Field of Invention
This invention relates to a process for producing (S)-1-(2-Amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cychlopropyl-2-propane-1-ol. In particular, the present invention provides an improved enantioselective process for producing (S)-1-(2-Amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cychlopropyl-2-propane-1-ol (Efaverinz intermediate) employing 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroacetophenone.

Background of the Invention
(S)-1-(2-Amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cychlopropyl-2-propane-1-ol is a key intermediate for preparing non-nucleoside antiviral drugs, more specifically for the synthesis of active pharmaceutical ingredient, Efaverinz. This drug is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by US Food and Drug administration (FDA) for the treatment of the acquired immunodeficiency syndrome (AIDS.

Thompson et al in tetrahedron letter, 1995, 36, 8937-8940 disclosed the asymmetric synthesis of amino alcohol based on enantioselective addition of lithium cyclopropylacetylene to PMP-protected ketoaniline. This process involves protection and deprotection of ketamine, preparation of lithium cyclopropylacetylene and the reaction was carried out at 0-5 0C temperature. This process is tedious and hence it is not economical commercially.

EP 582455 describes a process for the preparation of amino alcohol by grignard addition to the ketamine which leads to formation of a racemic product and requires separation of the required enantiomer and hence the process is practically unviable for large scale production.

WO 9520389, Young describes a process for the preparation of amino alcohol by the addition of cyclopropylethynyl-lithium reagent, wherein the desired optical purity and yield of the final product are less.
WO 9827073 describes the process of preparation of amino alcohol using lithium cyclopropyl acetylide and protected ketamine. This process involves protection and deprotection steps which results in low yield.

JOC 1998, 63(23), 8536-8543, discloses a process for the preparation of amino alcohol by protecting the ketamine and reacting with cyclopropyl lithium-acetylide at subzero temperature. The process is not economical.

CN 1449865 mentions the preparation of amino alcohol using zinc triflate, triethyl amine and cyclopropylacetylene. The yield and optical purity is very less.

CN101125834 describes a process for the preparation of intermediate (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol involving, reaction of cyclopropylethynylmagnesium chloride with 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone in toluene in presence of (aR)-[(1R)-1-(dimethylamino)-2-(tert-butoxy)ethyl]-4-nitrobenzenemethanol and diethyl zinc. The process has the disadvantages of preparing cyclopropylethynylmagnesium chloride employing costly grignard reagent.

US 20060217552 discloses a process of asymmetric alkylation of ketone or ketimine involving the chiral ligand mediated asymmetric addition of zinc or copper acetylide to a trifluoromethyl ketone or ketimine intermediate to give a chiral tertiary propergylic alcohols or amines. The zinc or copper triflate employed in the process, is hygroscopic, corrosive and highly acidic in nature and therefore difficult to handle.

Lushi et al in Angw. Chem. Int. 1999, 38, No. 5 page 711-713 discloses a novel, highly enantioselective ketone alkynylation reaction mediated by chiral zinc aminoalkoxides. In this process high volume of tetrahydrofyran (THF) and heptane are used, which are costly and difficult to recover. The use of chloromagnisium cyclopropylacetylenide during the process involves an additional step and hence additional operation. Furthermore, the process provides little conversion and low enantioselectivity.
The prior art processes are tedious and involve use of corrosive reagents, expensive and cumbersome steps for preparing, isolating and purifying the final product. Therefore, there still exists a need for a novel and an improved process for the preparation of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol that involves minimal steps and use of non-corrosive and non-hazardous reagents. Furthermore, the process is enantioselective and amenable for large scale production.

Object and Summary of the Invention
It is a principal object of the present invention to provide an improved process for producing (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol as a pure enantiomer form.

It is another object of the present invention to provide an expeditious, efficient and economical process for producing (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol from 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroacetophenone, wherein the process involves fewer steps, operationally easy, less time consuming and hence economical .

It is yet another object of the present invention to provide a process for producing (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol, wherein the process employs non-toxic, non-corrosive and inexpensive reagents.

It is still another object of the present invention to provide an enatioselective process for producing (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol.

The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments hereinafter.

In accordance with a preferred embodiment of the present invention, there is provided a process for producing pure (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol, which comprises:
a) reacting chiral zinc alkoxide and cyclopropyl acetylene in presence of a solvent;
b) adding 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone to the resultant complex, and
c) isolating and optionally purifying the obtained (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol to obtain the pure form.

In accordance with another embodiment of the present invention, there is provided a process for producing (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol, wherein the process comprises of preparing zinc alkoxide by reaction of diethyl zinc, a chiral ligand selected from the group consisting of (1R, 2S)-ephedrine, (1R, 2S)-nor ephedrine, (1R, 2S)-N-methyl ephedrine and (1R, 2S)-N-pyrrolidinylnorephedrine, preferably (1R, 2S) N-pyrrolidinyl nor-ephedrine and achiral alcoholic auxiliary selected from the group methanol, ethanol, 2,2-dimethyl propanol, preferably 2,2,2-trifluoroethanol in toluene or THF media at room temperature.
According to another embodiment of the present invention, the chiral ligand employed in the process is recoverable upto 98% and reusable.

