Title of Invention	OPTICALLY PURE 1-ALKYL/ARYL-1-PHENYL-2-METHYLAMINOPROPANOL HYDROCHLORIDES AND PROCESS FOR THEIR PREPARATION
Abstract	The invention disclosed in this application relates to optically pure 1-alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides and new synthetic process for their preparation. This process involves the stereospecific nucleophilic addition of the alkyl/aryl Grignard reagents to the carbonyl function in chiral l-phenyl-2-methylamino-1-propanone. The optimal experimental reaction conditions for this stereospecific synthesis involving asymmetric induction have been established.

Title of Invention

OPTICALLY PURE 1-ALKYL/ARYL-1-PHENYL-2-METHYLAMINOPROPANOL HYDROCHLORIDES AND PROCESS FOR THEIR PREPARATION

Abstract

The invention disclosed in this application relates to optically pure 1-alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides and new synthetic process for their preparation. This process involves the stereospecific nucleophilic addition of the alkyl/aryl Grignard reagents to the carbonyl function in chiral l-phenyl-2-methylamino-1-propanone. The optimal experimental reaction conditions for this stereospecific synthesis involving asymmetric induction have been established.

Full Text	FIELD OF INVENTION The objective of the present invention relates to optically pure 1-alkyl/aryl-l-phenyl-2-methylaminopropanols and their preparation by addition of alkyl/aryl Grignard reagents to chiral l-phenyl-2-methylamino-l-propanone. BACKGROUND OF INVENTION l-Alkyl/aryl-l-phenyl-2-methylaminopropanols are a class of organic compounds belonging to the category of phenylaminoalcohols. These phenylaminoalcohols are widely used in pharmaceutical industry as decongestants, analgesics, bronchodilators and mydriatics. Ephedrine, (lR,2S)-(-)-l -phenyl-2-aminomethylpropanol is one such compound in this group with decongestant activity. Except ephedrine, no other optically pure l-alkyl/aryl-l-phenyl-2-methylaminopropanols are reported in the literature. In the prior art, the preparation of racemic l-alkyl-l-phenyl-2-methylaminopropanols from racemic 2-methylaminopiopiophenone through Grignard reactions is reported in J.Am.Chem.Soc, Vol. 64, pp. 2451-2452, pp. 533-536. The study of physiological properties of these compounds revealed that the presence of alkyl group in the a-position of l-phenyl-2-methylaminopropanols lowers the toxicity without significant loss of therapeutic activity. For this study, the starting material, racemic-2-methylamino- propiophenone was synthesized from phenacylbromide and hexamine. Racemic means a mixture of 50% d-isomer and 50% /-isomer with an optical rotation of 0°. In yet another prior art, Patent no: 302,940 (France) describes a method for the preparation of ephedrine by synthetic process via 2-methylaminopropiophenone from propiophenone by bromination and condensation with methylamine followed by reduction. The 2-methylaminopropiophenone obtained from this process is also a racemic mixture. In the synthesis of chiral molecules, especially in drugs, it is extremely important to isolate the compound with high optical purity as presence of other isomer is regarded as an undesirable impurity. This is because, in some cases, enantiomers differ widely in their therapeutic properties. For example, dextro-propoxyfene is an analgesic agent while levo-propoxyfene is devoid of any analgesic properties but is an effective antitussive agent. The development of a chiral molecule requires multiple skills and expertise since their preparation depends primarily on the nature and properties of the molecule. The possible approaches are based on two basic concepts of either introducing chirality in the synthetic route or by appropriate resolution of racemic mixtures. Resolution of racemic mixtures using chiral reagents including acids and bases is a well known and much-used method. A number of commercially important products have been developed, such as S-naproxen, S-ibuprofen, S-omeprazole, R-fluoxetine etc. by employing the resolution procedure. In this method the synthesis of racemic molecules and their resolution to single enantiomers affords the advantage of evaluating both isomers for therapeutic activity. At the same time the processes are often ineffective, particularly, when kinetic resolution is not possible. The best possible way of introducing chirality in a synthetic sequence would be to use either a natural product or a product derived from inexpensive fermentation/microbial synthesis with the desired chiral characteristics which can then be chemically modified. It has the advantage that the conversions can result better yields with little loss of material since the unwanted isomer is not involved. Asymmetric induction on aminoketones is possible through Grignard reactions. The Grignard reaction is an organometallic chemical reaction involving alkyl- or aryl-magnesium halides (also referred as Grignard reagents) as electrophiles. These reactions are versatile tools in organic chemistry to increase the number of carbons in the molecules. Alkylation at the carbonyl caibon of a ketone leads to a tertiary alcohol through a Grignard reaction. When the a-carbon with respect to the carbonyl group of a ketone is asymmetric, a new chiral centre can be formed at the reaction site during Grignard reaction. J.Am.Chem.Soc, Vol. 75, pp. 4458-4461, discloses asymmetric induction during Grignard synthesis of the P-dialkylaminopropiophenones and a-alkyl-P-dialkylamino-propiophenones using benzylmagnesium chloride to give the tert-carbinol viz., 4-dialkyl-amino-l,2-diphenyl-2-butanols predominantly as one diastereoisomer, either a or p. The optical purities of the compounds isolated are not mentioned in the report. In J.Organomet.Chem., Vol. 88, No. 3, pp. 303-314, correlation of the structure of Grignard reagents and the stereochemistry of the addition reaction with a variety of a-aminoketones is revealed. The study inferred that the stereoselectivity decreased with increasing size of the halide ion and also depends on the degree of solvation or aggregation of the Grignard reagent by the solvent. But the products obtained are racemates with the same configurations at both asymmetric carbons or with opposite configuration at asymmetric carbons. Acta.Chim.Acad.Sci.Hung., Vol. 68, No. 3, pp. 253-259; Chem.Abstr., 75: 20720 . decsribes a method for preparation of 3-substituted-3-tropanols by Grignard reactions of the corresponding aminoketones. All the phenylketo bases yield only one of the two possible diastereoisomeric 1-phenyl-l-methyl-3-aminopropan-1-ol while the corresponding methylketo bases yield the other diastereoisomer. The ratios of mixture of diastereoisomers are determined and the steric configurations assigned. Tetrahedron Lett., Vol.13, pp. 2329-2332, provides the synthesis of several pure erythro-and threo-aminoalcohols by reduction of the corresponding a-aminoketone with lithium aluminium hydride as well as by the treatment of the corresponding a-aminoaldehydes with Grignard reagents. The erythro/threo product ratio is dependent on the size of the NR2 group. Tetrahedron, Vol. 25, pp. 4211-4216 describes a study on the stereospecific synthesis of (+) or (-)-l-phenyl-l,2-dimethyl-3-dimethylaminopropanols using suitable Grignard reagents with phenylketo base (1) or methylketo base (II). The stereochemistry of Mannich keto bases is reported in order to clarify the stereochemistry of reactions between a-substituted P-aminoketones and Grignard reagent. The absolute configuration of (+)-a-methyl-p-dimethylaminopropiophenone is found to be S by chemical correlation with (R)-(-)-a-methyl-P-alanine. In Tetrahedron Lett., Vol. 31, No. 38, pp. 5479-5482, 1990, a selective synthesis of either enantiomer of tertiary alcohol starting from the same chiral carbonyl compound by a suitable choice of organometallic reagent has been reported. In this method, the unique affinity of sulfur atom to metals has been exploited. Cram and Elhafez in 1952, describe in detail (J.Am.Chem.Soc, Vol.74, pp. 5828-5835) the "Cram's rule" of steric control of asymmetric induction applicable in correlating and predicting the stereochemistry of asymmetric induction in reactions of acyclic systems in which a new asymmetric centre is created adjacent to an old one. Tetrahedron Lett., Vol. 32, No. 25, pp. 2919-2922, 1991 discloses that the reaction of chiral 2-acyloxazolidines, derived from S-prolinol, with organometallics was found to be diastereoselective giving rise to S-or R-tertiary alcohols depending on the organometallic reagent used. Further in the Angew.Chem.Int.Ed., 2004, Vol. 43, pp. 284-287, a method for synthesis of a variety of chiral tertiary alcohols by catalytic enantioselective addition of unreactive zinc reagents to poorly electrophilic ketones in presence of a chiral ligand is described in excellent diastereoselectivity. Thus in the prior art, chiral tertiary alcohols are prepared using Grignard and organometallic reagents. The application of the Crams rule is used to predict the stereochemistry of the resultant alcohols. Excellent enantioselectivity was observed only when chiral catalysts were employed. But no reports were found on optically pure 1 -alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and their method of preparation. The present invention relates to the compounds of the Structural formula -1 namely optically pure l-alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochloride wherein R is alkyl and aryl group. In a preferred embodiment of the present invention, a process for the preparation of the compounds of formula (1) in which the compound corresponding to structural formula (2) namely chiral l-phenyl-2-methylamino-l-propanone are subjected to treatment with aiyl/alkyl Grignard reagent in the presence of organic solvents leading to only one of the diastereomer either erythro/threo in high optical purity (99-100%) and yield (65-75%) as the first crop Specifically, the object of the present invention is to provide a new process for optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides by stereospecific addition of aryl/alkyl Grignard reagent to the chiral 1-phenyl-2-methylamino-1-propanone after liberating the base from the corresponding hydrochloride salts, in the presence of organic solvents Objectives of the invention The main objective of the present invention is to provide new optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides of the (Structure-!) Another objective of the present invention is to provide a new process for the synthesis of optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides of the (Structure-1). Another objective of the present invention is to provide a process for optically purealkyl/aryl-l-phenyl-2-methylaminopropanolhydrochlorides by the stereospecific addition of alkyl/aryl Grignard reagents chiral l-phenyl-2-methylamino-l-propanones in the presence of solvents of the type dialkyl/alicyclic ethers. Yet another objective of the present invention is to provide a process to isolate optically alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides in 65-75% yield as the first crop. Still another objective of the present invention is to provide process for the preparation of (+) or (-)-alkyl/aiyl-l-phenyl-2-methylaminopropanol hydrochlorides in optically pure form (99-100%). DETAILED DESCRIPTION OF THE INVENTION Accordingly the present invention relates to optically pure alkyl/aryl-1-phenyl-2-methylaminopropanolhydrochlorides. According to another embodiment of the present invention there is provided a new process for the preparation of optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides by the addition of alkyl/aryl Grignard reagent to chiral 1-phenyl-2-methylamino-1-propanones which comprises 1) adding of Mg metal to dialkyl/alicyclic ethers 2) adding of the catalyst to the resulting solution 3) adding of alkyl/arylhalide dissolved in organic solvent to the solution obtained in step (2) in 5 min to 10 h and heating the solution to reflux for a period ranging from 15 min to 24 h. 4) adding of 1 -phenyl-2-methylamino-1-propanone dissolved in organic solvent to the solution obtained in step (3) at a temperature in the range from -30 °C to +100 °C for a period of 5 min to 10 h. 5) stirring the resulting solution for a period ranging from 15 min to 24 h. 6) quenching the resulting solution of step (5) in to a salt solution and extracting the product alkyl/aryl-l-phenyl-2-methylaminopropanols in an organic solvent. 