Indian Patents. 253356:AN EFFICIENT PROCESS TO INDUCE ENANTIOSELECTIVITY IN PROKETONES

Title of Invention	AN EFFICIENT PROCESS TO INDUCE ENANTIOSELECTIVITY IN PROKETONES
Abstract	Abstract: An efficient method to induce the enantioselectivity in procarbonyl compoxinds using chiral organometallic complexes The present invention is also described a method for producing oregano metallic complexes using a base and a metal halide.

Full Text	Field of invention: Present invention is directed towards the cost effective and industrially applicable process to induce enantioselectivity with improved yields. The present invention is also describes an improved process for making organometallic complexes. Background of the invention: Asymmetric addition of organometallic compounds to carbonyls is a useful method for the production of chiral secondary/tertiary-alcohols. Typically for asymmetric synthesis, the active catalyst is generated in situ by the reaction of Lewis acid with chiral ligands. Addition of organometallic reagents to aldehydes and activated ketones has been achieved with excellent enantioselectivity. With inactivated ketones there has been some success, e.g., using salon 1 and camphanosulphonamide ligand 2. Generally, stoichiometric amount of the promoters [Lewis acid, e.g., ZnR2 (R = alkyl/aryl), Zn(0Tf)2, Cu(0Tf)2, etc] is required for these asymmetric syntheses. Although, employing these promoters chiral alcohols has been obtained in high yields and upto 99%, they have limited applicability in industrial scale synthesis of the pharmaceutical intermediates, because they are expensive, difficult to store, difficult to handle, especially dialkyl zinc's are highly pyrophoric and require special modification to transfer the reagent. Moreover the liberated byproduct methane/ethane (when using ZnMe2/ ZnEt2) are a conked on industrial scale synthesis. To overcome this problem, herein we report an efficient synthesis of active organometallic catalyst formed in situ from chiral auxiliaries and Metal halides. For example norephidrine (chiral auxiliary) with a base (e.g. NaH); to the resulting alkoxides was added zinc halides (scheme lA). The advantages include the low cost of zinc halides, ease of storing, handling and transfer. Moreover, the byproduct (sodium halides) formed has no safety issues. Based upon this concept, other active catalysts were synthesized using chiral ligands (such as bindles, amino alcohols, amino alcohol derivatives, ethylenediamine, alkalized ethylene diamines and ethylenediamine derivatives in combination with metal source based on zinc and copper (scheme 1). Using these chiral catalysts alkylation/alkynation of aldehydes afforded correspond secondary alcohols (scheme-2), while addition to ketones/p-ketoses afforded corresponding tertiary alcohols (scheme 3A and 3B). Summary of the invention: The main object of the present invention is to provide an improved process to make organometallic complexes using metal halides Another object of the present invention is to provide a process to induce the enantioselectivity in proketones. Another object of the present invention is to provide a process to prepare an amino alcohol of formula by the addition of (un) substituted alkane/alkyne (R) to a ketone using an organometallic complex Another object of the present invention is to provide an improved process to prepare organometallic complex without using Dialkyl zinc. Detailed description of the invention: In accordance with the present invention the main object is to prepare organometallic complex comprising the steps of; • Preparing the salts of chiral and/or achiral additives • Adding metal halide to the above obtained salts and converting to chiral and/or achiral metal complex • Adding Grignard reagent/lithium reagent or Zinc reagent etc, to the above chiral and/or achiral metal complex to form chiral organometal complex. (or) • Adding terminal alkyne and a base to the above chiral metal complex to form chiral organometal complex. The process as described above wherein metal salts of chiral and achiral additives are prepared by treating the chiral and/or achiral additives with a base selected from metal hydrides, metal alkoxides or metal hydroxides or organic bases such as DBU, HMDS, lower alkyl amines etc, and metal hydrides are more preferred. The process as described above wherein the metal halide is a transitional metal halide and the most preferred metal halides are being Zinc and copper halides. The process as described above wherein the Grignard reagent is selected from alkyl, alkenyl, alkynyl and aryl magnesium halides. hi a specific embodiment of the present invention is to provide an efficient method to induce the enantioselectivity in procarbonyl compounds and their enantiomer which are shown below; comprising the steps of: • Preparing the salts of chiral and/or achiral additives • Adding metal halide to the above obtained salts and converting to chiral and/or achiral metal complex • Adding the Grignard reagent/ lithium reagent or Zinc reagent etc, to the above chiral and/or achiral metal complex to form chiral organometal complex. • Adding the procarbonyl compounds to the chiral organometal complex The process as described above wherein salts of chiral and achiral additives are prepared by treating the chiral and achiral additives with metal hydride or metal alkoxides or metal hydroxides or organic bases whereas metal hydrides are more preferred. The process as described above wherein the metal halide is a transitional metal halide and the most preferred metal halides are being Zinc and copper halides. The process as described above wherein the Grignard reagent is selected from alkyl, alkenyl, alkynyl and aryl magnesium halides. The process as described above wherein the Lithium/Zinc reagent is selected from alkyl, alkenyl, alkynyl and aryl Lithium/Zinc reagents. A further embodiment of the invention is the process for the preparation of an amino alcohol of formula: Wherein R’ is halo (CI, Br, F, I) R’ is amino or substituted amino -alkyl, C2 -Ce -alkenyl, or C2 -Ce -alkynyl, unsubstituted or mono- or di- substituted with a substituent selected from the group consisting of: halo (CI, Br, F, I), CF3, CN, NO2, NH2, NH -alkyl), N’C, -C. -alkvlV. CONH,. CONH -alkyl), CON(Ci -Cs -alkyl):, NHC0NH2, NHCONH(Ci -Cg -alkyl). NHCON (C, -Ce -alkyl):, CO2 --Ci -Cs -alkyl, C3 -CT -cycloalkyl, or Ci -Ce -alkoxy; comprising the steps of: • Adding slowly an alkanol and chiral additive to a base in an organic solvent • Treating the above reaction mass with a metal halide to get chiral/achiral metal complex • Adding organometallic reagent of formula R’M, wherein M represents Li, Zn or MgX; X is CI, Br, I and F; to the metal complex to get an organometal complex • Mixing a carbonyl compound with the organometal complex to give the chiral alcohol. The process as described above wherein the chiral additive is pyrrolidinyl norephidrine or its enantiomer or diastereomer. The process as described above wherein the metal halide is a transitional metal halide and the most preferred metal halides are being Zinc and copper halides. The process as described above wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases. The process as described above wherein the preferred metal hydride is sodium hydride. The compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof Examples: The present invention will now be further explained in the foUovdng examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results. A solution of chloromagnesixun-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (3.62 g, 54.7 mmol) to a stirred solution of n-butyl magnesium chloride (2M solution in THF, 26.8 ml, 53.7 mmol) at 0-5 "C. The solution was stirred for another 2h at 0-5 °C. In another dry flask, to anhydrous THF (80 ml) at 0-5 'C, NaH (57% dispersion in mineral oil, 4.71 g, 117.7 mmol) was added slowly. The ice-bath was removed and the contents stirred at ambient temp for 30 min and cooled again to 0-5 °C. 2,2,2-Trifluoroethanol (4.3g, 3.13 ml, 42.9 mmol), and (IR, 2S)-pyrrolidinyl norephidrine (13.5 g, 65.8 mmol) were added and the resulting pale yellow solution was stirred at ambient temp for 60 min. A solution of