FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
"IMPROVED PROCESS FOR MANUFACTURE OF (S)-5-CHLORO-ct-
(CYCLOPROPYLETHYNYL)-2-AMINO-a-(TRlFLUOROMETHYL)
BENZENEMETHANOL"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D-C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF INVENTION
The present invention relates to a method for asymmetric alkynylation of ketones with cyclopropyl metal acetylide, utilizing various chiral auxiliaries, chiral ligands and bases. These chiral alcohols are intermediates for the preparation of a potent HIV reverse transcriptase inhibitor.
BACKGROUND OF INVENTION:
Human immunodeficiency virus (HIV) is prone to mutation and leads to drug resistance. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of HIV, and similar diseases, Azido thymidine or AZT and Efavirenz are second generation HIV non-nucleoside reverse transcriptase (NNRTIs) with enhanced potency.
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.
Recently, CN 101125834 and EP 1614672 (assigned to Shanghai Record Pharmaceuticals Co., Ltd) has disclosed a process for preparation of Efavirenz and 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)-[(1R)-1 -(dimethylamino)-2-(tert-butoxy)ethyl]-4-nitrobenz^nemethanol and diethylzinc to give an intermediate (S)-5-Chloro-a-(cyclopropylethynyl)-2-amino-a-

(trifluoromethyl)benzenemethanol, 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.
OBJECT OF THE INVENTION
An object of the present invention is to provide a method for preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino-a(trifluoromethyl) benzenemethanol with high enantiomeric purity by avoiding hazardous bases such as dialkyl zinc.
Another object of the present invention is to provide an improved method which is simple cost effective, environmentally safe and commercially viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for asymmetric alkynylation of ketones with cyclopropyl metal acetylide, utilizing various chiral auxiliaries, chiral ligands and a base.

wherein R is hydrogen or halogen (chlorine fluorine, iodine).and R' is hydrogen or
Fluorine.
One aspect of the present invention is to provide an improved method for preparation of
chiral tertiary propargylic alcohol of formula (I) by asymmetric alkynylation of ketones

comprising, reaction of a chiral ligand, a chiral auxiliary, a transition metal salt and a base in an organic solvent; adding a cyclopropyl acetylide metal salt to the above reaction mixture to form a chiral organometallic complex followed by addition of ketone of the formula (II) or (III) or (IV) to chiral organometallic complex and isolating the compound of formula (I) followed by optional purification.

Another aspect of the present invention is to provide an improved method for preparation of chiral tertiary propargylic alcohol i.e. (S)-5-chloro-a-(cyclopropylemynyl)-amino-a(trifluoromethyl) benzenemethanol of formula ( I a ) by asymmetric alkynylation of 4-chloro-2-trifluromethylketone of formula (II) comprising, reaction of (1R, 2S) N-pyrrolidinylephedrine, trifluroethanol, zinc halide 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 (II) to chiral organometallic complex and isolating (S)-S-chloro-a-(cyclopropylethynyl)-amino-a(trifluoromethyl) benzenemethanol of formula (la) followed by optional purification.
A further aspect of the invention, is the utilization of chiral auxiliaries, selected from the group comprising of trifluroethanol, trichloroethanol, CF3CMe20H, CF3CH[CH(CH3)2]OH and CF3CH[CH(CH3)2]OH.
Yet another aspect of the invention, is the utilization of a base, selected from the group comprising of sodium hydride, lithium hydride, potassium tert-butoxide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl) amide and sodamide.

In still another aspect the present invention provides a method of for asymmetric alkynylation of ketone which is simple, economical and commercially viable.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel chiral ligands, chiral auxiliaries and various bases, which are either used alone or optionally in combination with each other in the alkynylation reaction of ketone. The invention further provides the various chiral ligands, chiral auxiliaries and various bases that can be utilized alone and in combination with each other in the alkynylation of 4-Chloro-2-trifluromethyl keto aniline of formula (II) using cyclopropyl transition metal acetylide of formula (V).
Present invention comprises of following steps:
i) Reaction of Chiral ligand with base. The ligands and various bases used in the
process are disclosed but are not limiting.



