Title of Invention

OPTICALLY PURE 1-N-ALKYLAMINO-1-PHENYL-2-(1-PYRROLIDINYL) PROPANE HYDROCHLORIDES AND THEIR SYNTHETIC PROCESSES

Abstract

This process involves the initial alpha-chlorination of l-phenyl-2-(1 -pyrrolidinyl)propane-l-ol hydrochloride with thionyl chloride to obtain the chloro derivative at carbon-1, namely, l"Chloro-l-phenyI-2-(l-pyrrolidinyl)prepare hydrochloride. The chloro compound is then subjected to nucleophilic substitution reactions at carbon -1 with excess of alkylamines. This process involves two Walden inversions leading to the retention of configuration with the same stereochemistry in the final product as in the starting molecule.

Full Text

FIELD OF INVENTION The present invention relates to new optically pure l-N-alkylamino-l-phenyl-2-(l-pyrrolidinyl)propane hydrochlorides (formula-1) and process for their preparation via formation of novel intermediate 1 -chloro-1 -phenyl-2-(l -pyrrolidinyl)propane hydrochloride (formula-2) by chlorination of l-phenyl-2-(l-pyrrolidinyl)propane-l-ol hydrochloride (formula-3) with thionyl chloride followed by reaction with excess of alkyl amine . BACKGROUND OF INVENTION Amination reactions constitute an important class of regiospecific substitution reactions in view of their impact on the mechanistic and synthetic organic chemistry as well as their commercial applications. Optically pure l-N-alkylamino-l-phenyl-2-(l-pyrrolidinyl)propanes belong to the family of 1,2-diamines. The products of a-amination such as diamines and triamines and their derivatives are known to have vital applications such as chelating agents in radiopharmaceuticals [J. Org. Chem., Vol. 54, pp.1940-1943 (1989)], precursors of aza-macrocycles (Lehn , Ace. Chem. Res., Vol. 11, pp. 49-57,1978) and in medicinal chemistry (Kasina, J. Med. Chem., Vol. 29, pp. 1933-1940, 1986). They also play a vital role as chiral auxiliaries in a variety of asymmetric transformations involving chiral phosphonamides, [J. Am. Chem, Soc, Vol. 106, pp. 5754-5756. (1984)] Lewis acids, metal enolates [(Corey J. Am. Chem. Soc, Vol. Ill, pp. 5493-5495. 1989)], dienophiles (Tetrahedron Lett., Vol. 28, pp. 2681.1987) and transition metal reagents (Bull. Chem. Soc.Jpn., pp. 2012-2015. 1980). N-Alkylated derivatives of (1 R,2 S)-(-)-ephedrine, (1 R,2R)-(")-pseudo-ephedrine and (IR, 2S)-(-) norephedrine are excellent substrates for regiospecific a-amination reactions via the intermediacy of reactive a-halo or a-ester derivatives such as mesylates, tosylates etc. These substitution reactions could be with sodium azide, amines, imides, thiols, thiolactic acid, n-hydroxyphthalimide and diphenylphosphine to give, in each case, a single isomer. The methods for preparing the vicinal diamines are rather limited, particularly when other sensitive functionalities are present elsewhere in the molecule. Olefins react with azide anion oxidatively to form vicinal diazides (Fristad , J. Org. Chem., Vol. 50, pp. 3647-3649 (1985), Moriarty 1986, Becker 1980). The reduction of these diazides to diamines is prone to alternative reactions and requires careful selection of reductants. Another drawback of the use of azides is their possible explosiveness. J.Org.Chem.,Vol. 54, pp.1940-1943 (1989) describes the use of the readily available and inexpensive l,3-diamino-2-propanols as starting materials for the synthesis of diamines. J.Org.Chem., Vol. 57, pp. 1663-1671 (1992) highlights methods of synthesis for amines and triamines for use as ligands in organocopper conjugate addition reactions with ephedrine and pseudoephedrine as starting aminoalcohols. The |3-hydroxy tertiary amines were prepared by alkylation of (IR, 2S)-(-)-ephedrine, (lR,2R)-(-)-pseudo-ephedrine with a-chloro-N, N-dimethylacetamide. These P-hydroxy tertiary amines were mesylated in-situ with methanesulphonyl chloride in THF in presence of triethylamine and then treated with various amines and the corresponding diamines were isolated. Treatment of the mesylate in-situ with sodium azide gave the corresponding azide, which on reduction with lithium aluminium hydride gave the triamine . Organic Syntheses, Coll.Vol.lO, p.556 , Vol. 77, p. 12.