zinc bromide (11.98 g, 54 mmol) in THF (40 ml) was added and the suspension was stirred for 60 min at 25-30 °C. The solution of CPA-MgCl was then warmed to 25-30 °C and then transferred to the ephedrine zincate reagent by cannula, over 15 min., with THF (5 ml) as a wash, and the suspension was stirred for another 2h. 4-Chloro-2-trifluoroacetylaniline (10 g, 44.7 mmol) was added in one portion to the reaction mixture and stirred for 15h. The reaction mixture was quenched with 30% aq K2CO3 (5.5 ml) and aged for Ih. The solid material was filtered and washed with THF (5x10 ml). The combined filtrate concentrated to approx 10 ml under reduced pressure, toluene (100 ml) was added and sequentially washed with 30% citric acid (2 x 50 ml) and water (50 ml). The combined aqueous layer was back-extracted with toluene (25 ml) and saved for pyrrolidinyl norephidrine recovery. The combined organic phase was concentrated to approx 10 ml and hexane (50 ml) was added slowly with stirring. The mixture was cooled to 0°C, the solid was collected by filtration, washed with cold hexane (2 x 10 ml) and dried to give 10 g of pure fS)-5-Chloro-a-(cyclopropylethynyl)-2-amino-a- (trifluoromethyl) benzene methanol as a white solid. Example-2: Preparation of ‘S’-5-Chloro-a-(cyclopropylethynvlV2-amino-a'rtrifluoromethvn benzene methanol hydrochloride A solution of chloromagnesiirai-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (3.62 g, 54.7 mmol) to a stirred solution of Ai-butyl magnesium chloride (2M solution in THF, 26.8 ml, 53.7 mmol) at 0-5 "C. The solution was stirred for another 2h at 0-5 °C. In another dry flask, to anhydrous THF (80 ml) at 0-5 °C, NaH (57% dispersion in mineral oil, 4.71 g, 117.7 mmol) was added slowly. The ice-bath was removed and the contents stirred at ambient temp for 30 min and cooled again to 0-5 °C. 2,2,2-Trifluoroethanol (4.3g, 3.13 ml, 42.9 mmol), and (IR, 2S)-pyrrolidinylnorephidrine (13.5 g, 65.8 mmol) were added and the resulting pale yellow solution was stirred at ambient temp for 60 min. A solution of zinc bromide (11.98 g, 54 mmol) in THF (40 ml) was added and the suspension was stirred for 60 min at 25-30 °C. The solution of CPA-MgCl was then warmed to 25-30 °C and then transferred to the ephedrine zincate reagent by cannula, over 15 min., with THF (5 ml) as a wash, and the suspension was stirred for another 2h. 4-Chloro-2-trifluoroacetylaniline (10 g, 44.7 mmol) was added in one portion to the reaction mixture and stirred for 15h. The reaction mixture was quenched with 30% aq K2CO3 (5.5 ml) and aged for Ih. The solid material was filtered and washed with THF (5 x 10 ml). The combmed filtrate concentrated completely under reduced pressure. The residue was dissolved in isopropyl acetate (100 ml) and sequentially washed with 30% citric acid (2 x 50 ml) and water (50 ml). The combmed aqueous layer was back-extracted with IP Ac (25 ml) and saved for pyrroHdmylnorephidrine recovery. To the combmed organic phase was added 12N HCl (4.1 ml). The resulting mixture was aged at 25-30°C and then dried azeotropically and flushed with IP Ac (2 x 25 ml). The slurry was aged for another 24 h at 25-30°C and then filtered and washing was performed with cold IP Ac (3 X 10 ml) and dried to afford 10 g of analytically pure (S)-5-Chloro-a-(cyclopropylethynyl)-2-amino-a-(trifluoromethyl) benzene methanol hydrochloride as a white solid. Example -3: Preparation of r5’-5-Chloro-a-('cvcloDropvlethvnvl')-2-amino-g- Ctrifluoromethyn benzene methanol. A solution of chloromagnesium-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (36.2 g, 0.548 mol) to a stirred solution of «-butyl magnesium chloride (2M solution in THF, 268.0 ml, 0.535 mol) at 0-5°C. The solution was stured for another 2h at 0-5 °C. In another dry flask, to anhydrous THF (300 ml) at 0-5°C, NaH (57% dispersion in mineral oil, (44.0 g, 0.916 mol) was added slowly. The ice-bath was removed and the contents stirred at ambient temp for 30 min and cooled again to 0-5°C. 2,2,2-Trifluoroethanol (43g, 0.429 mol), and (IR, 2S)-pyrrolidinyl norephidrine (135 g, 0.65 mol) were added and the resulting pale