7) drying the organic solvent layer containing the product alkyl/aryl-1-phenyl-2- methylaminoproDanols obtained in step (6) with solid drying agent and concentrating under vacuum. 8) adding of organic solvent to the resulting mass obtained in step (7) and acidifying to pH by passing dry HC1 gas in the range 1.0 to 6.0 to obtain the crude alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochloride. 9) recrystallising the crude product obtained in step (8) using organic solvent or water. 10) obtaining physical data and spectroscopic data (IR, H NMR, C NMR and mass spectra) to confirm the structure of the product. The solvent used in step (1) may be selected from dialkyl/alicyclic ether preferably diethyl ether. The catalyst used to initiate the Grignard reaction in step (2) is chosen from iodine, dibromo ethane, ethyl iodide preferably iodine. The solvent used in step (3) for dissolving aryl/alkyl halide is selected from organic solvents preferably diethyl ether. The aryl/alkyl halide used in step (3) may be selected from aralkyl chloride or aralkyl bromide or aralkyl iodide preferably aralkyl bromide. The addition of aryl/alkyl halide in step (3) is effected in 5 min to 10 h preferably 2 h and resulting solution in step (3) is refluxed for a period of 15 min to 24 h preferably 4 h. The solvent used for dissolving l-phenyl-2-methylamino-l-propanones in step (4) is selected from organic solvents preferably diethyl ether. The l-phenyl-2-methylamino-l-propanones used in step (4) is chosen from isomers of l-phenyl-2-methylamino-l-propanones. The addition of 1-phenyl-2-methylamino-1-propanones in step (4) is carried at a temperature range of-30 °C to +100 °C preferably 30-35 °C for a period ranging from 5 min to 10 h preferably 1 h. The resulting solution is stirred for a period ranging from 5 min to 24 h preferably 8 h. The resulting solution of step (6) is quenched into a salt solution, the salt used is selected from nonmetal halides preferably ammonium chloride. The product alkyl/aryl-1-phenyl-2-methylaminopropanols obtained in step (6) is extracted using organic solvents preferably ether. The organic solvent layer containing the product obtained in step (7) is dried with solid drying agent preferably anhydrous sodium sulphate before concentrating under vacuum. The organic solvent added in step (8) is selected from organic solvents preferably diethyl ether, which is acidified by passing dry HC1 gas to pH in the range between 1.0 to 6.0 preferably 3.0 to obtain crude alkyl/aryl-1-phenyl-2-methylaminopropanol as hydrochloride salt The crude product obtained in step (9) is recrystallised using organic solvents like acetone and /-propyl alcohol. The structure of the final product obtained in step (10) is confirmed using physical and spectroscopic data. The details of the invention are given in the examples given below which are provided solely to illustrate the invention and therefore should not be construed to limit the scope of the invention. Example 1 Preparation of erythro-(lS,2R)-a-(+)-l-rt-mefliyI-l-phenyl-2-methylaminopropanol hydrochloride Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and the mixture was slightly warmed. To this, methyl iodide (46g, 0.3 mol) was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the methylmagnesium iodide, (2R)-(+)-l-phenyl-2-methylamino-l-propanone (lOg, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction mixture was further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq.NHUCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone/z-propyl alcohol. Pure white solid of eiythro-(lS,2R)-a-(+)-l-«-methyl-l-phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 97.2% Chiral purity . 99.27% Yield : 70% (9.2g) mp : 206-208 °C MD + 13.3°(c = 5%inH20) Spectroscopic interpretation The structure of the product, erythro-(lS,2R)-ct-(+)-l-w-methyl-l -phenyl-2-methylaminopropanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr) O-H str. at 3327-3279, HN-H str. at 2450, benzenoid bands at 1595 and 1501, ON str. at 1366, CO str. at 1067, CH out of plane bending of mono-substituted benzene ring at 768, 704. b) 'H NMR (DMSO-dfc 300 MHz) (5H) 0.92 (3H, d, CH-CBb), L64 (3H, s, protons), 8.32-8.53 (2H, 2bs, NH2). c) 13C NMR (DMSO-d6,300 MHz) (8C) 11.17 (CHCH3), 27.75 (-C-CH3), 31.75 (t^-Nt^ ), 62.73 ( CH-CH3), 73.71 (-C-CH3), 125.37-144.55 (aromatic carbons). d) Mass spectrum (CI, methanol) [MH]+ at m/z 180 (49), [MH^- H20] at m/z 162 (8), [CH3-NH=CH-CH3] at m/z 58(100). Example 2 Preparation of erythro-(lS,2R)-(+)-l-/f-ethyl-l-phenyl-2-methyIaminopropanol hydrochloride Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, «-ethyl bromide (33g, 0.3 mol) dissolved in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the H-ethylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-l -propanone (1 Og, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aqueous ammonium chloride (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using /-propyl alcohol. Pure white solid of erythro-(l S,2R)-(+)-l -w-ethyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC Chiral purity Yield mp 99.0% 98.79% 9.8 g (70%) 204-206 °C + 9.68° (c = 5% in H20) Spectroscopic interpretation The structure of the product, eiythro-(lS,2R)-(+)-l-/?-ethyl»l-phenyl-2-methylamino-propanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr) OH str. at 3345-3308, H^.H str. at 2460, benzenoid bands at 1595 and 1495, C-N str. at 1371, C-O str. at 1034, OH out of plane bending of mono-substituted benzene ring at 764, 702. b) H NMR (DMSO-d6,300 MHz) (6H) ^CH3 0.69 (t, 3H, -CH2-CH3), 1.03 (d, 3H, CHCH3), 2.06 (2H, two merging quartets, + representing two diastereotopic CH2CH3 protons), 2.59(3H, s, CH3-NH2 ), 3.48 (1H, m, CH CH3), 5.81 (1H, bs, OH), 7.32-7.51 (m, 5H, aromatic protons), 8.42 (bs, 2H, NH2). c) 13C NMR (DMSO-d6 ,300 MHz) (5C) 7.54 (-CH2-CH3), 11.29 (-CH-CH3), 30.79 (CH2-CH3), 31.76 (CH3-NH2), 62.82 (-CH-CH3), 76.77 ^C OH), 126.14-141.38 (aromatic carbons). d) Mass spectrum (CI, methanol) [MHf at m/z 194(17), [MHf-H20] at m/z 176(19), [CH3-NH=CH-CH3]at m/z 58(100). Example 3 Preparation of erythro-(lS,2R)-(+)-l-/i-butyH-phenyl-2-methylaminopropanol hydrochloride Magnesium (7.63g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, n-butyl bromide (42g, 0.3 mol) dissolved in diethyl ether was added slowly in 2h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4h. To the w-butylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-l -propanone (1 Og, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq. NH4C1 (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone. Pure white solid of erythro-(l S,2R)-(+)-l -w-butyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 98.3% Chiral purity 100% Yield 72%(11.5g) mp 176-178 °C [afD +10.0°(c = 5%inH2O) Spectroscopic interpretation: The structure of the product, eiythro-(lS,2R)-(+)-l-w-butyl-l-phenyl-2-methylamino-propanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm"1) (KBr) OH str. at 3304, HN-Hstr. at 2450, benzenoid bands at 1591 and 1499, ON str. at 1369, CO str. at 1013, OH out of plane bending of mono-substituted benzene ring at 766, 706. b) H NMR (DMSO-d6,300 MHz) (5H) Hb 0.82 (3H, t, ~(CH2)3-CH3), 0.84 (1H, m, HO-C-C' ), l.02(3H, d, CHCH3), 1.25 (2H, m, CH2CH3), 1.30 (1H, m, HO-C-C' ) 2.02 (2H, m, -CH2-CH2 CH3), 2.59(3H, s, 3 + CH3-NH2), 3.46 (1H, m, ^HCH3), 5.80 (1H, bs,-OH), 7.31-7.50 (5H, m, aromatic protons), 8.31-8.47 (2H, bd, NH2 ). Ha and Hb are two diastereotopic hydrogens adjacent to the chiral carbon atom. c) 13C NMR (DMSO-d6,300 MHz) (8C) 11.20 eCH2-CH3), 13.86 (-CHCH3), 22.32 (CH2CH3), 25.02 (-CH2-CH2CH3), 31.78 + (-CH2-OOH), 3786 (CH3-NH2 )? 63.03 (-CH-CH3), 76.45 (^-OH), 126.03-141.70 (aromatic carbons). d) Mass spectrum (CI, methanol) [MH]+ at m/z 222(56), [MH'-HzO] at m/z 204(6), [CH3-NH=CH-CH3]at m/z 58(100). Example 4 Preparation of erythro-(lS»2R)-(+)-l-/i-pentyl-l-phenyI-2-methylaminopropanol hydrochloride: Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, n-pentyl bromide (46g, 0.3 mol) dissolved in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the n-pentylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-1 -propanone (lOg, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq. NH4CI (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained was filtered and recrystallised by using acetone. Pure white solid of eiythro-(lS,2R)-(+)-l-w-pentyl-l-phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 96.8% Chiral purity 100% Yield 10g(66%) mp 160-162 °C MD + 12.8°(c = 5%inH20) Spectroscopic interpretation: The structure of the product, eiythro-(l S,2R)-(+)-l -w-pentyl-1 -phenyl-2- methylaminopropanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr) OH str. at 3337-3318, HN-H str. at 2446, benzenoid bands at 1576-1499, ON str. at 1379, CO str. at 1051, OH out of plane bending of mono-substituted benzene ring at 760, 704. b) H NMR (DMSO-d6,200 MHz) (8H) 0.77-1.17 (12H, m, OH2 (Cfib^ CH3, -CHCH3), 2.01 (2H, m,-CH2-CH2-C-OH), 2.56 (3H, s, CH3-NH2 ), 3.49 (1H, m, -CHCH3), 5.73 (1H, m, -OH), 7.42 (5H, m, aromatic + protons), 8.59 (2H, bd, Mi,). The signals of the diastereotopic methylene hydrogens of the n-pentyl group appear to have merged with those of the rest of the chain. c) 13C NMR (DMSO-d6,200 MHz) (8C) 9.87 (-CH2CH3), 12.43 (-CHCH3), 20.51 ( CH2-CH3), 21.10 (rCH2-CH2 CH3), 30.07 (CH3 CH2^CH2-CH2C-OH), 30.39 (CH3CH2CH2- CH2COH), 36.81 (CH3-NH2), 61.71 ( CH CH3), 75.21 ( C OH), 124.05-140.53 (aromatic carbons). d) Mass spectrum (EI) [M]+> at m/z 236( m/z 146(2), (C6H5CO)+ at m/z 105 (3), [CH,-NH=CH-CH3] at m/z 58(100). Example 5 Preparation of erythro-(lS^2R)-(+)-l-/f-heptyH-phenyl-2-methyIaminopropanol hydrochloride: Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly wanned. To this, n-heptyl bromide (55g, 0.3 mol) dissolved in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. Tothe rt-heptylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-l -propanone (lOg, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were fiirther stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq.NHtCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone. Pure white solid of erythro-(l S,2R)-(+)-l -w-heptyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 96.8% Chiral purity 100% Yield 10.6g (66%) mp 160-162 °C [a]D + 12.8°(c = 5%inH20) Spectroscopic interpretation: The structure of the product, erythro-(lS,2R)-(+)-l-n-heptyl-l-phenyl-2-methylaminopropanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr) OH str. at 3362, HN-Hstr. at 2444, benzenoid bands at 1584,1495, ON str.at 1342, CO srr. at 1055, OH out of plane bending of mono-substituted benzene ring at 758, 702. b) H NMR (DMSO-ds, 300 MHz) (6H) 0.82 (4H, m, CH2- CH3, H0_c \?