(2000)describes the method for preparing diamine by N,N-bis alkylation of norephedrine with 1,4-dibromobutane and subsequent double inversion of the benzylic stereogenic centre in N-pyrrolinylnorephedrine. Thus, treatment of (1 R,2S)-norephedrine with 1,4-dibromobutane, tetra-butylammonium iodide and sodium carbonate in refiuxing THF for 48 h followed by mesylation and reaction with methylamine gave the expected diamine (lR,2S)-l-N-methyl-l-phenyl-2-N-pyrrolidinylpropanamine in 83% overall yield as the only diastereoisomer as confirmed by1H NMR. The other diastereoisomer was prepared by a similar approach in 84% yield from (IS, 2R)-norephedrine. J.Org.chem., Vol .26, pp.3507-3509 reports synthetic procedure for (IS, 2S)-norpseudoephedrine hydrochloride involving Mitsunobu cyclisation and conversion to the required (IS, 2S)-1-N-methyl-l-phenyl-2-N-pyrrolidinylpropanamine. The structure of the propanamine was confirmed by H and C NMR. Tetrahedron; Asymmetry, Vol. 10, pp. 4175-4182 (1999) describes the use of (IR, 2S)-l-N-methyl-l-phenyl-2-N-pyrrolidinylpropanamine as chiral base. Tetrahedron: Asymmetry, Vol. 14, pp. 1995-2004, (2003) reports synthesis of (R*,R*)-benzyl-(1, 2'-diphenyl-2-pyrrolidin-l-yl-ethyl)amine in a four step synthetic sequence starting from 1,2-diphenylethene with a low but significant enantioselectivity (15%) and yield of 82%. Another report by Peters and co-workers (Org. Lett., Vol. 7, pp. 4137-4140, 2005) highlights a four-step synthetic sequence starting from (-)-ephedrine and (+)-pseudo-ephedrine by converting the amino alcohols to the corresponding sulfamidates followed by hydrazinolysis giving rise to the chiral diamines Amedj Kouth and co-workers (Chem. Eur. J., Vol. 7, pp. 4368-4377, 2001) have reported improved stereoselectivity by using chiral lithium amide of (lR,2S)-l-N-methyl-l-phenyl-2-pyrrolidinylpropanamine in place of lithium diisopropylamide as a bulk base in catalytic deprotonatiom Synthesis of S-cyclohex-2-en-l-ol in 93% enantiomeric excess from cyclohexene oxide in 96% chemical yield has also been reported by these authors. Chem. Commun., pp.1521-1522. (2000) describes the role of 1-N-methyl-l-phenyl-2-pyrrolidinylpropanamine as a chiral catalyst. Reaction of epoxide with the lithium amide derived from racemic l-N-methyl-l-phenyl-2-pyrrolidinylpropanamine in cyclopentane resulted in diastereomeric product in 89%yield. Keeping in view the importance of chiral di and triamines in development of new drugs and also in various other fields as mentioned above, it is aimed to develop a simple one pot synthesis for 1 -N-alkylamino-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochlorides via formation of intermediate 1 -chloro-1 -phenyl-2-( 1 -pyrrolidinyl) propane hydrochloride from l-phenyl-2-(l-pyrrolidinyl)propan-l-ol hydrochloride. OBJECTIVES OF THE PRESENT INVENTION Accordingly the main objective of the present invention is to provide new chiral 1 -N-alkylamino-1 -phenyl-2-(l -pyrrolidinyl )propane hydrochlorides of the formula-1 and their intermediate 1-chloro-l-phenyl-2-(l-pyrrolidinyl)propane hydrochloride of the formula-2. Another objective of the present invention is to provide processes for the preparation of the above-mentioned new compounds which involves the initial alpha-chlorination of 1-phenyl-2-(l-pyrrolidinyl)propane-l-ol hydrochloride to obtain the chloro derivative at carbon-1, namely, 1 -chloro-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochloride. The chloro compound is then subjected to nucleophilic substitution reactions at carbon -1 with excess of alkyl amines to yield chiral 1 -N-alkylamino-1 -phenyl-2-( 1 -pyrrolidinyl) propane hydrochlorides. This process involves two Walden inversions leading to the retention of configuration with the same stereochemistry in the final product as in the starting molecule. Yet