yellow solution was stirred at ambient temp for 60 min. Zinc chloride (73.1 g, O.53mol) was added in four lots and stirred for 60 min at 25-30 °C. The solution of CPA-MgCl was then warmed to 25-30 °C and then transferred to the ephedrine zincate reagent, over 15 min., and the suspension was stirred for another 2h. 4-Chloro-2-trifluoroacetylaniline (100 g, 0.447 mol) was added in one portion to the reaction mixture and stirred for reaction completion. The reaction mixture was diluted with toluene (300ml) and stirred for Ih and quenched into IM citric acid solution (1000ml) and stirred for 10 min. Toluene layer was separated and washed with water (2X500ml). The toluene layer was concentrated completely to give residue. The obtained residue was dissolved in methanol (300ml) and isolated by adding DM water (450ml). Yield: 130 g We claim; 1. A process to prepare organometallic complex comprising the steps of; • Preparing the salts of chiral and/or achiral additives • Adding metal halide to the above obtained salts and converting to chiral and or achiral metal complex • Adding Granary reagent/ lithium reagent or Zinc reagent to the above chiral and/or achiral metal complex to form chiral organometal complex. (or) • Adding terminal alkyne and a base to the above chiral metal complex to form chiral organometal complex. 2. The process as claimed in claim 1, wherein the salts of chiral and/or achiral additives are prepared by treating the chiral and/or achiral additives with a base . 3. The process as claimed in claim 2, wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases 4. The process as claimed in claim 2, wherein the preferred base is a metal hydride. 5. The process as claimed in claim 1, wherein the metal halide is a transitional metal halide 6. The process as claimed in claim 5, wherein the most preferred metal halides are being Zinc and copper halides. 7. A process to induce the enantioselectivity in procarbonyl compounds and their enantiomers of formula; Comprising the steps of: • Preparing the salts of chiral and/or achiral additives • Adding metal halide to the above obtained salts and converting to chiral and/or achiral metal complex • Adding the Grignard reagent/ lithium reagent or Zinc reagent to the above chiral and/or achiral metal complex to form chiral organometal complex. • Adding the procarbonyl compounds to the chiral organometal complex 8. The process as claimed in claim 7, wherein the metal salts of chiral and/or achiral additives are prepared by treating the chiral and/or achiral additives with a base . 9. The process as claimed in claim 8, wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases. 10. The process as claimed in claim 8, wherein the preferred base is a metal hydride. 11. The process as claimed in claim 7, wherein the metal halide is a transitional metal halide 12. The process as claimed in claim 11, wherein the most preferred metal halides are being Zinc and copper halides. 13. A process for the preparation of an amino alcohol of formula: Wherein R^ is halo (CI, Br, F, I) R is amino or substituted amino R alkyl, C2 -Ce -alkenyl, or C2 -Ce -alkynyl, unsubstituted or mono- or di- substituted with a substituent selected from the group consisting of: halo (CI, Br, F, I), • Adding slowly an alkanol and chiral additive to a base in an organic solvent • Treating the above reaction mass with a metal halide to get chiral metal complex • Adding organometallic reagent of formula R^M, wherein M represents Li, Zn or Mix; X is CI, Br, I and F; to the chiral metal complex in a solvent and the suspension was stirred to get chiral organometal complex • Mixing a carbonyl compound with the chiral organometal complex to give the chiral alcohol. 14. The process as claimed in claim 13, wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases 15. The process as claimed in claim 14, wherein the preferred base is a metal hydride. 16. The process as claimed in claim 13, wherein the metal halide is a transitional metal halide 17. The process as claimed in claim 13, wherein the most preferred metal halides are being Zinc and copper halides.

