered, washed with 10% aqueous methanol to afford 98% of N-(4- chlorophenyl)pivalamide.

Sodium hydride (2.4 mmol) was added to a solution of N-(2-bromo-4-chlorophenyl) pivalamide (1 mmol) & lithium chloride (0.25 mmol) in THF (4 vol.) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to -15°C. Then ethyl trifluoroacetate (1.4 mmol) was added at -15°C. After complete addition the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml) and extracted with MTBE (2X50 ml). The organic layer was separated and washed with water and dried. The crude compound was added to a mixture of acetic acid (4 vol.) and HC1 (2 vol.) and slowly heated to 75°C and stirred for 4 h at the same temperature. The reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate (1 vol.) to afford 40% of the title compound. Example 5

Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:

Sodamide (3.2 mmol) was added to a solution of N-(2-bromo-4-chlorophenyl) pivalamide (1 mmol) & lithium chloride (0.25mmol) in THF (4 vol.) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to -15°C. Then ethyltrifluoro acetate (1.4 mmol) was added at -15°C. After complete addition the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml) and extracted with MTBE (2X50 ml). The organic layer was separated and washed with water and dried. The crude compound was added to a mixture of acetic acid (4 vol.) and HC1 (2 vol.) and slowly heated to 75°C and stirred for 4 h at the same temperature. The reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate (1 vol.) to afford 40% of the title compound.

Example 6

Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:

Step 3: Synthesis of l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone hydrochloride from N- (2-bromo -4-chlorophenyl)pivalamide :

Magnesium (2.3 mmol) was added to a solution of N-(2-bromo-4-chlorophenyl) pivalamide (1 mmol) & lithium chloride (0.25mmol) in THF (4 vol.) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to -15°C. Then ethyltrifluoro acetate (1.4 mmol) was added at -15°C. After complete addition the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml) and extracted with MTBE (2X50 ml). The organic layer was separated and washed with water and dried. The crude compound was added to a mixture of acetic acid (4 vol.) and HC1 (2 vol.) and slowly heated to 75°C and stirred for 4 h at the same temperature. The reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate (1 vol.) to afford 40% of the title compound.

Example-7:

Step 1: Synthesis of 4-chloro-2-bromo phenyl pivalamide

4-chloro-2-bromoaniline was added to the solution of aqueous NaOH (1.2mmol) and water (1.2 times) in toluene (4 vol). The reaction mixture was cooled to 15°C and pivaloyl chloride (1.2eq) was added slowly at a temperature below 40°C. Cooled the reaction mass to 100°C for about 2hrs after completion of reaction. Filtered and washed with 10% aqueous methanol to afford 98% of (4-chloro-2-bromophenyl)pivalamide.

Step 2: Synthesis of l-(2-amino-5-chlorophenyl)-2,2,2,-trifluoroethanone hydrochloride from 4-chloro-2-bromo phenyl pivalamide.

To the mixture of Magnesium turnings (leq) and 2 vol of THF were added few particles of iodine for initiating and starting material i.e (4-chloro-2-bromophenyl)pivalamide (1 gr) at room temperature and waited for initiation. Slowly add starting material (dissolved in Ivol of THF) drop wise once initiation was started. Lithium chloride (0.25 mmol) was added to the reaction mixture after completion of addition and stirred for about 6hrs at room temperature. Cooled the reaction mixture to -15°C and ethyl trifluoroacetate (1.4mmol) was added. Raised the temperature of the reaction mixture to 20°C, maintained for about 30 mints and quenched the reaction mixture with ammonium chloride solution. Extracted the reaction mixture with MTBE and combined organic layers were concentrated under reduced pressure. To the crude compound thus obtained was added acetic acid (4 vol) and HC1 (2 vol). Slowly heated the reaction mixture to 75°C and maintained the reaction mixture at the same temperature for about 4hrs. Cooled the reaction mixture to 0-5°C for 2hrs, filtered and washed with Ivol of ethylacetate to afford 70% of title compound.

Example-8: Preparation of Efavirenz

Step 1:

Part:A

To the mixture of Magnesium turnings (leq) and 2 vol of THF were added few particles of iodine for initiating and starting material i.e (4-chloro-2-bromophenyl)pivalamide (1 gr) at room temperature and waited for initiation. Slowly add starting material (dissolved in Ivol of THF) drop wise once initiation was started. Lithium chloride (0.25 mmol) was added to the reaction mixture after completion of addition and stirred for about 6hrs at room temperature. Cooled the reaction mixture to -15°C and ethyl trifluoroacetate (1.4mmol) was added. Raised the temperature of the reaction mixture to 20°C, maintained for about 30 mints. Part-B:

In another RBF mixture of cyclopropyl acetylene (0.36eq) and 2 molar isopropyl magnesium chloride solution (leq) was added at 25°C and stirred for about 2hrs at room temperature.