>r), 0.96 (d, 3H, -CH-€Hj), 1.20 (9H, m, Ha HO_c~^~bCH~iQUli~), 1-97 (2H, m, -CH2-CH2-C-OH), 2.54 (3H, s, CH3-NH2 ), 3.49 (IH, m, CH-CH3), 5.78 (IH, bs, -OH), 7.26-7.44 (5H, m, aromatic protons), 8.17-8.37 (2H, two bs,NH2). The Ha and Hb are two diastereotopic hydrogens adjacent to a chiral carbon atom, c) !3C NMR (DMSO-d6,300 MHz) (5C) 11.22 ( CH2-£H3), 13.87 (CH-£H3), 21.97 ( £H2CH3), 22.75 e£H2~CH2-CH3), 28.50 (rCH2 (CH2)2<:h3> (-CH2-(CH2)5-CH3), 38.09 (CH3-NH2), 63.05 (^H^H3), 76.49 (-C-OH), 126.04-141.70 (aromatic carbons). d) Mass spectrum (CI, methanol) MHat m/z 264(29), [MH^O] at m/z 246(32), C6H5C+(OH) (C7H15) at m/z 205(7) and [CH3-NH=CH-CH3]at m/z 58(100). Example 6 Preparation of erythro-(lR,2S)-(+)-l-jp-tolyH-phenyl-2-methy!aminopropanol hydrochloride: Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, p-bromo toluene (54g, 0.3 mol) in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the p-tolylmagnesium bromide, (2R)-(+)-l-phenyl-2-methylamino-l-propanone (10g, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq.NFLiCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and diy HC1 gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and reciystallised by using /-propyl alcohol. Pure white solid of erythro-(lR,2S)-(+)-l-p-tolyl-l-phenyl-2-methylamino-propanol hydrochloride was obtained. Purity by GC 99% Chiral purity 99.6% Yield 13g(73%) mp 218-220 °C [a]D + 32.3°(c = 5%inCH3OH) Spectroscopic interpretation: The structure of the product erytiiro-(lR,2SH+)-l-/7-tolyl-l-phenyl-2-methylamino propanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr) OH str. at 3281, HN-H str. 2413, benzenoid bands 1591 and 1516, ON str.1375, OO str. 1030, OH out of plane bending of mono-substituted benzene ring 762, 708. b) !H NMR (DMSO-d6, 200 MHz) (5H) 1.12 (3H, d, CH-CH3), 2.27 (3H, s, benzylic CH3), 2.48 (3H, s, CHj-NHa), 4.63 (1H, q, -CH-CH3), 6.60 (1H, bs, -OH), 7.15-7.61 (9H, m, aromatic protons), 8.78 (2H, bs, NH,). c) 13C NMR (DMSO-de, 200 MHz) (8C) 10.62 (-CH-CH3), 19.10 (benzylic carbon), 30.93(CH3-NH2), 59.19 (-CH-CH3), 77.0 ( C OH), 124.11-143.33 (aromatic carbons). d) Mass spectrum (CI, methanol) Mtf at m/z 256(26), [Mtf-HzO] at m/z 238(18), [CH3-NH=CH-CH3] at m/z 58(100). Example 7 Preparation of erythro-(lR,2R)-(+)-a-l-naphthyl-l-phenyl-2-methylaminopropanol hydrochloride: Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this 1-bromonaphthalene (65g, 0.3 mol) in diethyl ether was added slowly 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the 1 -naphthylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-1 -propanone (1 Og, 0.0613 mol) in diethyl ether was added slowly inl h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq.NHiCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone. Pure white solid of erythro-(lR,2R)-(+)-a-(l-naphthyl)-l-phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 99.8% Chiral purity 100% Yield 15g(74%) mp 298-300 °C [a]D : + 145° (c = 5% in CH3OH) Spectroscopic interpretation: The structure of the product, erythro-(lR,2R)-(+)-a-(l-naphthyl)-l-phenyl-2-methylaminopropanol hydrochloride was confirmed with the help of the Following spectroscopic data. a) IR (cm1) (KBr) O-H str. at 3273, HN-H str. at 2461, benzenoid bands at 1593, 1506, ON str. at 1341, C-0 str. at 1020, OH out of plane bending of mono-substituted benzene ring at 777, 710. b) XH NMR (DMSO-de, 300 MHz) (5H) 1.16 (3H, d, -CH-CH3), 2.71 (3H, s, CH3-NH2 ), 4.45 (1H, bs, -€H-CH3), 6.92 (1H, bs, - OH), 7.17-7.95 (12H, m, aromatic protons), 8.10-8.13 (2H, two bs, NB). c) 13C NMR (DMSO-d6,300 MHz) (8C) 13.13 (-CH-€H3), 32.43 (CH3-NH2 ), 61.50 (-CHCH3), 78.65 (~C-OH), 123.95-142.11 (aromatic carbons). d) Mass spectrum (CI, methanol) MH" at m/z 292(6), [MH^O] at m/z 274(99), [C6H5C+ (OHXC10H7)] at m/z 233(10) and [CH3-NH=CH-CH3]at m/z 58(100). Example 8 Preparation of eryfliro-(lS,2S)-(-)-a-(l-naphthyI-l-phenyI-2-methylaminopropanoI hydrochloride: Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this 1-bromonaphthalene (65g, 0.3 mol) in diethyl ether was added slowly in 2h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4h. To the 1-naphthylmagnesium bromide, (2S)-(-)-l-phenyl-2-methylamino-l-propanone (10g, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2; hexane 8]. The reaction was quenched in saturated aq. NH4CI (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and reciystallised by using acetone. Pure white solid of erythro-(lS,2S)-(-)-a-(l«naphthyl-l-phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 97.02% Chiral purity 100% Yield 14.6g (72%) mp 292-296 °C MD -142°(c = 5%inCH3OH) Example 9 Preparation of racemic-(lS^S)(lR^R)-(±)-a-(l-naphthyl-l-phenyl-2-methyIamino-propanol hydrochloride: Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this 1-bromonaphthalene (65g, 0.3 mol) in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the 1-naphthylmagnesium bromide, (2RS)-(±)-l-phenyl-2-methylamino-l-propanone (10g, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq. NH4CI (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained was filtered and recrystallised by using acetone. Pure white solid of racemic-(lS,2S)(lR,2R)-(±)-a-(l-naphthyl-l-phenyl-2-methylamino-propanol hydrochloride was obtained. Purity by GC Chiral purity Yield mp [a]D 96.05% 100% 14.2g(70%) 268-272 °C 0° (c = 5% in CH3OH) Example 10 Preparation of hydrochloride: erythro-(lR,2S)-(-)-l-benzyH-phenyl-2-methylaminopropanol Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, bromobenzene (52g, 0.3 mol) in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the benzylmagnesium bromide, (2R)-(+)-l-phenyl-2-methylamino-l-propanone (lOg, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8]. The reaction was quenched in saturated aq.NHUCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and reciystallised by using acetone. Pure white solid of erythro-(lR,2S)-(-)-l -benzyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained. Purity by GC 97.9% Chiral purity 100% Yield 65%(10g) mp 248-250 °C fab -62° (c = 5% in H20) Spectroscopic interpretation: The structure of the product, erythro-(lR,2S)-(-)-l-benzyl-l-phenyl-2-methylamino- propanol hydrochloride was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr) OH str. at 3337, HN-Hstr. at 2546, benzenoid bands at 1578, 1493, ON str. at 1381, C-0 str. at 1051, OH out of plane bending of mono-substituted benzene ring at 768, 756, 723, 702. b) *H NMR (DMSO-dfi, 300 MHz) (8H) 1.11 (3H, d, -CH-CH3), 2.51 (3H, s, CH3-NH2 ), 3.22 (1H, d, H, of benzylic group u. _ > -C^-C6H5) 3 38 (1Ij5 m> _CH<:h3 hb of benzylic group ha> and Hb are the two benzylic diastereotopic protons], 6.09 (1H, s, -OH), 7.10-7.47(1 OH, + m, aromatic protons), 8.25-8.52 (2H, two bs, NHj). c) 13C NMR (DMSO-d6,300 MHz) (6C) 11.36 (-CH-CH3), 31.92 (CH3-NH2), 43.31 (-CH2-QH5), 62.52 (-CH-CH3), 76.70 (OOH), 125.89-140.78 (aromatic carbons). d) Mass spectrum (CI, methanol) + MIT at m/z 256(70), [MlT-HiO] at m/z 238(100), C6H5C(OH)(CH2C6H5) ^ m/z ]9? (lg) and [CH3-NH=CH-CH3]at m/z 58(72). Advantages of invention 1. The products obtained in the present invention are not reported in the literature and hence new. 2. The products described in the invention are expected to show therapeutic properties. 3. The presence of these alkyl/aryl groups in a-position with respect to the benzene ring is expected to show lower toxicity. 4. The products obtained using the above said processes are optically pure. 5. The process described above gives highly enantioselective products. 6. The process lead to new products in good yields. We claim 1. New optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation by the addition of alkyl/aryl Grignard reagent to chiral l-phenyl-2-methylamino-l-propanone which comprises i) adding of Mg metal to dialkyl/alicyclic ethers ii) adding of the catalyst to the resulting solution iii) adding of alkyl/arylhalide dissolved in organic solvent in to the solution obtained in step (ii) in 5 min to 10 h and heating the solution to reflux for a period ranging from 15 min to 24 h. iv) adding of chiral l-phenyl-2-methylamino-l-propanone dissolved in organic solvent to the solution obtained in step (iii) at a temperature in the range from -30°C to +100°C slowly for a period of 5 min to 10 h. Stirring the resulting solution for a period ranging from 15 min to 24 h. v) quenching the resulting solution of step (iv) into a salt solution and extracting the product alkyl/aryl-l-phenyl-2-methylaminopropanols in organic solvent. vi) drying the organic solvent layer containing the product alkyl/aryl-1- phenyl-2-methylaminopropanols obtained in step (v) with solid drying agent before concentrating under vacuum. vii) adding organic solvent to the resulting mass obtained in step (vi) and acidifying by using diy hydrochloride gas to pH in the range 1.0 to 6.0 preferably 3.0 to obtain the crude alkyl/aryl-l-phenyl-2-methylamino-propanol as HC1 salt. viii) recrystallising the crude product obtained in step (vii) using organic solvent or water. 2. The new optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claim 1 where in the solvent used in step (i) is selected from dialkyl/alicyclic ethers preferably diethyl ether. 3. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claims 1 to 2 wherein the catalyst used in step (ii) to initiate the Grignard reaction is chosen from iodine, ethyl bromide, dibromoethane and ethyl iodide preferably iodine. 4. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claim 1 to 3 wherein the solvent used for dissolving aiyl/alkyl halide in step(iii) is selected from organic solvents preferably diethyl ether. The aryl/alkyl halide used in step (iii) is selected from aralkyl chloride or aralkyl bromide or aralkyl iodide preferably aralkyl bromide is added for a period ranging from 5 min to 10 h preferably 2 h and refluxed for a period of 15 min to 24 h preferably 4 h. 5. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claims 1 to 4 where in l-phenyl-2-methylamino-l-propanone used in step(iv) is chosen from the isomers R(+) or S(-)-l-phenyl-2-methylamino-l-propanone. The organic solvent used for dissolving!-phenyl-2-methylamino-l-propanone is chosen from organic solvents like diethyl ether and the addition is carried at a temperature range of-30 °C to +100 °C preferably 30-35 °C in 5 min to 10 h preferably 1 h. The resulting mass is stirred for a period ranging from 15 min to 24 h, preferably 8h. 6. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 5 wherein salt used in solution in step (v) is selected from nonmetal halides preferably ammonium chloride and extraction of the product alkyl/aryl-1 -pheny 1-2-methylamino-propanols is effected in organic solvents preferably tert-butyl methyl ether. 7. The new optically pure alkyl/aryl-1 -pheny 1-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 6 where in organic solvent layer containing the product is dried in step (vi) using solid drying agent preferably anhydrous sodium sulphate before concentrating under vacuum. 8. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 7 where in solvent added in step (vii) is selected from organic solvents preferably tert-butyl methyl ether and the resulting solution is acidified bv using dry HC1 gas to pH in the range 1.0 to 6.0 preferably 3.0 to obtain the crude aIkyl/aryl-l-phenyl-2-methylamino-propanols as HC1 salt. 9. The new optically pure alkyl/aryl-l-phenyl-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 8 wherein the solvent used for recrystallisation in step (viii) is selected from organic solvents or water preferably acetone or /-propyl alcohol.