Full Text

Field of invention:
Present invention is directed towards the cost effective and industrially applicable process to induce enantioselectivity with improved yields. The present invention is also describes an improved process for making organometallic complexes.
Background of the invention:
Asymmetric addition of organometallic compounds to carbonyls is a useful method for the production of chiral secondary/tertiary-alcohols. Typically for asymmetric synthesis, the active catalyst is generated in situ by the reaction of Lewis acid with chiral ligands. Addition of organometallic reagents to aldehydes and activated ketones has been achieved with excellent enantioselectivity. With inactivated ketones there has been some success, e.g., using salon 1 and camphanosulphonamide ligand 2.

Generally, stoichiometric amount of the promoters [Lewis acid, e.g., ZnR2 (R = alkyl/aryl), Zn(0Tf)2, Cu(0Tf)2, etc] is required for these asymmetric syntheses. Although, employing these promoters chiral alcohols has been obtained in high yields and upto 99%, they have limited applicability in industrial scale synthesis of the pharmaceutical intermediates, because they are expensive, difficult to store, difficult to handle, especially dialkyl zinc's are highly pyrophoric and require special modification to transfer the reagent. Moreover the liberated byproduct methane/ethane (when using ZnMe2/ ZnEt2) are a conked on industrial scale synthesis.
To overcome this problem, herein we report an efficient synthesis of active organometallic catalyst formed in situ from chiral auxiliaries and Metal halides. For example

norephidrine (chiral auxiliary) with a base (e.g. NaH); to the resulting alkoxides was added zinc halides (scheme lA). The advantages include the low cost of zinc halides, ease of storing, handling and transfer. Moreover, the byproduct (sodium halides) formed has no safety issues. Based upon this concept, other active catalysts were synthesized using chiral ligands (such as bindles, amino alcohols, amino alcohol derivatives, ethylenediamine, alkalized ethylene diamines and ethylenediamine derivatives in combination with metal source based on zinc and copper (scheme 1).

Using these chiral catalysts alkylation/alkynation of aldehydes afforded correspond secondary alcohols (scheme-2),

while addition to ketones/p-ketoses afforded corresponding tertiary alcohols (scheme 3A and 3B).

Summary of the invention:
The main object of the present invention is to provide an improved process to make organometallic complexes using metal halides
Another object of the present invention is to provide a process to induce the enantioselectivity in proketones.
Another object of the present invention is to provide a process to prepare an amino alcohol of formula

by the addition of (un) substituted alkane/alkyne (R) to a ketone using an organometallic complex
Another object of the present invention is to provide an improved process to prepare organometallic complex without using Dialkyl zinc.

Detailed description of the invention:
In accordance with the present invention the main object is to prepare organometallic complex comprising the steps of;
• Preparing the salts of chiral and/or achiral additives
• Adding metal halide to the above obtained salts and converting to chiral and/or achiral
metal complex
• Adding Grignard reagent/lithium reagent or Zinc reagent etc, to the above chiral and/or
achiral metal complex to form chiral organometal complex.
(or)
• Adding terminal alkyne and a base to the above chiral metal complex to form chiral
organometal complex.
The process as described above wherein metal salts of chiral and achiral additives are prepared by treating the chiral and/or achiral additives with a base selected from metal hydrides, metal alkoxides or metal hydroxides or organic bases such as DBU, HMDS, lower alkyl amines etc, and metal hydrides are more preferred.
The process as described above wherein the metal halide is a transitional metal halide and the most preferred metal halides are being Zinc and copper halides.
The process as described above wherein the Grignard reagent is selected from alkyl, alkenyl, alkynyl and aryl magnesium halides.
hi a specific embodiment of the present invention is to provide an efficient method to induce the enantioselectivity in procarbonyl compounds and their enantiomer which are shown below;

