This application claims priority to Indian patent applications numbered 2095/CHE/2011 filed on Jun 21, 2011 and 4617/CHE/2011 filed on Dec 28, 2011 the contents of which are incorporated by reference in their entirety.

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 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 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, 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.

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 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 avoiding hazardous chemicals.

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-(trifluoromethyl) benzenemethanol (alcohol Intermediate of Formula-II) by asymmetric alkynylation of ketones comprising, reacting of a chiral ligand, achiral auxiliary, with a base and a salt of transition metal with an 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-(cyclopropylethyny 1 )-amino- a-(trifluoromethyl) benzenemethanol (alcohol Intermediate of Formula-II) by asymmetric alkynylation of ketones comprising, reacting of a chiral ligand, achiral auxiliary, with a base and a salt of transition metal with an 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, the achiral auxiliaries used in the present invention is selected from group comprising of trifluroethanol, trichloroethanol, CF3CMe2OH, CF3CH[CH(CH3)2]OH, PhCH2OH, (CH3)2CCO2H and 4-NO2PhOH.

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, a salt of transition metal with an organic acid salt used in the present invention is a salt of transition metal with acetic acid like Zinc acetate, copper acetate.

In one more embodiment, Zinc acetate used in this invention is milled and sieved.

The present inventors surprisingly found that usage of milled and sieved Zinc acetate will stop the formation of the impurity of Formula-IV. The particle size of the milled Zinc acetate used for this reaction is 100 to 400 microns, preferably 200-300 microns (d90).

Alternatively the impurity can be arrested by changing the mole ratio of the base like sodium hydride. The mole ratio of sodium hydride used in this reaction is 2.5 to 3.5, preferably 3.0 to 3.2 with respect to compound of Formula-Ill. The mole ratio of transition metal salt for example Zinc acetate used in the reaction is 1.5 to 2.5, preferably 1.9 to 2.0 with respect to compound of Formula-Ill. The mole ratio of alcohols like 2,2,2-trifluoroethanol used in the reaction is 0.5 to 1.5, preferably 0.9 to 1.1 with respect to compound of Formula-Ill. The mole ratios of chiral auxiliary like (\R, 2S) - N-pyrrolidinylephedrine used in the reaction is 1.0 to 1.9, preferably 1.5 to 1.6 with respect to compound of Formula-Ill. The mole ratio of Cyclopropyl acetylene magnesium chloride used in the reaction is 1.0 to 1.6, preferably 1.2 to 1.4 with respect to compound of Formula-Ill.

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.

Another aspect of the present invention is to provide the compound of Formula-IV which is formed as an impurity at 0.45 RRT in the preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino- a- (trifluoromethyl) benzenemethanol of formula-II.

In another aspect of the present invention, 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-IH comprising, reaction of (1R, 2S) N-pyrrolidinylephedrine, trifluroethanol, zinc acetate 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-chloro-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-(cyclopropylethynyl)-amino-a-(trifluoromethyl) benzenemethanol

Toluene (920 ml), Sodium hydride (166 g), anhydrous Zinc acetate (368 g) and Tetrahydrofuran (184 ml) were mixed under nitrogen atmosphere at a temperature of 90 °C. To this, a solution of (1R, 2S)-N-Pyrrolidinyl Norephedrine(500 g) and trifluoroethanol (97.5 g) in toluene was added slowly and cooled to 4 °C. In another flask a mixture of THF (100 ml) and Cyclo Propyl Acetylene (140g) was added to n-Butyl Magnesium Chloride (221 g) and stirred for half an hour. The obtained Grignard solution was slowly added to above reaction mixture. To this a solution of 4-Chloro-2-trifluoro acetyl aniline (prepared by adding sodium hydroxide to 460 g of 4-Chloro-2-trifluroacetyl aniline hydrochloride hydrate) in THF was added and the temperature was raised to 30 °C. The reaction mass was cooled to 15 °C and the product was quenched with Citric Acid monohydrate solution. The aqueous layer was separated for the recovery of (1R, 2S)-N-Pyrrolidinyl Norephedrine. The organic layer was washed with water and distilled completely under vacuum. To the residue toluene (175 ml) was added and distilled under vacuum. The residue was washed with n-hexane (370 ml), filtered and dried under vacuum. Water (1700 ml) was added to the dry material. To this HC1 was added washed with a solution of hydrochloric acid and water. The obtained solution was suck dried and a mixture of water and Methanol was added. The pH of the reaction mixture was adjusted with sodium hydroxide solution (800 ml) and washed with water. The material was dried under vacuum to yield pure (S)-5-chloro-a-(cyclopropylethynyl)-amino-a-(trifluoromethyl) benzenemethanol.

Example-2: Process for the preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino-a-(trifluoromethyl) benzenemethanol

Sodium hydride (~ 60 % dispersion in oil, 55 g) was charged into a dry RB flask containing a mixture of Toluene (100 mL) and Tetrahydrofuran (150 mL) at 25-35 °C under N2-atomosphere. The resulting suspension was cooled to 0-5 °C and a solution of 2, 2, 2-trifluoroethanol (48 g) in THF (50 mL) was slowly added at below 5 °C and stirred for 30 min. To this a solution of (\R, 2S) - 7V-pyrrolidinylephedrine (146.5 g) in toluene (100 mL) was added over a period of 4-5 hrs at below 5 °C and allowed to raise the reaction mass temperature to ambient temperature. The resulting reaction mass was stirred at 25-35 °C with continuous N2-gas purging to expel the liberated hydrogen gas. The resulting reaction mass was cooled to 0-5 °C and Zinc acetate (164 g) was added portion wise over a period of 3-4 hrs at same temperature. Reaction mass was stirred at 0-5 °C, allowed to raise 25-35 °C and stirred for 45-60 min. A solution of Cyclopropyl acetylene magnesium chloride was added to the reaction mass at below 35 °C over a period of 4-5 hrs and stirred for 1.5-2 hrs. The resulting reaction mass was cooled to -2 °C and added a solution of keto compound (100 g) in Toluene (100 mL) + THF (50 mL) for 20-40 min at below 5 °C. The resulting reaction mass was stirred at below 20 °C for 4-6 hrs, added toluene (125 mL) and quenched by adding aqueous citric acid solution (160 g in 750 mL) at below 20 °C. The biphasic layers were separated and aqueous layer was extracted with toluene. The aqueous layer was taken for chiral auxiliary recovery and combined organic layer was washed with water (400 mL). The final organic layer was subjected to complete distillation at below 60 °C under vacuum. To the residue toluene (175 ml) was added and distilled under vacuum. The resulting crude substance was triturated in toluene (50 mL) upon heating to 45 °C and cooled to -6 °C. The solid precipitated was filtered, washed with hexane (100 mL) and then dried at 45-50 °C for 4-6 hrs. The resulting dry substance was purified in Aqueous HC1 solution and neutralized in aqueous methanol solution upon adjusting pH of the solution to 7.5- 9 using 10 % NaOH solution to obtain enantiopure compound.

We claim:

1. A method for the preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino-