This application claims priority to this Indian patent applications numbered filed 2244/CHE/2011 filed on Jul 01,2011 and 2357/CHE/2011 filed on Jul 11,201 l.The contents

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of chiral alcohols compounds by asymmetric alkynylation of ketones. The chiral alcohols are used as intermediates 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)-l, 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 such as 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 along with a PCT application WO 0170707 describe various methods for the synthesis of Efavirenz. In these methods, Efavirenz is either prepared by fractional crystallization or by 1,4-distereoselective addition protocol using chiral auxiliary or via chiral ligand mediated asymmetric addition. However, in these processes, large excess of a strong base like alkyl lithium or lithium hexamethyldisilazine (LHMDS), excess chiral ligand and cryogenic reaction conditions are utilized, which make the process unviable for commercial purpose.

IN 262/CHE/2008 (Assigned to Aptuit Laurus), IN 2207/MUM/2008 (Assigned to Emcure) and US 7439400 (Assigned to Shanghai Record Pharmaceuticals Co., Ltd) discloses alkylation of ketones into alcohol intermediates by using metal halides and achiral additives.

US 6015926 (Assigned to Merck & Co) discloses a process for preparation of Efavirenz and its intermediates, which comprises of reacting cyclopropylethynyl magnesium chloride with l-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone in toluene in the presence of (R)- [(lR)-l-(dimethylamino)-2-(tert-butoxy)ethyl]-4-nitrobenznemethanol and diethylzinc to give an intermediate (S)-5-Chloro-a-(cyclopropylethynyl)-2-amino- a-(trifluoromethypbenzenemethanol, with 99.3% e.e. (92%). This process although providing a product having high enantiomeric excess (ee), has the disadvantage of utilizing large quantity of diethyl zinc, which is quite hazardous for industrial purpose, due to its pyrophoric nature.

Thus the present invention provides an improved process for the preparation of alcohol intermediates by using novel achiral additives and further conversion into Efavirenz.

OBJECT AND SUMMARY OF THE INVENTION:

An object of the present invention is to provide a method for preparation of (S)-5-chloro-
a-(cyclopropylethyny 1 )-amino-a-(trifluoromethyl)benzenemethanol (alcohol

Intermediate of Formula-II) with high enantiomeric purity by using novel achiral additives.

Another object of the present invention is to provide further conversion of alcohol intermediate into Efavirenz.

The main aspect of the present invention is to provide a method for the preparation of (S)-5-chloro-a-(cyclopropylethyny 1 )-amino- a-(trif[uoromethyl) benzenemethanol (alcohol Intermediate of Formula-II) by asymmetric alkynylation of ketones comprising, reacting of a chiral ligand; achiral additives selected from carboxylic acids or phenols, with a base; and metal halides or salt of transition metal with organic acid, in an organic solvent; adding a cyclopropyl acetylide metal salt to form a chiral organometallic complex followed by addition of ketone of the formula (III) to chiral organometallic complex and isolating the compound of formula (II) followed by optional purification.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of alcohol intermediate of Formula-II.

The present invention also relates to further conversion of compound of Formula-II into Efavirenz.

The main aspect of the present invention is to provide a method for the preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino- a-(trifluoromethyl) benzenemethanol (alcohol Intermediate of Formula-II) by asymmetric alkynylation of ketones comprising, reacting of a chiral ligand; achiral additives selected from carboxylic acids or phenols, with a base; and metal halides or salt of transition metal with organic acid, in an organic solvent; adding a cyclopropyl acetylide metal salt to form a chiral organometallic complex followed by addition of ketone of the formula (III) to chiral organometallic complex and isolating the compound of formula (II) followed by optional purification.

In one embodiment, achiral additive carboxylic acid is selected from aliphatic carboxylic acid such as aceticacid, trifluoroacetic acid, and the like; aromatic carboxylic acid such as benzoic acid, alkoxy substituted benzoic acids, halo substituted benzoic acids, pthalic acid, preferably benzoic acid. The phenols used in this reaction are optionally substituted.

In another embodiment, the base used in the present invention is selected from sodium hydride, lithium hydride, potassium tert-butoxide, sodium bis(trimethylsilylamide, lithium bis(trimethylsilyl)amide, sodamide, sodium ethoxide and sodium methoxide.

In one more embodiment, the chiral ligand used in the present invention is selected from the following disclosed group but not limited.

In one more embodiment, metal halides used in the present invention is selected from Zinc halide or copper halide, preferably zinc halides such as zinc chloride or zinc bromide.

In one more embodiment, a salt of transition metal with an organic acid salt used in the present invention is selected from Zinc acetate, copper acetate. Zinc isopropylacetate, copper isopropylacetate and Zinc trifluoroacetate.

In one more embodiment, the metal used in the cyclopropyl acetylide metal salt is selected from MgX, Li, Na, K, Zn, Cu or Sn. Here X is halogen like chlorine, bromine, fluorine or Iodine.

The compound of Formula-II is purified by making an acid addition salt like hydrochloric acid of Formula-II and the desaltification by using a base like Sodium hydroxide. In another .embodiment, the obtained compound of Formula-II is converted into Efavirenz by the conventional methods for example as disclosed in US 6147210, US6114569 and US 7205402 and WO 2009095931.