comprising the steps of:
• Preparing the salts of chiral and/or achiral additives
• Adding metal halide to the above obtained salts and converting to chiral and/or achiral metal complex
• Adding the Grignard reagent/ lithium reagent or Zinc reagent etc, to the above chiral and/or achiral metal complex to form chiral organometal complex.
• Adding the procarbonyl compounds to the chiral organometal complex
The process as described above wherein salts of chiral and achiral additives are prepared by treating the chiral and achiral additives with metal hydride or metal alkoxides or metal hydroxides or organic bases whereas metal hydrides are more preferred.
The process as described above wherein the metal halide is a transitional metal halide and the most preferred metal halides are being Zinc and copper halides.
The process as described above wherein the Grignard reagent is selected from alkyl, alkenyl, alkynyl and aryl magnesium halides.
The process as described above wherein the Lithium/Zinc reagent is selected from alkyl, alkenyl, alkynyl and aryl Lithium/Zinc reagents.
A further embodiment of the invention is the process for the preparation of an amino alcohol of formula:

Wherein
R’ is halo (CI, Br, F, I)
R’ is amino or substituted amino
-alkyl, C2 -Ce -alkenyl, or C2 -Ce -alkynyl, unsubstituted or mono- or di-
substituted with a substituent selected from the group consisting of: halo (CI, Br, F, I), CF3, CN,
NO2, NH2, NH -alkyl), N’C, -C. -alkvlV. CONH,. CONH -alkyl), CON(Ci -Cs -alkyl):,

NHC0NH2, NHCONH(Ci -Cg -alkyl). NHCON (C, -Ce -alkyl):, CO2 --Ci -Cs -alkyl, C3 -CT -cycloalkyl, or Ci -Ce -alkoxy;
comprising the steps of:
• Adding slowly an alkanol and chiral additive to a base in an organic solvent
• Treating the above reaction mass with a metal halide to get chiral/achiral metal complex
• Adding organometallic reagent of formula R’M, wherein M represents Li, Zn or MgX; X is CI, Br, I and F; to the metal complex to get an organometal complex
• Mixing a carbonyl compound with the organometal complex to give the chiral alcohol.
The process as described above wherein the chiral additive is pyrrolidinyl norephidrine or its enantiomer or diastereomer.
The process as described above wherein the metal halide is a transitional metal halide and the most preferred metal halides are being Zinc and copper halides.
The process as described above wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases.
The process as described above wherein the preferred metal hydride is sodium hydride.
The compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof
Examples:
The present invention will now be further explained in the foUovdng examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.

A solution of chloromagnesixun-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (3.62 g, 54.7 mmol) to a stirred solution of n-butyl magnesium chloride (2M solution in THF, 26.8 ml, 53.7 mmol) at 0-5 "C. The solution was stirred for another 2h at 0-5 °C. In another dry flask, to anhydrous THF (80 ml) at 0-5 'C, NaH (57% dispersion in mineral oil, 4.71 g, 117.7 mmol) was added slowly. The ice-bath was removed and the contents stirred at ambient temp for 30 min and cooled again to 0-5 °C. 2,2,2-Trifluoroethanol (4.3g, 3.13 ml, 42.9 mmol), and (IR, 2S)-pyrrolidinyl norephidrine (13.5 g, 65.8 mmol) were added and the resulting pale yellow solution was stirred at ambient temp for 60 min. A solution of zinc bromide (11.98 g, 54 mmol) in THF (40 ml) was added and the suspension was stirred for 60 min at 25-30 °C. The solution of CPA-MgCl was then warmed to 25-30 °C and then transferred to the ephedrine zincate reagent by cannula, over 15 min., with THF (5 ml) as a wash, and the suspension was stirred for another 2h. 4-Chloro-2-trifluoroacetylaniline (10 g, 44.7 mmol) was added in one portion to the reaction mixture and stirred for 15h.
The reaction mixture was quenched with 30% aq K2CO3 (5.5 ml) and aged for Ih. The solid material was filtered and washed with THF (5x10 ml). The combined filtrate concentrated to approx 10 ml under reduced pressure, toluene (100 ml) was added and sequentially washed with 30% citric acid (2 x 50 ml) and water (50 ml). The combined aqueous layer was back-extracted with toluene (25 ml) and saved for pyrrolidinyl norephidrine recovery. The combined organic phase was concentrated to approx 10 ml and hexane (50 ml) was added slowly with stirring. The mixture was cooled to 0°C, the solid was collected by filtration, washed with cold hexane (2 x 10 ml) and dried to give 10 g of pure fS)-5-Chloro-a-(cyclopropylethynyl)-2-amino-a- (trifluoromethyl) benzene methanol as a white solid.