another objective of the present invention is to provide processes for the 1 -N-alkylamino-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochlorides and their intermediate 1-chloro-l-phenyl-2-(l-pyrrolidinyl)propane hydrochloride from 1-phenyl- 2-(l-pyrrolidinyl)propan-l-ol hydrochloride (formula-3) which can be synthesized from norephedrine. Yet another objective of the present invention is to provide one pot synthetic process for 1 -N-alkylamino-1 -phenyl-2-(l -pyrrolidinyl)propane hydrochlorides. Still another objective of the present invention is to provide a new process for the synthesis of l-N-alkyiamino-l-phenyl-2-(l-pyrrolidinyl)propane hydrochlorides , without use of any expensive and hazardous reagents there by making the process not only simple and economical but also eco-friendly. Still another objective of the present invention is to provide a process for synthesis of 1-N-alkylamino-l-phenyl-2- 1-pyrrolidinyl)propane hydrochlorides in high optical purity (99-100%) DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention provides new optically pure 1-N-alkylamino-l-phenyl-2-(l-pyrrolidinyl)propane hydrochlorides of the formula-1 and their intermediate namely l-chloro-l-phenyl-2-(l-pyrrolidinyl)propane hydrochloride (formula-2) Accordingly the present invention provides new process for the preparation of 1-N-alkylamino-l-phenyl-2-(l-pyrrolidinyl)propane hydrochlorides of the formula-1, which comprises. 1. adding of l-phenyl-2-(l-pyrrolidinyl) propan-1-ol hydrochloride to the organic solvent and heating to a temperature ranging from 40-100°C. 2. adding of chlorination reagent to the step-1 solution and maintaining at a temperature of 10-100°C for a period of 15min to 10 h. 3. concentrating the step-2 reaction mass to obtain l-chloro-l-phenyl-2-(l-pyrrolidinyl) propane hydrochloride. 4. adding of organic solvent to the step-3 residue and cooling to -30 to+30°C. 5. adding of amine and maintaining for 15 min to 24h at -30 to +30 °C. 6. concentrating the reaction mass of step- 5 to obtain residue. 7. adding organic solvent to the resulting residue obtained in step-6 and acidifying using dry hydrochloric acid gas to pH in the range 1.0 to 5.0 to obtain the crude 1-alkylamino-1 -phenyl-2-(N-pyrrolidinyl)propane dihydrochloride 8. recrystallising the crude product obtained in step-7 using organic solvents and water. 9. obtaining physical and spectroscopic data (IR,'H NMR13C NMR and mass spectral) of the purified material to confirm the structure of the product. l-Phenyl-2-(l-pyrrolidinyl)propan-l-ol hydrochloride used in step -1 is selected from isomers of pyrrolidinylnorephedrines. The organic solvent used is selected from the group of chloro solvents preferably chloroform. Chlorination agent in step-2 may be HCl, PCI5, POCI3, thionylchloride etc. but preferred is thionyl chloride. Reaction mass of step -2 is maintained at a temp range of 10-100°C for 15min -10 h preferably 2 h. Step -2 mass is further concentrated under vacuum or at atmospheric pressure preferably under vacuum to obtain 1-chloro-1-phenyl-2-(l-pyrrolidinyl) propane hydrochloride. In step-4 organic solvent added is selected from alcohols preferably ethanol and cooling is effected at +30°Cto-30°C preferred is 15°C-20°C. Amine used in step -5 is selected from the group of alkylamines and the resulting mass is maintained for 15 to 24 h preferably 6 h at a temperature range of-30 to +30 °C preferably 15-20°C. Reaction mass in step-6 is concentrated at atmospheric pressure or under vacuum preferably under vacuum. In step-7 organic solvent used is selected from a group of organic solvents such as ethylene dichloride, tert-butylmethyl ether etc. preferably ethyl acetate and acidifying using dry hydrogen chloride gas to pH in the range 1.0 to 5.0 preferably 1.5 to 2.0 to obtain the crude l-N-alkylamino-l-phenyl-2-(l-pyrrolidinyl)propane dihydrochloride. The crude product obtained in step-8 is recrystallised by using organic solvents and water, preferred is acetone. Products