Other ligands used in the process are the chiral oxazolidine derivatives, Binol-Ti (IV) derivatives etc.
The various bases utilized are selected from the group comprising of sodium hydride, lithium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide and sodamide.
ii) Addition of a chiral auxiliary with a chiral ligand and a base. Some of the chiral auxiliaries used in the process are selected from the group comprising of trifluroethanol, trichloroethanol, CF3CMe2OH, CF3CH[CH(CH3)2]OH and CF3CH[CH(CH3)2]OH.
iii) Addition of transition metal salt in the mixture of chiral ligand, chiral auxiliary and base: The transition metal salts used in the process are selected from the group comprising of zinc halides, zinc triflate, copper halides, copper triflate, stannous chloride, stannous triflate etc.

iv) Preparation and addition of Cyclopropyl acetylide metal salt of formula (V) to the mixture of chiral ligand, a chiral auxiliary and a base. The resulting mixture was termed as "organometallic complex". The cyclopropyl acetylides used in the process were as under.

v) Reaction of ketone with organometallic complex. Various ketones of formula (II), (III) and (IV) used in the process are as follows.

vi) Quenching and work up of the reaction mixture to isolate the crude product: The product is isolated from the reaction mixture by suitable methods, which are specifically related to the product.
vii) Purification of crude product by crystallization using non polar solvents and their mixture thereof. The non polar solvents utilized in the process are selected from the group comprising of aromatic hydrocarbons, aliphatic hydrocarbons etc. The solvents are selected from the group comprising of toluene, n-Hexane, Cyclohexane, n-Heptane and their mixture thereof.

viii) Alternatively the crude product is purified by forming the amine salts using chiral acids, its purification and neutralization using base to get purified amine. The list of chiral acids used in this process is tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, mandelic acid etc.
The invention is further explained with the help of following illustrative example, however, in no way this example should be construed as limiting the scope of the invention.
EXAMPLE
Prep aration of (S)-5 -chloro-a-(cyclopropyle1liynyl)-2-amino-a-(triiluoromethyl) benzenemethanol.
Tetrahydrofuran (400ml), sodium hydride (38 gms) and (1R, 2S) N-pyrroIidinylephedrine (120 gms) were mixed under nitrogen at ambient temperature. To this mixture trifluroethanol (55 gms) and zinc chloride (109 gms) were added and maintained the ambient temperature for 5 hours. To this mixture, magnesium cyclopropylacetylide (103 gms) was added at ambient temperature and maintained the temperature for 4 hours; followed by the addition of 4-Chloro-2-trifluoromethyl keto aniline (100 gms) was added and maintained for 1 hour. TLC was checked. The product was quenched with citric acid (10%) solution (1430 ml) and extracted with 1000 ml toluene. Toluene layer was washed with 10% brine solution (230 ml) and concentrated. Hexane (500 ml) was added to the residue, and the resulting mixture was filtered and dried under vacuum. Yield =110 gms; Purity: 99.98 % ee.

CLAIMS
1. A method for preparation of chiral tertiary alcohol of formula (I) by asymmetric alkynylation of ketones comprising, reaction of a chiral ligand, a chiral auxiliary, a transition metal salt, a base and cyclopropyl acetylide metal salt in an organic solvent to form chiral organometallic complex followed by addition of ketone to the chiral organometallic complex, isolating the chiral tertiary alcohol of formula (I).
2. The method as claimed in claim 1, wherein chiral ligand is selected from the group comprising of,



3. The method as claimed in claim 2, wherein the preferred chiral ligand is (1R, 2S) N-pyrrolidinylephedrine.
4. The process as claimed in claim 1, wherein chiral auxiliaries are selected from the group comprising of trifluroethanol, trichloroethanolfCF3CMe20H, CF3CHCIOH, CF3CH[CH(CH3)2]OH and CF3CH[CH(CH3)2]OH.
5. The method as claimed in claim 4, wherein the preferred chiral auxiliary trifluroethanol.
6. The process as claimed in claim 1, wherein the transition metal salts are selected from the group comprising of zinc halides, zinc triflate, copper halides, copper triflate, stannous chloride and stannous triflate.

7. The process as claimed in claim 6, wherein the preferred transition metal salts are zinc halides, most preferably zinc chloride.
8. The process as claimed in claim 1, wherein the base is selected from the group comprising of, sodium hydride, lithium hydride, potassium tert-butoxide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide and sodamide.
9. The process as claimed in claim 8, wherein the most preferred base is sodium hydride.
10. A method for preparation of (S)-5-chloro-a-(cyclopropylethynyl)-amino-a(trifluoromethyl) benzenemethanol of formula ( I a ) by asymmetric alkynylation of 4-chloro-2-trifluromethyl ketone of formula (II) comprising, reaction of (1R, 2S) N-pyrrolidinylephedrine, trifluroethanol, zinc chloride, sodium hydride and cyclopropyl acetylide magnesium salt in an organic solvent to form a chiral organometallic complex followed by addition of 4-chloro-2-trifluromethylketone of the formula (II) to the chiral organometallic complex, isolating (S)-5-chloro-a-(cyclopropylethynyl)-amino-a(trifluoromethyI) benzenemethanol of formula (la).