Another aspect of the present invention is to provide a method for preparation of chiral tertiary propargylic alcohol i.e. (S)-5-chloro-a-(cyclopropylethynyl)-amino- a-(trifluoromethyl) benzenemethanol of formula-II by asymmetric alkynylation of 4-chloro-2-trifluromethylketone of formula-Ill comprising, reaction of (IR, 2S) N-pyrrolidinylephedrine, benzoic acid, zinc bromide and a base in an organic solvent; adding a cyclopropyl acetylide magnesium salt to the above reaction mixture to form a chiral organometallic complex followed by addition of 4-chloro-2-trifluromethylketone of the formula-Ill to chiral organometallic complex and isolating (S)-5-cliloro-a-(cyclopropylethynyl)-amino- a-(trifluoromethyl) benzenemethanol of formula-II followed by optional purification.

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 (S)-5-chloro-a-(cyclopropyIethyny 1)-
amino-a-(trifluoromethyl)benzenemethanol

A mixture of Tetrahydrofuran (24 ml) and Sodium hydride (0.85 g) was taken in a flask and stirred at a temperature of 35 °C for half an hour. The reaction mixture was cooled to 2°C. To this, a solution of (IR, 2S)-N-Pyrrolidinyl Norephedrine (3.9 g) and benzoic acid (1.5 g) in tetrahydrofuran was added. The temperature of the reaction mixture was maintained at 35 °C for 1 hour and cooled to 10 °C. To this anhydrous Zinc bromide (3.5 g) was added. In another flask a mixture of Cyclo Propyl Acetylene (1.1 g) and n-Butyl Magnesium Chloride (8 ml) was taken and maintained for one hour. The obtained solution was slowly added to above reaction mixture. To this a solution of 4-Chloro-2-trifluoro acetyl aniline (3 g) was added. The reaction mass was cooled to 8 °C and the product was quenched with Citric Acid (7.5 g) in water. The temperature of the reaction mass was raised to 25 °C and toluene (30 ml) was added. The layers were separated and aqueous layer was washed with sodium hydroxide and mixed with organic layer. The layers wear again separated and water was added to the organic layer and aqueous layer was separated. The solvent was distilled off under vacuum below 60 °C. Toluene was added to the obtained residue and cooled. To this n-hexane (13.5 ml) was added and solid was filtered. The material was washed with hexane and dried to yield pure (S)-5-chloro-a-(cyclopropylethyny 1 )-amino-a-(trifluoromethyl) benzenemethanol.

Example-2: Process for the preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino-a-(trifluoromethyl) benzenemethanol
A mixture of Tetrahydrofuran (80 ml) and Sodium hydride (2.85 g) was taken in a flask and stirred at a temperature of 30 °C for half an hour. The reaction mixture was cooled to 0-2 °C. To this, a solution of (IR, 2S)-N-Pyrrolidinyl Norephedrine (13.4 g) and Trifluoroethanol (4.2 g) in tetrahydrofuran was added. The temperature of the reaction mixture was maintained at 35 °C for 1 hour and cooled to 2 °C. To this Zinc trifluoro acetate (15.6 g) was added. In another flask a mixture of Cyclo Propyl Acetylene (3.6 g)
and n-Butyl Magnesium Chloride (26.7 ml) was taken and maintained for one hour. The obtained solution was slowly added to above reaction mixture. To this a solution of 4-Chloro-2-trifluoro acetyl aniline (10 g) was added. The reaction mass was cooled to 8 °C and the product was quenched with Citric Acid (25 g) in water. The temperature of the reaction mass was raised to 25 °C and toluene (100 ml) was added. The layers were separated and water was added to the organic layer and aqueous layer was separated. The organic layer was distilled off under vacuum below 60 °C. Toluene was added to the obtained residue and cooled. To this n-hexane (45 ml) was added and solid was filtered. The material was washed with hexane and dried to yield pure (S)-5-chloro-a-(cyclopropylethyny 1 )-amino-a-(trifluoromethyl) benzenemethanol.

We claim:
1. A method for the preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino- a-(trifluoromethyl) benzenemethanol of Formula-II by asymmetric alkynylation of ketones comprising, reacting of a chiral ligand; achiral additives selected from carboxylic acids or phenols, with a base; and metal halides or salt of transition metal with organic acid, in an organic solvent; adding a cyclopropyl acetylide metal to form a chiral organometallic complex followed by addition of ketone of the formula (III) to chiral organometallic complex and isolating the compound of formula (II) followed by optional purification.
Formula-II Formuia-III

2. The method according to claim 1, wherein the chiral ligand is selected from

3. The method according to claim 1, wherein achiral additive carboxylic acid is selected from aliphatic or aromatic carboxylic acids.

4. The method according to claim 4, wherein achiral additive carboxylic acid is selected from aceticacid, trifluoroacetic acid, benzoic acid, alkoxy substituted benzoic acids, halo substituted benzoic acids and pthalic acid.

5. The method according to claim 4, wherein achiral additive carboxylic acid is benzoic acid.

6. The method according to claim 1, wherein the base is selected from sodium hydride, lithium hydride, potassium tert-butoxide, sodium bis(trimethylsilylamide, lithium bis(trimethylsilyl)amide, sodamide, sodium ethoxide and sodium methoxide.

7. The method according to claim 1, wherein metal halides is selected from Zinc halide or copper halide such as zinc chloride or zinc bromide.

8. The method according to claim 1, wherein a salt of transition metal with organic acid salt is selected from Zinc acetate, copper acetate, Zinc isopropylacetate, copper isopropylacetate and Zinc trifluoroacetate.

9. The method according to claim 1, wherein a salt of transition metal with organic acid salt is Zinc trifluoroacetate.

10. The method according to claim 1, wherein the compound of formula (II) is further converted into Efavirenz.