Example-2: Preparation of ‘S’-5-Chloro-a-(cyclopropylethynvlV2-amino-a'rtrifluoromethvn benzene methanol hydrochloride
A solution of chloromagnesiirai-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (3.62 g, 54.7 mmol) to a stirred solution of Ai-butyl magnesium chloride (2M solution in THF, 26.8 ml, 53.7 mmol) at 0-5 "C. The solution was stirred for another 2h at 0-5 °C. In another dry flask, to anhydrous THF (80 ml) at 0-5 °C, NaH (57% dispersion in mineral oil, 4.71 g, 117.7 mmol) was added slowly. The ice-bath was removed and the contents stirred at ambient temp for 30 min and cooled again to 0-5 °C. 2,2,2-Trifluoroethanol (4.3g, 3.13 ml, 42.9 mmol), and (IR, 2S)-pyrrolidinylnorephidrine (13.5 g, 65.8 mmol) were added and the resulting pale yellow solution was stirred at ambient temp for 60 min. A solution of zinc bromide (11.98 g, 54 mmol) in THF (40 ml) was added and the suspension was stirred for 60 min at 25-30 °C. The solution of CPA-MgCl was then warmed to 25-30 °C and then transferred to the ephedrine zincate reagent by cannula, over 15 min., with THF (5 ml) as a wash, and the suspension was stirred for another 2h. 4-Chloro-2-trifluoroacetylaniline (10 g, 44.7 mmol) was added in one portion to the reaction mixture and stirred for 15h.
The reaction mixture was quenched with 30% aq K2CO3 (5.5 ml) and aged for Ih. The solid material was filtered and washed with THF (5 x 10 ml). The combmed filtrate concentrated completely under reduced pressure. The residue was dissolved in isopropyl acetate (100 ml) and sequentially washed with 30% citric acid (2 x 50 ml) and water (50 ml). The combmed aqueous layer was back-extracted with IP Ac (25 ml) and saved for pyrroHdmylnorephidrine recovery. To the combmed organic phase was added 12N HCl (4.1 ml). The resulting mixture was aged at 25-30°C and then dried azeotropically and flushed with IP Ac (2 x 25 ml). The slurry was aged for another 24 h at 25-30°C and then filtered and washing was performed with cold IP Ac (3 X 10 ml) and dried to afford 10 g of analytically pure (S)-5-Chloro-a-(cyclopropylethynyl)-2-amino-a-(trifluoromethyl) benzene methanol hydrochloride as a white solid.

Example -3: Preparation of r5’-5-Chloro-a-('cvcloDropvlethvnvl')-2-amino-g- Ctrifluoromethyn benzene methanol.
A solution of chloromagnesium-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (36.2 g, 0.548 mol) to a stirred solution of «-butyl magnesium chloride (2M solution in THF, 268.0 ml, 0.535 mol) at 0-5°C. The solution was stured for another 2h at 0-5 °C. In another dry flask, to anhydrous THF (300 ml) at 0-5°C, NaH (57% dispersion in mineral oil, (44.0 g, 0.916 mol) was added slowly. The ice-bath was removed and the contents stirred at ambient temp for 30 min and cooled again to 0-5°C. 2,2,2-Trifluoroethanol (43g, 0.429 mol), and (IR, 2S)-pyrrolidinyl norephidrine (135 g, 0.65 mol) were added and the resulting pale yellow solution was stirred at ambient temp for 60 min. Zinc chloride (73.1 g, O.53mol) was added in four lots and stirred for 60 min at 25-30 °C. The solution of CPA-MgCl was then warmed to 25-30 °C and then transferred to the ephedrine zincate reagent, over 15 min., and the suspension was stirred for another 2h. 4-Chloro-2-trifluoroacetylaniline (100 g, 0.447 mol) was added in one portion to the reaction mixture and stirred for reaction completion.
The reaction mixture was diluted with toluene (300ml) and stirred for Ih and quenched into IM citric acid solution (1000ml) and stirred for 10 min. Toluene layer was separated and washed with water (2X500ml). The toluene layer was concentrated completely to give residue. The obtained residue was dissolved in methanol (300ml) and isolated by adding DM water (450ml).
Yield: 130 g