In accordance with yet another embodiment of the present invention, the cyclopropyl acetylene used is neat cyclopropyl acetylene. Here the neat cyclopropyl acetylene refers the use of cyclopropyl acetylene without making a Grignard reagent or a metal acetylide.

In accordance with still another embodiment of the present invention, the 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone is added to the reaction mass as a solution in tetrahydrofuran, wherein tetrahydrofuran is used in minimal quantity to dissolve the compound.

In accordance with yet another embodiment of the present invention, the step of isolation of the (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol comprises quenching the reaction mass containing the (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol with aqueous citric acid solution, preferably 30% solution, extracting with a solvent selected from the group consisting of toluene, hexane, heptanes, preferably toluene, followed by distillation and precipitation to obtain the (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol.
In another embodiment of the invention the obtained the (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol can be optionally purified by dissolving it in isopropanol (IPA), hexane, heptane, octane or a mixture thereof.

In accordance with yet another embodiment of the present invention, the pure (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol is characterized by having HPLC purity of about 99.9% and specific optical rotation of about -27.2°.

Detailed Description of the Invention
Specification of the invention concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention. It is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention discloses a simple and enantioselective process for producing (S)-1-(2-amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cychlopropyl-2-propane-1-ol. Further, the process involves asymmetric alkynylation of the ketoaniline for large scale production of (S)-1-(2-amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cychlopropyl-2-propane-1-ol.
According to the present invention, there is provided a novel, economical and efficient process for producing (S)-1-(2-Amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cychlopropyl-2-propane-1-ol from 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone.

In accordance with the present invention, the process for producing pure (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol comprises reacting chiral zinc alkoxide and cyclopropyl acetylene in presence of a solvent selected from toluene or THF, adding 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone to the resultant complex, and isolating and optionally purifying (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol to obtain the pure form.

The 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone (I) employed as a starting material for the present invention is commercially available or it can be prepared as per the process reported in prior art.

According to the invention, the chiral zinc alkoxide is prepared by reacting a chiral ligand selected from the group consisting of (1R, 2S)-ephedrine, (1R, 2S)-nor ephedrine, (1R, 2S)-N-methyl ephedrine and (1R, 2S)-N-pyrrolidinylnorephedrine, preferably (1R, 2S) N-pyrrolidinyl nor-ephedrine and achiral alcoholic auxiliary selected from the group methanol, ethanol, 2,2-dimethyl propanol, preferably 2,2,2-trifluoroethanol in toluene or THF media at room temperature in toluene or THF media.
According to the invention, the reaction is carried out at room temperature, preferably at 20-25°C and stirred for 1 to 5 hours preferably for 2 hours.

In accordance with the invention, the diethyl zinc is used as 10 to 20% solution in toluene or hexane. The diethyl zinc solution was added to the mixture of achiral alcoholic auxiliaries preferably trifluoroethanol and chiral ligand preferably (1R, 2S)-N-pyrrolidinyl nor-ephedrine in toluene or THF at 0 to 40 oC preferably at 20-30°C.

Subsequently, according to the invention the chiral zinc alkoxide was reacted with the cyclopropyl acetylene in presence of a solvent preferably toluene without making a Grignard or metal acetylide, to form zincate complex (II) which attacks nucleophilically to the keto group of unprotected ketamine (I) to give desired selectivity. The cyclopropylacetylene employed herein according to the invention is neat cyclopropylacetylene i.e. without making a Grignard or metal acetylide.

Alternatively, according to the invention, the neat cyclopropylacetylene was added to cooled reaction mixture containing the chiral zinc complex at low temperature, preferably between 0-5°C

Subsequently, according to the invention, the cooled reaction mixture was stirred for 30 minutes to 5 hours preferably for 1 hour at 0-5°. The temperature of reaction mixture is brought to room temperature, preferably to 25-30° and further stirred for 1 hour followed by slow addition of a solution of 1-(2-amino-5-chlorophenyl)-2, 2, 2-trifluoroacetophenone at the same temperature.

Furthermore, the resulting reaction mass was quenched with 10 volume 30% citric acid solution followed by extraction with toluene, hexane, heptanes or octane, preferably toluene and distillation and /or precipitation with a solvent, preferably hexane to isolate (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol. Aqueous layer left is preserved for recovery of chiral ligands such as (1R, 2S)-N-pyrrolidinyl nor-ephedrine.

Further, according to the present invention, there is provided a process for upto 98% recovery and reuse of the chiral ligand such as (1R, 2S) –N-pyrrolidinyl nor-ephedrine with the same results. The recovered chiral ligand has purity 98.5% or more whereas in case of (1R, 2S) –N-pyrrolidinyl nor-ephedrine, the SOR is +14°. It can be further reused and recycled several times with little fresh toppings.

In accordance with the present invention, the purification of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol is performed by using solvent selected from the group consisting of IPA, hexane, heptanes, octane or mixture thereof to obtain about 99.9% pure compound, preferably at reflux temperature.
The following is the schematic representation of the present invention.