Full Text

FIELD OF INVENTION
The objective of the present invention relates to optically pure 1-alkyl/aryl-l-phenyl-2-methylaminopropanols and their preparation by addition of alkyl/aryl Grignard reagents to chiral l-phenyl-2-methylamino-l-propanone.
BACKGROUND OF INVENTION
l-Alkyl/aryl-l-phenyl-2-methylaminopropanols are a class of organic compounds belonging to the category of phenylaminoalcohols. These phenylaminoalcohols are widely used in pharmaceutical industry as decongestants, analgesics, bronchodilators and mydriatics. Ephedrine, (lR,2S)-(-)-l -phenyl-2-aminomethylpropanol is one such compound in this group with decongestant activity. Except ephedrine, no other optically pure l-alkyl/aryl-l-phenyl-2-methylaminopropanols are reported in the literature.
In the prior art, the preparation of racemic l-alkyl-l-phenyl-2-methylaminopropanols from racemic 2-methylaminopiopiophenone through Grignard reactions is reported in J.Am.Chem.Soc, Vol. 64, pp. 2451-2452, pp. 533-536. The study of physiological properties of these compounds revealed that the presence of alkyl group in the a-position of l-phenyl-2-methylaminopropanols lowers the toxicity without significant loss of therapeutic activity. For this study, the starting material, racemic-2-methylamino- propiophenone was synthesized from phenacylbromide and hexamine. Racemic means a mixture of 50% d-isomer and 50% /-isomer with an optical rotation of 0°.
In yet another prior art, Patent no: 302,940 (France) describes a method for the preparation of ephedrine by synthetic process via 2-methylaminopropiophenone from propiophenone by bromination and condensation with methylamine followed by reduction. The 2-methylaminopropiophenone obtained from this process is also a racemic mixture.
In the synthesis of chiral molecules, especially in drugs, it is extremely important to isolate the compound with high optical purity as presence of other isomer is regarded as an undesirable impurity. This is because, in some cases, enantiomers differ widely in their therapeutic properties. For example, dextro-propoxyfene is an analgesic agent while levo-propoxyfene is devoid of any analgesic properties but is an effective antitussive agent. The development of a chiral molecule requires multiple skills and expertise since their preparation depends primarily on the nature and properties of the molecule. The possible approaches are based on two basic concepts of either introducing chirality in the synthetic route or by appropriate resolution of racemic mixtures.
Resolution of racemic mixtures using chiral reagents including acids and bases is a well known and much-used method. A number of commercially important products have been developed, such as S-naproxen, S-ibuprofen, S-omeprazole, R-fluoxetine etc. by employing the resolution procedure. In this method the synthesis of racemic molecules and their resolution to single enantiomers affords the advantage of evaluating