obtained were confirmed by physical and spectroscopic data (IR, ^H NMR,*^C NMR and mass spectra). The following examples are given for the purpose of providing the man of the art with sufficiently clear and complete explanation of the present invention and therefore should not be construed to limit the scope of the invention. Example: 1 Preparation of (IR, 2S)-l-phenyl-2(l-pyrrolidinyl) propan-1-ol hydrochloride: To a three-necked 500mL round-bottom flask, equipped with a stirrer, addition funnel and a Dean-Stark setup, was added (lR,2S)-l-phenyl-2-amino-propan-l-ol (75g, 0.496 mol) dissolved in toluene (220mL) followed by aq. sodium bicarbonate (93g, 1.1 mol) and stirred. 1, 4-Dibromobutane (120g, 0.556 mol) was added slowly through the addition funnel and refluxed for 12 h. During the reflux, water collected in the Dean-Stark apparatus was removed from time to time. The reaction was stopped when the refluxing toluene was clear and almost theoretical amount of water was obtained. The reaction mixture was filtered through hyflo-bed and the filtrate acidified with citric acid (225g) to a pH of 2-3. The layers were separated and the aqueous layer containing the product citrate was basified using 25% aq.sodium hydroxide and extracted Example: 3 Preparation of (IR, 2S)-l-phenyH-N"methylamino-2-(l-pyrrolidinyl) propane dihy drochloride: (IS, 2S)-l-Chloro-l-phenyl-2-(l-pyrrolidinyl) propane hydrochloride (lOg, 0.039mol) was added to 50mL of ethanol taken in a three-necked 500mL round bottom flask and stirred well at 15-20 °C. Then the methylamine 40ml (37%, 1.16mol) was added slowly to the reaction mixture followed by maintenance at 15-201'C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to 0-5 °C and dry HCl gas was bubbled through it. When the pH became 1.5-2.0, HCl gas was stopped and allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-45 °C under vacuum. Spectroscopic interpretation: The structure of the product, 1-phenyl-l-N-methylamino-2-(l-pyrrolidinyl) propane dihydrochloride was confirmed with the help of spectroscopic data. a) IR (cm^) (KBr) N-H str. 3393, aromatic C-H str. 2982, aliphatic C-H str.2874, N - H str. 2689 and 2482, N-H bending 1634, benzenoid bands 1591 and 1501, C-N str.1319, C-H oop bending of mono substituted benzene ring 756, 704. with toluene (200mL). The toluene layer was concentrated under vacuum and acidified using dry HCl gas to pH 1.5-2.0. The reaction mass was concentrated under vacuum. The residue was triturated in1-heptane at 5-10°C and the white solid obtained was filtered and dried. Purity of (IR, 2S)-l-phenyl-2-(l-pyrrolidinyl) propan-1-ol hydrochloride by HPLC : 98.6% Yield :106g(90%) m p : 222-224 °C [a]D :-13.0°(5%inCHCl3) Optical purity (by HPLC) : 100% Example: 2 Preparation of (IS, 2S) l-chloro-l-phenyl-2-(l-pyrrolidinyI)propane hydrochloride: (lR,2S)-l-Phenyl-2-(l-pyrrolidinyl)propan-l-ol hydrochloride (lOg, 0.041mol) dissolved in chloroform (50ml) was taken in a three-necked 500 mL round-bottom flask, and it was heated to 45-50°C. Thionyl chloride (7.5g) was added slowly through addition funnel under stirring. The temperature was maintained at 50-551C for 2 h. After completion of the reaction (as indicated by TLC, ethyl acetate: triethylamine), the excess thionyl chloride and chloroform were removed under vacuum. The syrupy residue obtained was taken for amination as such without isolation. Weight of (IS, 2S) l-chloro-l-phenyl-2-(l-pyrroIidinyl) propane hydrochloride: 7.5g (80%) The structure of the chloro derivative corroborated with the IR spectrum. a) IR(cm-1)(KBr): Aromatic C-H str. 2994, aliphatic C-H str. 2918, benzenoid bands 1601, 1495, C-N str. 1315, C-Cl str. 768, C-H out-of-plane bending in mono substituted benzene ring 698. The disappearance of the O- str. and the appearance of the C-Cl str. confirms the successful chlorination at the a-position. The electrospray ionization method adopted for running the mass spectra of these diamines produced only the mono protonated version