Part-C

Mixture of toluene (4 volumes) and sodium hydride (2eq) was cooled to 0°C and (1R,2S pyridine norephedrine) (1.4eq) & 2,2,2 trifluoroethanol (1.07eq) were added. Slowly raised the temperature of the reaction mixture to room temperature and stirred for about 60mints. Cooled the reaction mixture to 0°C after maintenance and zinc chloride (2eq) was added and raised the temperature of the reaction mixture to room temperature. Maintained the reaction mixture at the same temperature for about lhr and Part-B was added slowly at the same temperature and stirred the reaction mass for about 2hrs at the same temperature. Cooled the reaction mixture to 0°C and Part -A was added slowly for about 30mints. Raised the temperature of the reaction mass to room temperature and maintained at the same temperature for about lOhrs. Monitored the reaction by chiral HPLC and if complete the reaction is quenched reaction mixture with aq citric acid solution. Extracted the reaction mixture with toluene, combined all the organic layers distilled under reduced pressure then distilled off completely. To the crude compound thus obtained was added acetic acid (4 vol) and HCl (2 vol). Slowly heated the reaction mixture to 75°C and maintained the reaction mixture at the same temperature for about 4hrs. Cooled the reaction mixture to 0-5°C for 2hrs, filtered and washed with lvol of ethylacetate to afford 90% of title compound with 99% HPLC.

Step 2:

To the mixture of Part B and toluene (4 volumes) was added 50% aq potassium carbonate slowly and adjusted the pH of the reaction mass to 8-9. Triphosgene (leq) dissolved in toluene was added slowly to the reaction mass and maintained the reaction mass for about lhr at room temperature. Check HPLC if complies then separated the organic layer and washed with ammonium chloride solution. Distilled off the combined layers below 40°C methanol (lvolume) & water (4 volumes) was added and stirred for 2hrs. Crystal materials observed then filtered washed with chilled methanol to obtain 98% yield with 99.9% HPLC purity.

Claims

We Claim:

1. An improved process for the preparation of Efavirenz of compound of Formula I

Formula I

which comprises reacting the com ound of Formula 2,

Formula 2

wherein X is a halogen atom; Xi is a leaving group with 2,2,2-trifluoroethanol or ethyl trifluoro acetic acid followed by the reaction with cyclopropylacetylene in the presence of a grignard reagent to give Efavirenz of Formula I.

2. An improved process for the preparation of Efavirenz of compound of formula I, which comprises the steps of:

i. reacting the compound of Formula 2,

Formula 2

Formula 3

X-\ is a leaving group

ii. reacting the compound of Formula 3 with cyclopropylacetylene in the presence of a grignard reagent to give Efavirenz of formula I. An improved process for the preparation of compound of formula 2

Formula 2

which comprises the steps:

i. acylating 4-chloroaniline of compound of Formula 4,

Formula 4 with a condensing agent to give compound of Formula 5,

Formula 5

Xi is a leaving gp

ii. halogenating the compound of formula 5 to give compound of formula 2.

4. The process according to claims 1, 2 and 3, wherein X is selected from chloro, bromo, iodo and X₁ is selected from chloro, bromo, iodo, mesyl, tosyl, imidazolyl, cyclohexyl, methyl, ethyl, phenyl and the like.

5. The process according to claims 1, 2 and 3, wherein the solvents used are selected from THF, diethyl ether, toluene, hexane, cyclohexane, methyl cyclopropyl hexane, MTBE, ethyl acetate, benzene, methanol, ethanol, acetonitrile, MDC, EDC, DMF, DMSO and the like.

6. The process according to claims 1, 2 and 3, wherein the temperature at which the reactions are carried out ranges from -78 to 120°C.

7. The process according to claims 1 and 2, wherein the grignard reagent used is selected from RMgX wherein R is methyl, ethyl, isopropyl, vinyl, phenyl, allyl and the like.

8. The process according to claim 2, wherein the intermediate of Formula 3 is reacted with cyclopropylacetylene without isolation for maintaining the chirality.

E . The process according to claim 3, wherein the acylation takes place in the presence of a condensating agent selected from Ν,Ν'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), phosgene, dimethylcarbonate, diphenylcarbonate, or di-(paranitrophenyl)carbonate and the like.

10. The process according to claim 3, wherein the halogenation is carried out using suitable0 halogenating reagents for the preparation of corresponding bromides or chlorides include for example NBS, Br₂/acetic acid, HBr/acetic acid, NCS, and S0₂C1₂. The reaction is carried out in a solvent selected from MDC, EDC and the like. 5

0

5

0