both isomers for therapeutic activity. At the same time the processes are often ineffective, particularly, when kinetic resolution is not possible.
The best possible way of introducing chirality in a synthetic sequence would be to use either a natural product or a product derived from inexpensive fermentation/microbial synthesis with the desired chiral characteristics which can then be chemically modified. It has the advantage that the conversions can result better yields with little loss of material since the unwanted isomer is not involved. Asymmetric induction on aminoketones is possible through Grignard reactions.
The Grignard reaction is an organometallic chemical reaction involving alkyl- or aryl-magnesium halides (also referred as Grignard reagents) as electrophiles. These reactions are versatile tools in organic chemistry to increase the number of carbons in the molecules. Alkylation at the carbonyl caibon of a ketone leads to a tertiary alcohol through a Grignard reaction. When the a-carbon with respect to the carbonyl group of a ketone is asymmetric, a new chiral centre can be formed at the reaction site during Grignard reaction.
J.Am.Chem.Soc, Vol. 75, pp. 4458-4461, discloses asymmetric induction during Grignard synthesis of the P-dialkylaminopropiophenones and a-alkyl-P-dialkylamino-propiophenones using benzylmagnesium chloride to give the tert-carbinol viz., 4-dialkyl-amino-l,2-diphenyl-2-butanols predominantly as one diastereoisomer, either a or p. The optical purities of the compounds isolated are not mentioned in the report.
In J.Organomet.Chem., Vol. 88, No. 3, pp. 303-314, correlation of the structure of Grignard reagents and the stereochemistry of the addition reaction with a variety of a-aminoketones is revealed. The study inferred that the stereoselectivity decreased with increasing size of the halide ion and also depends on the degree of solvation or aggregation of the Grignard reagent by the solvent. But the products obtained are racemates with the same configurations at both asymmetric carbons or with opposite configuration at asymmetric carbons.
Acta.Chim.Acad.Sci.Hung., Vol. 68, No. 3, pp. 253-259; Chem.Abstr., 75: 20720 . decsribes a method for preparation of 3-substituted-3-tropanols by Grignard reactions of the corresponding aminoketones. All the phenylketo bases yield only one of the two possible diastereoisomeric 1-phenyl-l-methyl-3-aminopropan-1-ol while the corresponding methylketo bases yield the other diastereoisomer. The ratios of mixture of diastereoisomers are determined and the steric configurations assigned.
Tetrahedron Lett., Vol.13, pp. 2329-2332, provides the synthesis of several pure erythro-and threo-aminoalcohols by reduction of the corresponding a-aminoketone with lithium aluminium hydride as well as by the treatment of the corresponding a-aminoaldehydes with Grignard reagents. The erythro/threo product ratio is dependent on
the size of the NR2 group.
Tetrahedron, Vol. 25, pp. 4211-4216 describes a study on the stereospecific synthesis of (+) or (-)-l-phenyl-l,2-dimethyl-3-dimethylaminopropanols using suitable

Grignard reagents with phenylketo base (1) or methylketo base (II). The stereochemistry of Mannich keto bases is reported in order to clarify the stereochemistry of reactions between a-substituted P-aminoketones and Grignard reagent. The absolute configuration of (+)-a-methyl-p-dimethylaminopropiophenone is found to be S by chemical correlation with (R)-(-)-a-methyl-P-alanine.
In Tetrahedron Lett., Vol. 31, No. 38, pp. 5479-5482, 1990, a selective synthesis of either enantiomer of tertiary alcohol starting from the same chiral carbonyl compound by a suitable choice of organometallic reagent has been reported. In this method, the unique affinity of sulfur atom to metals has been exploited.
Cram and Elhafez in 1952, describe in detail (J.Am.Chem.Soc, Vol.74, pp. 5828-5835) the "Cram's rule" of steric control of asymmetric induction applicable in correlating and predicting the stereochemistry of asymmetric induction in reactions of acyclic systems in which a new asymmetric centre is created adjacent to an old one.
Tetrahedron Lett., Vol. 32, No. 25, pp. 2919-2922, 1991 discloses that the reaction of chiral 2-acyloxazolidines, derived from S-prolinol, with organometallics was found to be diastereoselective giving rise to S-or R-tertiary alcohols depending on the organometallic reagent used.
Further in the Angew.Chem.Int.Ed., 2004, Vol. 43, pp. 284-287, a method for synthesis of a variety of chiral tertiary alcohols by catalytic enantioselective addition of unreactive zinc reagents to poorly electrophilic ketones in presence of a chiral ligand is described in excellent diastereoselectivity.
Thus in the prior art, chiral tertiary alcohols are prepared using Grignard and organometallic reagents. The application of the Crams rule is used to predict the stereochemistry of the resultant alcohols. Excellent enantioselectivity was observed only when chiral catalysts were employed. But no reports were found on optically pure 1 -alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and their method of preparation.
The present invention relates to the compounds of the Structural formula -1

namely optically pure l-alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochloride wherein R is alkyl and aryl group.
In a preferred embodiment of the present invention, a process for the preparation of the compounds of formula (1) in which the compound corresponding to structural formula (2)

namely chiral l-phenyl-2-methylamino-l-propanone are subjected to treatment with aiyl/alkyl Grignard reagent in the presence of organic solvents leading to only one of the diastereomer either erythro/threo in high optical purity (99-100%) and yield (65-75%) as the first crop
Specifically, the object of the present invention is to provide a new process for optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides by stereospecific addition of aryl/alkyl Grignard reagent to the chiral 1-phenyl-2-methylamino-1-propanone after liberating the base from the corresponding hydrochloride salts, in the presence of organic solvents

Objectives of the invention
The main objective of the present invention is to provide new optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides of the (Structure-!)
Another objective of the present invention is to provide a new process for the synthesis of optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides of the (Structure-1).
Another objective of the present invention is to provide a process for optically purealkyl/aryl-l-phenyl-2-methylaminopropanolhydrochlorides by the stereospecific addition of alkyl/aryl Grignard reagents chiral l-phenyl-2-methylamino-l-propanones in the presence of solvents of the type dialkyl/alicyclic ethers.
Yet another objective of the present invention is to provide a process to isolate optically alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides in 65-75% yield as the first crop.
Still another objective of the present invention is to provide process for the preparation of (+) or (-)-alkyl/aiyl-l-phenyl-2-methylaminopropanol hydrochlorides in optically pure form (99-100%).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention relates to optically pure alkyl/aryl-1-phenyl-2-methylaminopropanolhydrochlorides. According to another embodiment of the present invention there is provided a new process for the preparation of optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides by the addition of alkyl/aryl Grignard reagent to chiral 1-phenyl-2-methylamino-1-propanones which comprises
1) adding of Mg metal to dialkyl/alicyclic ethers
2) adding of the catalyst to the resulting solution
3) adding of alkyl/arylhalide dissolved in organic solvent to the solution obtained in step (2) in 5 min to 10 h and heating the solution to reflux for a period ranging from 15 min to 24 h.
4) adding of 1 -phenyl-2-methylamino-1-propanone dissolved in organic solvent to the solution obtained in step (3) at a temperature in the range from -30 °C to +100 °C for a period of 5 min to 10 h.
5) stirring the resulting solution for a period ranging from 15 min to 24 h.
6) quenching the resulting solution of step (5) in to a salt solution and extracting the product alkyl/aryl-l-phenyl-2-methylaminopropanols in an organic solvent.