of the molecular ion [M+H]^. The mass spectral fragmentation indicated the protonation at the pyrrolidinyl nitrogen in all the diamines study. Example: 4 Preparation of (IR, 2S)-l-phenyl-l-N-ethylammo-2-(l-pyrrolidinyl) propane- dihydrochloride: 1 -chloro-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochloride (1 Og,0.039mol) was added to 50mL of ethanol taken in a three-necked 500mL round-bottom flask and stirred well at 15-20°C. Then the ethylamine (35ml, 0.66mol) was added slowly to the reaction mixture followed by maintenance at 15-20°C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to 0-5°C and dry HCl was bubbled through it. When the pH became 1.5-2.0, HCl gas was stopped and allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-45 °C under vacuum. Spectroscopic interpretation: The structure of the product, l-phenyM-N-ethylamino-2-(l-pyrrolidinyl) propane dihydrochloride was confirmed with the help of spectroscopic data. a) IR (cm^) (KBr) N-H str. 3343, aromatic C-H str. 2994, aliphatic C-H str.2864, N - H str. 2681 and 2490, N-H bending 1643, benzenoid bands 1570 and 1504, C-N str.1335, C-H oop bending of mono substituted benzene ring 764, 716. Example: 5 Preparation of l-phenyl-l- N-/-propylamino-2- (l-pyrrolidinyl)propane- dihydrochloride: 1 -chloro-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochloride (1 Og,0.039mol) was added to 50mL of ethanol taken in a three-necked 500mL round-bottom flask and stirred well at 15-20°C. Then the required iso-propylamine (9.2g, 0.156mol) was added slowly to the reaction mixture followed by maintenance at 15-20°C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to O-S^'C and dry HCl gas was bubbled through it. When the pH became 1.5-2.0, HCl gas was stopped and allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-45 °C under vacuum. Purity of 1-phenyl-1- N-(z-propylamino)-2-(l-pyrrolidinyl) propane dihydrochloride Spectroscopic interpretation: The structure of the product, 1-phenyl-l-N-(/-propylamino)-2-(l-pyrrolidinyl) propane dihydrochloride was confirmed with the help of spectroscopic data. a) IR (cm^) (KBr) N-H str. 3456, aromatic C-H str. 2980, aliphatic C-H str.2941, N-H str. 2668 and 2479, benzenoid bands 1566 and 1458, C-N str. 1396, C-H oop bending of mono-substituted benzene ring 781, 718. Due to the presence of the quadropole effect of the nitrogen attached to a chiral centre, the two methyl group of the isopropyl function exhibit partial magnetic non-equivalence both in proton and carbon spectra. Example- 6 Preparation of (IR, 2S)-l-phenyl -l-(N-butylainino)-2- (1-pyrrolidinyl) propane dihydrochloride: (1 S,2S)-1 -Chloro-1 -phenyl-2-(l -pyrrolidinyl)propane hydrochloride (1 Og, 0.039mol) was added to 50mL of ethanol taken in a three-necked 500mL round-bottom flask and stirred well at 15-20. Then the required n-butylamine (10.2g, 0.14mol) was added slowly to the reaction mixture followed by maintenance at 15-201C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to 0-5 °C and dry HCl gas was bubbled through it. When the pH became 1.5-2.0, HCl gas was stopped and allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-451C under vacuum. Purity of (IR, 2S) - 1-phenyl-l-(N-butylamino)-2-( 1-pyrrolidinyl) propane Spectroscopic interpretation: The structure of the product, 1 -phenyl-1 -(N-butylamino)-2-( 1 -pyrrolidinyl)propane dihydrochloride was confirmed with the help of spectroscopic data. a) IR (cm^) (KBr) N-H str. 3458, aromatic C-H str. 3042, aliphatic C-H str.2876, N-Hstr. 2629 and 2457, benzenoid bands 1576 and 1456, C-N str. 1362, C-H oop bending of mono-substituted benzene ring 756, 700. Example-7 Preparation of (IR, 2S)-l-phenyl-l-(N-tert-butylamino)-2- (1-pyrrolidinyl) propane oxalate: (1 S,2S) 1 -Chloro-1 -pheny l-2-( 1 -pyrrolidinyl)propane hydrochloride (1 Og, 0.039mol) was added to 50mL of ethanol taken in a three-necked 500mL round-bottom flask and stirred well at 15-20°C. Then the tert-butylamine (9.2g, 0.126mol) was added slowly to the reaction mixture followed by maintenance at 15-20°C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to 0-5 °C and oxalic acid was added till pH became 3.0-4.0. Reaction mass was allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-45 °C under vacuum. Spectroscopic interpretation: The structure of the product, 1 -phenyl-1 -(N-tert-butylamino)-2-( 1 - pyrrolidinyl) propane oxalate was confirmed with the help of spectroscopic data. a) IR (cm^) (KBr) 0-H str. 3429, aromatic C-H str. 3042, aliphatic C-H str.2914, N - H str. 2681 and 2486, C=0 str. of carboxylic acid 1721, asymmetric and symmetric str. of carboxylate anion 1601 and 1589, benzenoid bands 1489 and 1460, tert.butyl group 1402 and 1383, C-N str. 1312, C-0 str.1196, C-H oop bending of mono substituted benzene ring 746, 708. There appears to be an equillibrium between the mono and dibasic salts of this compound and hence the -COOH signal is not seen.The proton NMR signals of the protons attached to the two amino nitrogens were noticed in the proton NMR spectrum of this compound because the solvent used was CDCI3. Example-8 Preparation of (IR, 2S) -l-phenyM-(N-cyclohexylamino)-2-(l-pyrrolidinyl) propane dihydrochloride: (IS, 2S)-l-Chloro-l-phenyl-2-(l-pyrrolidinyl)propane hydrochloride(10g ,0.039 mol) was added to 50mL of ethanol taken in a three-necked 500mL round-bottom flask and stirred well at 15-20 °C. Then the required cyclohexylamine (13.5g, 0.136mol) was added slowly to the reaction mixture followed by maintenance at 15-20 °C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to 0-5 °C and dry HCl gas was bubbled through it. When the pH became 1.5-2.0, HCl gas was stopped and allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-45 °C under vacuum. Purity of 1-phenyl-l-(N-cyclohexylamino)-2-(l-pyrrolidinyl) propane dihydrochloride Spectroscopic interpretation: The structure of the product, 1 -phenyl-1 -(N-cyclohexylamino)-2-( 1 -pyrrolidinyl) propane dihydrochloride was confirmed with the help of spectroscopic data. a) IR(cm"*)(KBr) N-H str.3429, aromatic C-H str. 2986, aliphatic C-H str.2940, N - H str. 2673 and 2434, benzenoid bands 1572 and 1501, C-N str.1352, C-H oop bending of mono-substituted benzene ring 775, 714. Exainple-9 Preparation of (IR, 2S)-l-phenyl-l-(N-dimethylainino)"2- (1-pyrrolidinyl) propane dihydrochloride: (1 S,2S)-1 -Chloro-1 -phenyl-2-(l -pyrrolidinyl)propane hydrochloride (1 Og, 0.039mol) was added to 50mL of ethanol taken in a three-necked 500mL round-bottom flask and stirred well at 15-201'C. Then dimethylamine (9.2g, 0.2mol) was added slowly to the reaction mixture followed by maintenance at 15-20 °C for 6 h. After the completion of the reaction as indicated by HPLC, the reaction mixture was concentrated under vacuum. The residue obtained was taken up in ethyl acetate as solution, cooled to 0-5°C and dry HCl gas was bubbled through it. When the pH became 1.5-2.0, HCl gas was stopped and allowed to stand for half an hour and the precipitate obtained was filtered and recrystallised from acetone. The solid was dried at 40-45°C under vacuum. Spectroscopic interpretation: The structure of the product, 1 -phenyl-1 -(N-dimethylamino)-2-( 1 -pyrrolidinyl) propane dihydrochloride was confirmed with the help of spectroscopic data. a) IR (cm^) (KBr) Aromatic C-H str. 3015, aliphatic C-H str.2945, N-H str. 2637 and 2457, benzenoid bands 1497 and 1458, C-N str.1339, C-H oop bending of mono-substituted benzene ring 764, 710. The signal at 4.74 merged with that of H2O in D2O. The protons on the amino nitrogen are not noticed in the proton NMR spectra of the diamines, when D2O was used as the solvent due to proton exchange. ADVANTAGES OF PRESENT INVENTION: 1. The products obtained in 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 products obtained using the above said processes are optically pure (99- 100%). 4. The process described above gives highly enantioselective products. 