We claim;
1. A process to prepare organometallic complex comprising the steps of;
• Preparing the salts of chiral and/or achiral additives
• Adding metal halide to the above obtained salts and converting to chiral and or achiral metal complex
• Adding Granary reagent/ lithium reagent or Zinc reagent to the above chiral and/or achiral metal complex to form chiral organometal complex.
(or)
• Adding terminal alkyne and a base to the above chiral metal complex to form
chiral organometal complex.
2. The process as claimed in claim 1, wherein the salts of chiral and/or achiral additives are prepared by treating the chiral and/or achiral additives with a base .
3. The process as claimed in claim 2, wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases
4. The process as claimed in claim 2, wherein the preferred base is a metal hydride.
5. The process as claimed in claim 1, wherein the metal halide is a transitional metal halide
6. The process as claimed in claim 5, wherein the most preferred metal halides are being Zinc and copper halides.
7. A process to induce the enantioselectivity in procarbonyl compounds and their enantiomers of formula;

Comprising the steps of:
• Preparing the salts of chiral and/or achiral additives
• Adding metal halide to the above obtained salts and converting to chiral and/or achiral metal complex
• Adding the Grignard reagent/ lithium reagent or Zinc reagent to the above chiral and/or achiral metal complex to form chiral organometal complex.
• Adding the procarbonyl compounds to the chiral organometal complex

8. The process as claimed in claim 7, wherein the metal salts of chiral and/or achiral additives are prepared by treating the chiral and/or achiral additives with a base .
9. The process as claimed in claim 8, wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases.
10. The process as claimed in claim 8, wherein the preferred base is a metal hydride.
11. The process as claimed in claim 7, wherein the metal halide is a transitional metal halide
12. The process as claimed in claim 11, wherein the most preferred metal halides are being Zinc and copper halides.
13. A process for the preparation of an amino alcohol of formula:

Wherein
R^ is halo (CI, Br, F, I)
R is amino or substituted amino
R alkyl, C2 -Ce -alkenyl, or C2 -Ce -alkynyl, unsubstituted or mono- or di-
substituted with a substituent selected from the group consisting of: halo (CI, Br, F, I),

• Adding slowly an alkanol and chiral additive to a base in an organic solvent
• Treating the above reaction mass with a metal halide to get chiral metal
complex
• Adding organometallic reagent of formula R^M, wherein M represents Li,
Zn or Mix; X is CI, Br, I and F; to the chiral metal complex in a solvent
and the suspension was stirred to get chiral organometal complex
• Mixing a carbonyl compound with the chiral organometal complex to give
the chiral alcohol.
14. The process as claimed in claim 13, wherein the base is selected from metal hydrides, metal alkoxides, metal hydroxides and organic bases
15. The process as claimed in claim 14, wherein the preferred base is a metal hydride.
16. The process as claimed in claim 13, wherein the metal halide is a transitional metal halide
17. The process as claimed in claim 13, wherein the most preferred metal halides are being
Zinc and copper halides.

AN EFFICIENT PROCESS TO INDUCE ENANTIOSELECTIVITY IN PROKETONES

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