7) drying the organic solvent layer containing the product alkyl/aryl-1-phenyl-2-
methylaminoproDanols obtained in step (6) with solid drying agent and concentrating under vacuum.
8) adding of organic solvent to the resulting mass obtained in step (7) and acidifying to pH by passing dry HC1 gas in the range 1.0 to 6.0 to obtain the crude alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochloride.
9) recrystallising the crude product obtained in step (8) using organic solvent or water.
10) obtaining physical data and spectroscopic data (IR, H NMR, C NMR and mass spectra) to confirm the structure of the product.
The solvent used in step (1) may be selected from dialkyl/alicyclic ether preferably diethyl ether. The catalyst used to initiate the Grignard reaction in step (2) is chosen from iodine, dibromo ethane, ethyl iodide preferably iodine. The solvent used in step (3) for dissolving aryl/alkyl halide is selected from organic solvents preferably diethyl ether. The aryl/alkyl halide used in step (3) may be selected from aralkyl chloride or aralkyl bromide or aralkyl iodide preferably aralkyl bromide. The addition of aryl/alkyl halide in step (3) is effected in 5 min to 10 h preferably 2 h and resulting solution in step (3) is refluxed for a period of 15 min to 24 h preferably 4 h. The solvent used for dissolving l-phenyl-2-methylamino-l-propanones in step (4) is selected from organic solvents preferably diethyl ether. The l-phenyl-2-methylamino-l-propanones used in step (4) is chosen from isomers of l-phenyl-2-methylamino-l-propanones. The addition of 1-phenyl-2-methylamino-1-propanones in step (4) is carried at a temperature range of-30 °C to +100 °C preferably 30-35 °C for a period ranging from 5 min to 10 h preferably 1 h. The resulting solution is stirred for a period ranging from 5 min to 24 h preferably 8 h. The resulting solution of step (6) is quenched into a salt solution, the salt used is selected from nonmetal halides preferably ammonium chloride. The product alkyl/aryl-1-phenyl-2-methylaminopropanols obtained in step (6) is extracted using organic solvents preferably ether. The organic solvent layer containing the product obtained in step (7) is dried with solid drying agent preferably anhydrous sodium sulphate before concentrating under vacuum.
The organic solvent added in step (8) is selected from organic solvents preferably diethyl ether, which is acidified by passing dry HC1 gas to pH in the range between 1.0 to 6.0 preferably 3.0 to obtain crude alkyl/aryl-1-phenyl-2-methylaminopropanol as hydrochloride salt The crude product obtained in step (9) is recrystallised using organic solvents like acetone and /-propyl alcohol.
The structure of the final product obtained in step (10) is confirmed using physical and spectroscopic data.

The details of the invention are given in the examples given below which are provided
solely to illustrate the invention and therefore should not be construed to limit the scope of the invention.
Example 1
Preparation of erythro-(lS,2R)-a-(+)-l-rt-mefliyI-l-phenyl-2-methylaminopropanol hydrochloride
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and the mixture was slightly warmed. To this, methyl iodide (46g, 0.3 mol) was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the methylmagnesium iodide, (2R)-(+)-l-phenyl-2-methylamino-l-propanone (lOg, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction mixture was further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq.NHUCl (5g in 15 mL of water) and
was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone/z-propyl alcohol. Pure white solid of eiythro-(lS,2R)-a-(+)-l-«-methyl-l-phenyl-2-methylaminopropanol hydrochloride was obtained.

Purity by GC 97.2%
Chiral purity . 99.27%
Yield : 70% (9.2g)
mp : 206-208 °C
MD + 13.3°(c = 5%inH20)
Spectroscopic interpretation
The structure of the product, erythro-(lS,2R)-ct-(+)-l-w-methyl-l -phenyl-2-methylaminopropanol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm1) (KBr)
O-H str. at 3327-3279, HN-H str. at 2450, benzenoid bands at 1595 and 1501, ON str. at 1366, CO str. at 1067, CH out of plane bending of mono-substituted benzene ring at 768, 704.
b) 'H NMR (DMSO-dfc 300 MHz) (5H)
0.92 (3H, d, CH-CBb), L64 (3H, s, protons), 8.32-8.53 (2H, 2bs, NH2).

c) 13C NMR (DMSO-d6,300 MHz) (8C)
11.17 (CHCH3), 27.75 (-C-CH3), 31.75 (t^-Nt^ ), 62.73 ( CH-CH3), 73.71 (-C-CH3), 125.37-144.55 (aromatic carbons).
d) Mass spectrum (CI, methanol)
[MH]+ at m/z 180 (49), [MH^- H20] at m/z 162 (8), [CH3-NH=CH-CH3] at m/z 58(100).
Example 2
Preparation of erythro-(lS,2R)-(+)-l-/f-ethyl-l-phenyl-2-methyIaminopropanol hydrochloride
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, «-ethyl bromide (33g, 0.3 mol) dissolved in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the H-ethylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-l -propanone (1 Og, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aqueous ammonium chloride (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using
/-propyl alcohol. Pure white solid of erythro-(l S,2R)-(+)-l -w-ethyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained.

Purity by GC Chiral purity Yield mp

99.0%
98.79%
9.8 g (70%)
204-206 °C
+ 9.68° (c = 5% in H20)

Spectroscopic interpretation
The structure of the product, eiythro-(lS,2R)-(+)-l-/?-ethyl»l-phenyl-2-methylamino-propanol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm1) (KBr)

OH str. at 3345-3308, H^.H str. at 2460, benzenoid bands at 1595 and 1495, C-N str. at
1371, C-O str. at 1034, OH out of plane bending of mono-substituted benzene ring at
764, 702.
b) *H NMR (DMSO-d6,300 MHz) (6H)
^CH3
0.69 (t, 3H, -CH2-CH3), 1.03 (d, 3H, CHCH3), 2.06 (2H, two merging quartets,
+ representing two diastereotopic CH2CH3 protons), 2.59(3H, s, CH3-NH2 ), 3.48 (1H,
m, CH CH3), 5.81 (1H, bs, OH), 7.32-7.51 (m, 5H, aromatic protons), 8.42 (bs, 2H, NH2).
c) 13C NMR (DMSO-d6 ,300 MHz) (5C)
7.54 (-CH2-CH3), 11.29 (-CH-CH3), 30.79 (CH2-CH3), 31.76 (CH3-NH2), 62.82 (-CH-CH3), 76.77 ^C OH), 126.14-141.38 (aromatic carbons).
d) Mass spectrum (CI, methanol)
[MHf at m/z 194(17), [MHf-H20] at m/z 176(19), [CH3-NH=CH-CH3]at m/z 58(100).
Example 3
Preparation of erythro-(lS,2R)-(+)-l-/i-butyH-phenyl-2-methylaminopropanol hydrochloride
Magnesium (7.63g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, n-butyl bromide (42g, 0.3 mol) dissolved in diethyl ether was added slowly in 2h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4h. To the w-butylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-l -propanone (1 Og, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq. NH4C1 (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone. Pure white solid of erythro-(l S,2R)-(+)-l -w-butyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained.
Purity by GC 98.3%
Chiral purity 100%

Yield 72%(11.5g)
mp 176-178 °C
[afD +10.0°(c = 5%inH2O)
Spectroscopic interpretation:
The structure of the product, eiythro-(lS,2R)-(+)-l-w-butyl-l-phenyl-2-methylamino-propanol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm"1) (KBr)
OH str. at 3304, HN-Hstr. at 2450, benzenoid bands at 1591 and 1499, ON str. at 1369, CO str. at 1013, OH out of plane bending of mono-substituted benzene ring at 766, 706.
b) *H NMR (DMSO-d6,300 MHz) (5H)
Hb
0.82 (3H, t, ~(CH2)3-CH3), 0.84 (1H, m, HO-C-C' ), l.02(3H, d, CHCH3), 1.25 (2H, m, CH2CH3), 1.30 (1H, m, HO-C-C' ) 2.02 (2H, m, -CH2-CH2 CH3), 2.59(3H, s,
3
+
CH3-NH2), 3.46 (1H, m, ^HCH3), 5.80 (1H, bs,-OH), 7.31-7.50 (5H, m, aromatic
protons), 8.31-8.47 (2H, bd, NH2 ).
Ha and Hb are two diastereotopic hydrogens adjacent to the chiral carbon atom.
c) 13C NMR (DMSO-d6,300 MHz) (8C)
11.20 eCH2-CH3), 13.86 (-CHCH3), 22.32 (CH2CH3), 25.02 (-CH2-CH2CH3), 31.78
+
(-CH2-OOH), 3786 (CH3-NH2 )? 63.03 (-CH-CH3), 76.45 (^-OH), 126.03-141.70 (aromatic carbons).
d) Mass spectrum (CI, methanol)
[MH]+ at m/z 222(56), [MH'-HzO] at m/z 204(6), [CH3-NH=CH-CH3]at m/z 58(100).
Example 4
Preparation of erythro-(lS»2R)-(+)-l-/i-pentyl-l-phenyI-2-methylaminopropanol hydrochloride:
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, n-pentyl bromide (46g, 0.3 mol) dissolved in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the n-pentylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-1 -propanone (lOg, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].

The reaction was quenched in saturated aq. NH4CI (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained was filtered and recrystallised by using acetone. Pure white solid of eiythro-(lS,2R)-(+)-l-w-pentyl-l-phenyl-2-methylaminopropanol hydrochloride was obtained.

Purity by GC 96.8%
Chiral purity 100%
Yield 10g(66%)
mp 160-162 °C
MD + 12.8°(c = 5%inH20)
Spectroscopic interpretation:
The structure of the product, eiythro-(l S,2R)-(+)-l -w-pentyl-1 -phenyl-2-
methylaminopropanol hydrochloride was confirmed with the help of the following
spectroscopic data.
a) IR (cm1) (KBr)
OH str. at 3337-3318, HN-H str. at 2446, benzenoid bands at 1576-1499, ON str. at 1379, CO str. at 1051, OH out of plane bending of mono-substituted benzene ring at 760, 704.
b) *H NMR (DMSO-d6,200 MHz) (8H)
0.77-1.17 (12H, m, OH2 (Cfib^ CH3, -CHCH3), 2.01 (2H, m,-CH2-CH2-C-OH), 2.56
(3H, s, CH3-NH2 ), 3.49 (1H, m, -CHCH3), 5.73 (1H, m, -OH), 7.42 (5H, m, aromatic
+ protons), 8.59 (2H, bd, Mi,).
The signals of the diastereotopic methylene hydrogens of the n-pentyl group appear to have merged with those of the rest of the chain.
c) 13C NMR (DMSO-d6,200 MHz) (8C)
9.87 (-CH2CH3), 12.43 (-CHCH3), 20.51 ( CH2-CH3), 21.10 (rCH2-CH2 CH3), 30.07
(CH3 CH2^CH2-CH2C-OH), 30.39 (CH3CH2CH2- CH2COH), 36.81 (CH3-NH2), 61.71 ( CH CH3), 75.21 ( C OH), 124.05-140.53 (aromatic carbons).
d) Mass spectrum (EI)
[M]+> at m/z 236( m/z 146(2), (C6H5CO)+ at m/z 105 (3), [CH,-NH=CH-CH3] at m/z 58(100).