According to the invention, the pure (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol obtained is characterized by having HPLC purity of about 99.9% and specific optical rotation of about -27.2°.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to limit the scope of present invention in any way.

Example
Preparation of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol

A 5L round bottom flask equipped with magnetic stir bar, reflux condenser, and nitrogen inlet was charged with 400 mL of toluene, 44.87g of trifluroethanol, 91.6 g of (1R, 2S) N-pyrrolidinyl nor-ephedrine and 66.2g (303.3 mL ) of 20 % DEZ in toluene solution was added in 1 hour and stirred for 2 hours at same temperature. The reaction mixture was cooled to 0-5°C and 38.35 g,( 0.581mole) of cyclopropyl acetylene was added, stirred for one hour at 0-5°C and further one hour at 20-25°C. Then the 100g of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroacetophenone in 100 mL of THF was added in 0.5 hour. After completion of the reaction, the reaction mixture was quenched with 1L of 1M citric acid solution. The two layers were separated and aqueous layer was extracted with 100 mL of toluene. The aqueous layer was saved for recovery of (1R, 2S)-N-pyrrolidinyl nor-ephedrine. The organic layer separated was collected (assay of this solution indicated 99.23% ee) and washed with 200 mL x 2 times of DM water. After concentration of toluene at 40-45 °C under vacuum 100 mL of hexane was added to the residue and stirred for one hour at 25-30°C, subsequently cooling the reaction mass to 0-5°C and maintaining for 30 minutes. The precipitated solid was collected by filtration and washed with 50 mL of hexane and dried under vacuum at 55-60°C to give 112.2 g of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol (112.2% yield, assay 99.23% ee).

Purification of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol
1L round bottom flask equipped with magnetic stir bar and reflux condenser was charged with 100 g of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol, 25 mL of IPA and 475 mL of hexane. The reaction mass was heated to reflux for one hour and gradually cooled to room temperature followed by stirring for one hour and cooling to 0-5°C and maintaining the same for 0.5 hours. The solid product was filtered and washed with 50 mL of hexane and dried under vacuum at 55-60°C to obtain 92 g (92% yield, assay 99.90%, ee-purity 99.84%).

Recovery of (1R, 2S) N-pyrrolidinyl nor-ephedrine
250g of 50% lye solution was added to the aqueous layer collected from the reaction mass at 20-25°C ( pH should be 12-12.5). The zinc salts were filtered and extracted from 200 mL x 2 times of toluene. The toluene layer was collected and dried over anhydrous sodium sulphate, the toluene being distilled and product dried under vacuum at 110 °C. Yield 90g, (Purity 98.21%, SOR +14°, C in chloroform).

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations, would present themselves to those skilled in the art without departing from the scope and spirit of this invention. This invention is susceptible to considerable variation in its practice within the spirit and scope of the appended claims.

We Claim

1. A process for producing pure (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol, which comprises:
a. reacting chiral zinc alkoxide and cyclopropyl acetylene in presence of a solvent;
b. adding 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone to the resultant complex, and
c. isolating and optionally purifying the obtained (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol to obtain the pure form.

2. The process according to claim 1, wherein the chiral zinc alkoxide is prepared by reacting diethyl zinc, a chiral ligand selected from the group consisting of (1R, 2S)-ephedrine, (1R, 2S)-nor ephedrine, (1R, 2S)-N-methyl ephedrine and (1R, 2S)-N-pyrrolidinylnorephedrine, preferably (1R, 2S) N-pyrrolidinyl nor-ephedrine and trifluoethanol in toluene or THF media.

3. The process according to claim 2, wherein the diethyl zinc solution was added to the mixture of trifluoroethanol and (1R, 2S)-N-pyrrolidinyl nor-ephedrine in toluene or THF at 20-30°C.

4. The process according to claim 2, wherein the reaction to form zinc alkoxide is carried out at room temperature, preferably between 20-25°C.

5. The process according to claim 1, wherein the cyclopropyl acetylene used is neat cyclopropyl acetylene.

6. The process according to claim 1, wherein the solvent is toluene.

7. The process according to claim 1, wherein the reaction between cyclopropyl acetylene and zinc alkoxide is carried out at a temperature between 0-5°C.

8. The process according to claim 1, wherein the 1-(2-amino-5- chlorophenyl)-2, 2, 2-trifluoroacetophenone is added as a solution in tetrahydrofuran.

9. The process according to claim 1, wherein the isolation of (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol in step (c) comprises quenching the reaction mass containing (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol with aqueous citric acid solution, extracting with a solvent, followed by distillation and/or precipitation in presence of a solvent to obtain the (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol.

10. The process according to claim 9, wherein the solvent used for extraction, distillation or precipitation is selected from the group consisting of toluene, hexane, heptanes and octane.
11. The process according to claim 1, wherein the purification is carried out using solvent selected from the group consisting of isopropanol, hexane, heptane, octane and a mixture thereof.
12. The processes according to claim 1, wherein the purification is carried out at reflux temperature.

13. The process according to claim 1, wherein the pure (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol is characterized by having HPLC purity of about 99.9% and specific optical rotation of about -27.2°.