5. Present invention uses simple and commercially available cheap raw materials such as thionyl chloride and alkylamines. We claim 1. New optically pure 1 -N-alkylamino-1 -pheny l-2-( 1 -pyrrolidinyl)propane hydrochlorides (formula-1) and process for their preparation via formation of novel intermediate 1 -chloro-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochloride (formula-2) from 1 -phenyl-2-( 1 -pyrrolidinyl)propane-1 -ol hydrochlorides (fonnula-3) which comprises, (i) adding of l-phenyl-2-(l-pyrroUdinyl)propan-l"Ol hydrochloride to the organic solvent and heating to a temperature ranging from 40-100'. (ii) adding of chlorination reagent to the step-1 solution and maintaining at a temp of 10- lOOfor a period of 15min to 10 h. (iii) concentrating the step-2 reaction mass to obtain novel compound 1-chloro-1-phenyl- 2-( 1 -pyrrolidinyl)propane hydrochloride. (iv) adding of organic solvent to the step-3 residue and cooling to -30 to+30°C . (v) adding of amine and maintaining for 15 min to 24 h at -30 to +30 °C. (vi) concentrating the reaction mass of step- 5 to obtain residue. (vii) adding solvent to the resulting mass obtained in step-6 and acidifying using dry hydrogen chloride gas to pH in the range 1.0 to 5.0 to obtain the crude 1-N-alkylamino- 1 -phenyl-2-( 1 -pyrrolidinyl)propane dihydrochloride. (viii) recrystalhsing the crude product obtained in step-8 using organic solvents and water. 2. A process according to claim 1 wherein l-phenyl-2-(l-pyrrolidinyl)propan-l-ol hydrochloride used in step - (i) is selected from pyrrolidinylnorephedrines. The organic solvent used is selected from the group of chloro solvents preferably chloroform. 3. A process according to claim 1 to 2 wherein Chlorination agent added in step-(ii) may be selected from HCl, PCI5, POCI3 thionylchloride etc., but preferred is thionyl chloride. Reaction mass of step - (ii) is maintained at a temperature range of 10-100°C preferably 50-55°Cfor 15min~10 h preferably 2 h. 4. A process according to claim 1 to 3 wherein concentration of the step -{iii) mass is effected under vacuum or at atmospheric pressure preferably under vacuum to obtain 1-chloro-1 -phenyl-2-( 1 -pyrrolidinyl)propane hydrochloride. 5. A process according to claim 1 to 4 wherein organic solvent used (iv) is selected from alcohols preferably ethanol and cooling is effected at +30°C to-30°C preferred is 20 6. A process according to claim 1 to 5 wherein amine used in step - (v) is selected from the group of alkylamines and the resulting mass is maintained for 15min to 24 h preferably 6 h at a temp range of-30 to +30 °C preferably 15-20°C. 7. A process according to claim 1 to 6 wherein the reaction mass in step- (vi) is concentrated at atmospheric pressure or under vacuum preferably under vacuum, 8. A process according to claim 1 to7 wherein solvent used in step (vii) is selected from the group of organic solvents such as ethylene dichloride, methyl tert.butyl ether etc. preferably ethyl acetate and acidifying using dry hydrogen chloride gas to pH in the range 1.0 to 5.0 preferably 1.5 to 2.0 to obtain the crude 1-alkylamino-l-phenyl-2-(N-pyrrolidinyl) propane dihydrochloride. 9. A process according to claim 1 to 8 wherein the crude l-alkylamino-l-phenyl-2-(N-pyrrolidinyl)propane dihydrochloride in step-8 is recrystalhsed by using organic solvents and water ,but preferred is acetone.

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1379-CHE-2007 AMENDED PAGES OF SPECIFICATION 03-06-2011.pdf

1379-CHE-2007 AMENDED CLAIMS 03-06-2011.pdf

1379-CHE-2007 AMENDED PAGES OF SPECIFICATION 30-01-2012.pdf

1379-CHE-2007 AMENDED CLAIMS 30-01-2012.pdf

1379-CHE-2007 AMENDED PAGES OF SPECIFICATION 31-01-2012.pdf

1379-CHE-2007 CORRESPONDENCE OTHERS 31-01-2012.pdf

1379-CHE-2007 FORM-13 03-06-2011.pdf

1379-CHE-2007 CORRESPONDENCE OTHERS 30-01-2012.pdf

1379-CHE-2007 EXAMINATION REPORT REPLY RECEIVED 03-06-2011.pdf

1379-che-2007-abstract.pdf

1379-che-2007-claims.pdf

1379-che-2007-correspondnece-others.pdf

1379-che-2007-description(complete).pdf

1379-che-2007-form 1.pdf