Example 5
Preparation of erythro-(lS^2R)-(+)-l-/f-heptyH-phenyl-2-methyIaminopropanol hydrochloride:
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly wanned. To this, n-heptyl bromide (55g, 0.3 mol) dissolved in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. Tothe rt-heptylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-l -propanone (lOg, 0.0613 mol) dissolved in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were fiirther stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq.NHtCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone. Pure white solid of erythro-(l S,2R)-(+)-l -w-heptyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained.

Purity by GC 96.8%
Chiral purity 100%
Yield 10.6g (66%)
mp 160-162 °C
[a]D + 12.8°(c = 5%inH20)
Spectroscopic interpretation:
The structure of the product, erythro-(lS,2R)-(+)-l-n-heptyl-l-phenyl-2-methylaminopropanol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm1) (KBr)
OH str. at 3362, HN-Hstr. at 2444, benzenoid bands at 1584,1495, ON str.at 1342, CO srr. at 1055, OH out of plane bending of mono-substituted benzene ring at 758, 702.
b) *H NMR (DMSO-ds, 300 MHz) (6H)
0.82 (4H, m, CH2- CH3, H0_c \?>r), 0.96 (d, 3H, -CH-€Hj), 1.20 (9H, m,
Ha
HO_c~^~bCH~iQUli~), 1-97 (2H, m, -CH2-CH2-C-OH), 2.54 (3H, s, CH3-NH2 ), 3.49 (IH, m, CH-CH3), 5.78 (IH, bs, -OH), 7.26-7.44 (5H, m, aromatic protons), 8.17-8.37

(2H, two bs,NH2). The Ha and Hb are two diastereotopic hydrogens adjacent to a chiral carbon atom,
c) !3C NMR (DMSO-d6,300 MHz) (5C)
11.22 ( CH2-£H3), 13.87 (CH-£H3), 21.97 ( £H2CH3), 22.75 e£H2~CH2-CH3), 28.50 (rCH2 (CH2)2<:h3> (-CH2-(CH2)5-CH3), 38.09 (CH3-NH2), 63.05 (^H^H3), 76.49 (-C-OH), 126.04-141.70 (aromatic carbons).
d) Mass spectrum (CI, methanol)
MH*at m/z 264(29), [MH^O] at m/z 246(32), C6H5C+(OH) (C7H15) at m/z 205(7) and
[CH3-NH=CH-CH3]at m/z 58(100).
Example 6
Preparation of erythro-(lR,2S)-(+)-l-jp-tolyH-phenyl-2-methy!aminopropanol hydrochloride:
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, p-bromo toluene (54g, 0.3 mol) in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the p-tolylmagnesium bromide, (2R)-(+)-l-phenyl-2-methylamino-l-propanone (10g, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq.NFLiCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and diy HC1 gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and reciystallised by using /-propyl alcohol. Pure white solid of erythro-(lR,2S)-(+)-l-p-tolyl-l-phenyl-2-methylamino-propanol hydrochloride was obtained.

Purity by GC 99%
Chiral purity 99.6%
Yield 13g(73%)
mp 218-220 °C
[a]D + 32.3°(c = 5%inCH3OH)
Spectroscopic interpretation:
The structure of the product erytiiro-(lR,2SH+)-l-/7-tolyl-l-phenyl-2-methylamino propanol hydrochloride was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
OH str. at 3281, HN-H str. 2413, benzenoid bands 1591 and 1516, ON str.1375, OO str. 1030, OH out of plane bending of mono-substituted benzene ring 762, 708.
b) !H NMR (DMSO-d6, 200 MHz) (5H)
1.12 (3H, d, CH-CH3), 2.27 (3H, s, benzylic CH3), 2.48 (3H, s, CHj-NHa), 4.63 (1H, q,
-CH-CH3), 6.60 (1H, bs, -OH), 7.15-7.61 (9H, m, aromatic protons), 8.78 (2H, bs, NH,).
c) 13C NMR (DMSO-de, 200 MHz) (8C)
10.62 (-CH-CH3), 19.10 (benzylic carbon), 30.93(CH3-NH2), 59.19 (-CH-CH3), 77.0 ( C OH), 124.11-143.33 (aromatic carbons).
d) Mass spectrum (CI, methanol)
Mtf at m/z 256(26), [Mtf-HzO] at m/z 238(18), [CH3-NH=CH-CH3] at m/z 58(100).
Example 7
Preparation of erythro-(lR,2R)-(+)-a-l-naphthyl-l-phenyl-2-methylaminopropanol hydrochloride:
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this 1-bromonaphthalene (65g, 0.3 mol) in diethyl ether was added slowly 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the 1 -naphthylmagnesium bromide, (2R)-(+)-l -phenyl-2-methylamino-1 -propanone (1 Og, 0.0613 mol) in diethyl ether was added slowly inl h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq.NHiCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and recrystallised by using acetone. Pure white solid of erythro-(lR,2R)-(+)-a-(l-naphthyl)-l-phenyl-2-methylaminopropanol hydrochloride was obtained.
Purity by GC 99.8%
Chiral purity 100%
Yield 15g(74%)
mp 298-300 °C
[a]D : + 145° (c = 5% in CH3OH)

Spectroscopic interpretation:
The structure of the product, erythro-(lR,2R)-(+)-a-(l-naphthyl)-l-phenyl-2-methylaminopropanol hydrochloride was confirmed with the help of the Following
spectroscopic data.
a) IR (cm1) (KBr)
O-H str. at 3273, HN-H str. at 2461, benzenoid bands at 1593, 1506, ON str. at 1341, C-0 str. at 1020, OH out of plane bending of mono-substituted benzene ring at 777, 710.
b) XH NMR (DMSO-de, 300 MHz) (5H)
1.16 (3H, d, -CH-CH3), 2.71 (3H, s, CH3-NH2 ), 4.45 (1H, bs, -€H-CH3), 6.92 (1H, bs, -
OH), 7.17-7.95 (12H, m, aromatic protons), 8.10-8.13 (2H, two bs, NB).
c) 13C NMR (DMSO-d6,300 MHz) (8C)
13.13 (-CH-€H3), 32.43 (CH3-NH2 ), 61.50 (-CHCH3), 78.65 (~C-OH), 123.95-142.11 (aromatic carbons).
d) Mass spectrum (CI, methanol)
MH" at m/z 292(6), [MH^O] at m/z 274(99), [C6H5C+ (OHXC10H7)] at m/z 233(10)
*
and [CH3-NH=CH-CH3]at m/z 58(100). Example 8
Preparation of eryfliro-(lS,2S)-(-)-a-(l-naphthyI-l-phenyI-2-methylaminopropanoI hydrochloride:
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this 1-bromonaphthalene (65g, 0.3 mol) in diethyl ether was added slowly in 2h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4h. To the 1-naphthylmagnesium bromide, (2S)-(-)-l-phenyl-2-methylamino-l-propanone (10g, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2; hexane 8].
The reaction was quenched in saturated aq. NH4CI (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and reciystallised by using acetone. Pure white solid of erythro-(lS,2S)-(-)-a-(l«naphthyl-l-phenyl-2-methylaminopropanol hydrochloride was obtained.

Purity by GC 97.02%
Chiral purity 100%
Yield 14.6g (72%)
mp 292-296 °C
MD -142°(c = 5%inCH3OH)
Example 9
Preparation of racemic-(lS^S)(lR^R)-(±)-a-(l-naphthyl-l-phenyl-2-methyIamino-propanol hydrochloride:
Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this 1-bromonaphthalene (65g, 0.3 mol) in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the 1-naphthylmagnesium bromide, (2RS)-(±)-l-phenyl-2-methylamino-l-propanone (10g, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq. NH4CI (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HC1 gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained was filtered and recrystallised by using acetone. Pure white solid of racemic-(lS,2S)(lR,2R)-(±)-a-(l-naphthyl-l-phenyl-2-methylamino-propanol hydrochloride was obtained.

Purity by GC Chiral purity
Yield mp
[a]D

96.05%
100%
14.2g(70%)
268-272 °C
0° (c = 5% in CH3OH)

Example 10
Preparation of hydrochloride:

erythro-(lR,2S)-(-)-l-benzyH-phenyl-2-methylaminopropanol

Magnesium (7.36g, 0.3 mol) was taken in diethyl ether (30 mL) under nitrogen atmosphere, a pinch of iodine was added and was slightly warmed. To this, bromobenzene (52g, 0.3 mol) in diethyl ether was added slowly in 2 h to initiate the reaction. After complete addition, the reaction mixture was refluxed for 4 h. To the benzylmagnesium bromide, (2R)-(+)-l-phenyl-2-methylamino-l-propanone (lOg, 0.0613 mol) in diethyl ether was added slowly in 1 h at 30-35 °C. The reaction products were

further stirred for 8 h. The completion of the reaction was monitored using thin layer chromatography [ethyl acetate 2, hexane 8].
The reaction was quenched in saturated aq.NHUCl (5g in 15 mL of water) and was extracted in 50 mL of tert-butyl methyl ether. The ether layer was dried over sodium sulphate and concentrated under vacuum. To the concentrated mass, diethyl ether (25 mL) was added and dry HCl gas was passed till it became acidic to a pH of 3.0. Pale white precipitate was obtained which was filtered and reciystallised by using acetone. Pure white solid of erythro-(lR,2S)-(-)-l -benzyl-1 -phenyl-2-methylaminopropanol hydrochloride was obtained.

Purity by GC 97.9%
Chiral purity 100%
Yield 65%(10g)
mp 248-250 °C
fab -62° (c = 5% in H20)
Spectroscopic interpretation:
The structure of the product, erythro-(lR,2S)-(-)-l-benzyl-l-phenyl-2-methylamino- propanol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm1) (KBr)
OH str. at 3337, HN-Hstr. at 2546, benzenoid bands at 1578, 1493, ON str. at 1381, C-0 str. at 1051, OH out of plane bending of mono-substituted benzene ring at 768, 756, 723, 702.
b) *H NMR (DMSO-dfi, 300 MHz) (8H)
1.11 (3H, d, -CH-CH3), 2.51 (3H, s, CH3-NH2 ), 3.22 (1H, d, H, of benzylic group
u. _ >
-C^-C6H5) 3 38 (1Ij5 m> _CH<:h3 hb of benzylic group ha> and Hb are the two benzylic diastereotopic protons], 6.09 (1H, s, -OH), 7.10-7.47(1 OH,
+ m, aromatic protons), 8.25-8.52 (2H, two bs, NHj).
c) 13C NMR (DMSO-d6,300 MHz) (6C)
11.36 (-CH-CH3), 31.92 (CH3-NH2), 43.31 (-CH2-QH5), 62.52 (-CH-CH3), 76.70 (OOH), 125.89-140.78 (aromatic carbons).
d) Mass spectrum (CI, methanol)
+
MIT at m/z 256(70), [MlT-HiO] at m/z 238(100), C6H5C(OH)(CH2C6H5) ^ m/z ]9? (lg) and [CH3-NH=CH-CH3]at m/z 58(72).

Advantages of invention
1. The products obtained in the present invention are not reported in the literature and hence new.
2. The products described in the invention are expected to show therapeutic properties.
3. The presence of these alkyl/aryl groups in a-position with respect to the benzene ring is expected to show lower toxicity.
4. The products obtained using the above said processes are optically pure.
5. The process described above gives highly enantioselective products.
6. The process lead to new products in good yields.
We claim
1. New optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides
and the process for their preparation by the addition of alkyl/aryl Grignard reagent to chiral l-phenyl-2-methylamino-l-propanone which comprises
i) adding of Mg metal to dialkyl/alicyclic ethers
ii) adding of the catalyst to the resulting solution
iii) adding of alkyl/arylhalide dissolved in organic solvent in to the solution obtained in step (ii) in 5 min to 10 h and heating the solution to reflux for a period ranging from 15 min to 24 h.
iv) adding of chiral l-phenyl-2-methylamino-l-propanone dissolved in
organic solvent to the solution obtained in step (iii) at a temperature in the range from -30°C to +100°C slowly for a period of 5 min to 10 h. Stirring the resulting solution for a period ranging from 15 min to 24 h.
v) quenching the resulting solution of step (iv) into a salt solution and
extracting the product alkyl/aryl-l-phenyl-2-methylaminopropanols in organic solvent.
vi) drying the organic solvent layer containing the product alkyl/aryl-1-
phenyl-2-methylaminopropanols obtained in step (v) with solid drying agent before concentrating under vacuum.
vii) adding organic solvent to the resulting mass obtained in step (vi) and
acidifying by using diy hydrochloride gas to pH in the range 1.0 to 6.0 preferably 3.0 to obtain the crude alkyl/aryl-l-phenyl-2-methylamino-propanol as HC1 salt.

viii) recrystallising the crude product obtained in step (vii) using organic solvent or water.
2. The new optically pure alkyl/aryl-l-phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claim 1 where in the solvent used in step (i) is selected from dialkyl/alicyclic ethers preferably diethyl ether.
3. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claims 1 to 2 wherein the catalyst used in step (ii) to initiate the Grignard reaction is chosen from iodine, ethyl bromide, dibromoethane and ethyl iodide preferably iodine.
4. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claim 1 to 3 wherein the solvent used for dissolving aiyl/alkyl halide in step(iii) is selected from organic solvents preferably diethyl ether. The aryl/alkyl halide used in step (iii) is selected from aralkyl chloride or aralkyl bromide or aralkyl iodide preferably aralkyl bromide is added for a period ranging from 5 min to 10 h preferably 2 h and refluxed for a period of 15 min to 24 h preferably 4 h.
5. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanol hydrochlorides and the process for their preparation as claimed in claims 1 to 4 where in l-phenyl-2-methylamino-l-propanone used in step(iv) is chosen from the isomers R(+) or S(-)-l-phenyl-2-methylamino-l-propanone. The organic solvent used for dissolving!-phenyl-2-methylamino-l-propanone is chosen from organic solvents like diethyl ether and the addition is carried at a temperature range of-30 °C to +100 °C preferably 30-35 °C in 5 min to 10 h preferably 1 h. The resulting mass is stirred for a period ranging from 15 min to 24 h, preferably 8h.
6. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 5 wherein salt used in solution in step (v) is selected from nonmetal halides preferably ammonium chloride and extraction of the product alkyl/aryl-1 -pheny 1-2-methylamino-propanols is effected in organic solvents preferably tert-butyl methyl ether.
7. The new optically pure alkyl/aryl-1 -pheny 1-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 6 where in organic solvent layer containing the product is dried in step (vi) using solid drying agent preferably anhydrous sodium sulphate before concentrating under vacuum.
8. The new optically pure alkyl/aryl-1 -phenyl-2-methylaminopropanols and the process for their preparation as claimed in claims 1 to 7 where in solvent added in step (vii) is selected from organic solvents preferably tert-butyl methyl ether and the resulting solution is acidified bv using dry HC1 gas to pH in the range 1.0 to

6.0 preferably 3.0 to obtain the crude aIkyl/aryl-l-phenyl-2-methylamino-propanols as HC1 salt.
9. The new optically pure alkyl/aryl-l-phenyl-2-methylaminopropanols and the
process for their preparation as claimed in claims 1 to 8 wherein the solvent used for recrystallisation in step (viii) is selected from organic solvents or water preferably acetone or /-propyl alcohol.

Documents:

1210-CHE-2007 AMENDED PAGES OF SPECIFICATION 23-01-2012.pdf

1210-CHE-2007 AMENDED CLAIMS 23-01-2012.pdf

1210-CHE-2007 AMENDED PAGES OF SPECIFICATION 11-02-2013.pdf

1210-CHE-2007 CORRESPONDENCE OTHERS 11-02-2013.pdf

1210-CHE-2007 FORM-1 23-01-2012.pdf

1210-CHE-2007 CORRESPONDENCE OTHERS 23-09-2010.pdf

1210-CHE-2007 CORRESPONDENCE OTHERS 27-01-2011.pdf

1210-CHE-2007 EXAMINATION REPORT REPLY RECEIVED 23-01-2012.pdf

1210-CHE-2007 FORM-13 27-01-2011.pdf

1210-che-2007-abstract.pdf

1210-che-2007-claims.pdf

1210-che-2007-correspondnece-others.pdf

1210-che-2007-description(complete).pdf

1210-che-2007-form 1.pdf

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Patent Number

255479

Indian Patent Application Number

1210/CHE/2007

PG Journal Number

09/2013

Publication Date

01-Mar-2013

Grant Date

26-Feb-2013

Date of Filing

12-Jun-2007

Name of Patentee

MALLADI DRUGS & PHARMACEUTICALS LTD

Applicant Address

52 JAWAHARALAL NEHRU ROAD EKKATTUTHANGAL CHENNAI-600097

Inventors:

#	Inventor's Name	Inventor's Address
1	TANGIRALA PRAKASAM	PLOT NO.12,3RD FLOOR "T1" "SRIPRIYAS MANANSA V.V.KOIL STREET , CHINMAYA NAGAR CHENNAI-600 092
2	DR.DEVALLA VENKATA RAMANA	NO.8 AYODHYA COLONY, VELACHERI,CHENNAI-600 042
3	DR.PATHANGI SAMPATH SRINIVASAN	NO.49/4 CAR STREET , TRIPLICANE ,CHENNAI-600 005
4	BORKATTE NARASIMA HITESHKUMAR	NO.103 STREET ,A.P.BLOCK, 14TH SECTOR ,K.K.NAGAR, ADYAR,CHENNAI-600 020
5	DR.BANUMATHI ARABINDOO	NEW NO.25(OLD NO.6/2),3RD STRRET, PARAMESWARI NAGAR, ADYAR ,CHENNAI-600020

PCT International Classification Number

A61K39/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA