Title of Invention

A METHOD FOR THE PREPARATION OF NEW CHIRAL BETA-AMINO ALCOHOLS FROM R(-)-PHENYL ACETYL CARBINOL

Abstract The invention disclosed in this application relates to new chiral beta-amino alcohols and their synthesis from R (-)-phenyl acetyl carbinol. This synthesis involves the preparation of imino derivative of R (-)-phenyl acetyl carbinol followed by asymmetric reduction in the presence of noble metal catalyst .The precise experimental conditions for this stereospecific synthesis have been established.
Full Text

Field of Invention
The objective of the present invention relates to new chiral beta amino alcohols and their synthesis from R (-)-phenyl acetyl carbinol by making imino derivative of R (-) phenyl acetyl carbinol subsequent reduction in the presence of noble metal catalyst.
Background of invention
Several syntheses of 1, 2-aminoalcohols and their application as chiral auxiliaries have been reviewed elaborately (Chem., Vol. 96, No. 2, pp. 835-875,1996). Enantioselective reductive amination of aldehydes and acyclic ketones in presence of amines and chiral Rh catalyst has been the subject of elaboration in ACS symposium series, No. 641, pp. 201-206(1996). Similarly in Chem. Soc. Rev., Vol. 27, No. 6, pp. 395-404(1998) Borohydride and borane reducing agents have been highlighted as the reagents of choice for carrying out reductive aminations of carbonyl compounds.
J.Am.Chem.Soc. Vol. 72, pp. 2718-2722 (1950) describes N-substituted (3-amino alcohols, which are prepared by a reaction between (3-amino alcohols and ketones.
J. Org. Chem., Vol. 46, No. 16, pp. 3234-3238(1981) describes Lithium aluminum hydride reduction of monoimines derived from benzil and 1-phenylethylamine to yield mixture of diastereoisomeric amino alcohols. When catalytic hydrogenation of the monoimines prepared from benzil is treated with LAH, a mixture of aminoethanols but with different stereochemical results was obtained.
Tetrahedron Lett. Vol. 20, pp.1355-1356 (1979) reported lithium aluminum hydride reduction of a series of imines to yield a variety of p-aminoethanols with multiple chiral centers.
Tetrahedron Lett., Vol. 35, pp. 4985-4986(1990) describes, conversion of amino esters to the imine derived from benzophenone, reduction of the ester function and subsequent reaction with an organometallic reagent for the synthesis of (3-amino alcohols. Sphingosine A was synthesized in 50% yield with stereoselectivity>20:l obtained by NMR spectroscopy.

Another method for the preparation of 1,2-aminoalcohols has been described in Tetrahedron Lett., Vol. 43, pp. 557-559(2002) by hydrolysis of N-substituted oxazolidinones to 1, 2-aminoalcohols in good yields with Dowex resin.
In, LOrg.Chem. Vol. 61, pp. 6183-6188(1996) and Tetrahedron, Vol.52, pp. 12111-12116(1996) synthesis of chiral (2S)-aziridine-2-carboxaldehydes, its (2R)-isomer and diastereoselective addition of organolithium reagents to the afore-mentioned aldehydes has been described. Addition products were regioselectively reduced by catalytic hydrogenation in the presence of Pearlman's catalyst [Pd (OLTh/C] to provide enantiomerically pure 1, 2-aminoalcohols. The absolute stereochemistry of the synthesized aminoalcohol was assigned as (IS, 2S) with phenyl as C-l substituent by comparison with commercially available norpseudoephedrine.
Tetrahedron, Vol. 57, pp. 10039-10046(2001) describes, one-pot organometallic addition and subsequent ring opening of a, P-aziridine aldehyde affording anti/syn-3-bromo-1, 2-aminoalcohols in high chemical yield and stereo selectivity. The sequence allows the stereo selective preparation of syn-1, 2-aminoalcohols. R and S-Cathinone hydrochlorides have been synthesized by a similar strategy
Tetrahedron Asymmetry.Vol.4, pp. 2095-2100(1993) describes asymmetric synthesis of amines by the reductive amination of ketones using (+) and (-) norephedrine followed by periodate oxidation to yield aralkylamines in 54-66%enantiomeric excess.
Similar reductive animations are also reported in 'Verfahren zur Herstellung von Aminoalkoholen', DE4400591 (1995), BASF Ag, Germany describing the synthesis of N-methyl-D-glucamine from D-glucose in the presence of aq.methyl amine. In, US5874601, Abbott Lab., Abbott Park, Illinois, USA, the synthesis of arbutamine, a well-known stress agent for diagnosis of coronary artery disease is reported through the reaction of 4-arylbutanal with protected 1,2-amino alcohols.

In JP2003327564 (2003), Toray industries, Japan, synthesis of optically active substituted aminoalcohols from an optically active a-hydroxyketone and an amine derivative the in presence of a catalyst is reported.
L-Ephedrine is currently produced through a microbial biotransformation process
using different species of yeast with Benzaldehyde as the aromatic substrate. The process
involves the condensation of an active acetaldehyde (which is generated from pyruvic
acid produced by yeast) and benzaldehyde-giving rise to R (-)-phenyl acetyl
carbinol. This on catalytic hydrogenation in the presence of methylamine yields Lr ephedrine (US patent 1956950, CA284072). Reduction of R (-)-phenyl acetyl carbinol using sodium borohydride was mentioned in the patent CZ98260, 1961 where as platinum catalyst was used for reduction in CZ186027 patent- Except these reports, no other synthesis has been reported in the literature for R (-)-phenyl acetyl carbinol. Chiral phenyl acetyl carbinol is one of the attractive substrates, which can be used to synthesize chiral (3-aminoalcohols, by a one-pot reductive amination procedure. This method offers an elegant route to synthesis chiral [3-aminoalcohols. The method described in the present invention avoids the use of expensive reagents such as DIBAL, organohthium reagents, a-aminoorganolithium reagents, lithium aluminum hydride chiral auxiliaries and also lengthy complicated work-up procedures
whereR'= i-propyl, n-butyl,cyclohexyl,benzyl, phenyl (R> (+)- 1-phenylethyl, (S)- (-)-l-phenylethyl
The present invention relates to the compounds of the structural formula (1) namely, optically pure l-phenyl-2- (N-alkyl/aryl amino)-propanol hydrochlorides where in R' is alkyl or aryl group.


The preferred embodiment of the present invention relates to compounds of the structural formula (1) and their process for the preparation in which the compound corresponding to structural formula (2) namely R (-)-Phenyl acetyl carbinol is treated with aryl/alkyl amines using a noble metal catalyst in the presence of hydrogen gas and an organic solvent leading to only one of the diastereomer in high optical purity (99-100%) and yield (60-70%) as first crop.

Specifically, the objective of the present invention is to provide a new process for optically pure l-phenyl-2 (N-alkyl/aryl amino)-propanol hydrochlorides involving the preparation of imino derivative of R (-)-phenyl acetyl carbinol with alkyl/aryl amines followed by asymmetric reduction in the presence of noble metal catalyst and hydrogen gas in the presence of organic solvents

In all the cases the starting material R (-)-phenyl acetyl carbinol used is prepared from the molasses by condensation of an active acetaldehyde (which is generated from pyruvic acid produced by yeast) and benzaldehyde.
Objectives of the invention
The main objective of the present invention is to provide a new synthetic route to optically pure l-phenyl-2- (N- alkyl/aryl amino) propanol hydrochlorides of the structural formula (1)


Another objective of the present invention is to provide a new process for the synthesis of optically pure -l-phenyl-2- (N- alkyl/aryl amino) propanol hydrochlorides of the structural formula (1)
Another objective of the present invention is to provide a new process for optically pure 1 -phenyl-2- (N-alkyl/aryl amino) propanol hydrochlorides by the preparation of imino derivative of R (-) phenyl acetyl carbinol followed by asymmetric reduction using platinum catalyst in the presence of organic solvents.
Yet another objective of the present invention is to provide a process to isolate optically pure l-phenyl-2- (N- alkyl/aryl amino) propanol hydrochlorides in 60-70%yield as first crop.
Still another objective of the present invention is to provide a process for isolating l-phenyl-2- (N-alkyl/aryl amino) propanol hydrochlorides in optically pure form (99-100%)
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention relates to optically pure l-phenyl-2- (N- alkyl/aryl amino) propanol hydrochlorides.
According to another embodiment of the present invention there is provided a new process for the preparation of optically pure l-phenyl-2- (N-alkyl/aryl amino) propanol hydrochlorides by the preparation of imino derivative of R (-) phenyl acetyl carbinol followed by asymmetric reduction using noble metal catalyst in the presence of hydrogen gas and organic solvents which comprises,

1) adding of phenyl acetyl carbinol dissolved in organic solvent in to a hydrogenator,
2) adding of water and noble metal catalyst to the resulting solution and cooling to a temperature in the range of 0°C to 25°C,
3) adding of aryl/alky amine dissolved in organic solvent to step (2) solution,
4) passing the hydrogen in to the hydrogenator to maintain a pressure of latm to lOatm till consumption of hydrogen ceases. At a temperature in the range from -30°c to +100°c for a period of 15min to 10 h. and further maintaining at a temperature in the range of-30°c to +100°c for a period ranging fromlSmin to 24hrs,
5) filtering the solution to recover the noble metal catalyst and separating the organic and aqueous layer of the filtrate,
6) drying the organic solvent layer containing the product l-phenyl-2-(N-alkyl/aryl
amino) propanol obtained in step- 6 with solid drying agent before concentrating under
vacuum,
7) adding of the organic solvent to the resulting mass obtained in step-(6) and acidifying using dry HC1 gas to pH in the range 1.0 to 6.0 to obtain the crude l-phenyl-2-(N-alkyl/aryl amino)propanol as HC1 salt,
8) recrystallising the crude product obtained in step-8 using organic solvents and water,
9) obtaining the physical and spectroscopic data (IR,1!! NMR,13C NMR and mass
spectral) to confirm the structure of the product.
The phenyl acetyl carbinol used in step-1 is chosen from isomers of phenyl acetyl carbinol preferably R-(-)-phenyl acetyl carbinol .The solvent used to dissolve R-(-)-phenyl acetyl carbinol in step(l) is selected from organic solvents preferably toluene . Catalyst used for reduction in step (2) is chosen from noble metal catalysts, preferably platinum and the resulting solution is cooled at a temp range of 0° to 25°C preferably 10 °C. The amine used in step (3) may be selected from alkyl/aryl amines and the solvent

used for dissolving is selected from organic solvents preferably toluene. Pressurizing the hydrogenator in step (4) to 1 atm to 10 atm preferably 6atm at a temp range of -30°C tol00°C preferably 10°-15°C for a period ranging from 5 min to 24 h preferably 2 h. Further maintained under stirring for a period ranging from 15 min to 24 hrs preferably 4 h at a temperature in the range from -30°C to +100°C preferably 10-15°C Filtering the solution of step- (5) to recover the catalyst followed by separation of org layer containing the product from the aqueous layer.
The organic solvent layer containing the product in step-6 is dried with solid drying agent preferably anhydrous sodium sulphate before concentrating under vacuum. Organic solvent added in step-7 is selected from dialkyl / alicyclic ethers preferably diethyl ether and acidifying by passing dry Hydrochloride gas to pH in the range between 1.0 to 6.0 preferably 1.5 to obtain crude l-phenyl-2- (N-alkyl/aryl amino) propanol as HC1 salt. The crude product obtained in step-8 is recrystallised using organic solvent or water preferably isopropyl alcohol. The structure of the final product obtained in step (8) 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-l
Preparation of (-) l-phenyl-2- (N-2-propylamino) propanol hydrochloride:
In a high-pressure hydrogenator, a solution of R (-) phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and 5g of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel, i- propylamine (19gm, 0.32 mol) in toluene was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased (approx 2hrs), the reaction mixture was agitated for more hours at the temperature range 10°C-15 °C. The contents of the hydrogenator flask were filtered to remove the catalyst.

The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether, cooled to 0-5 °C and dry HCl gas was bubbled through it. When the pH became 1.5 on the acidic side, HCl was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from /-propyl alcohol.
Purity of l-phenyl-2-(N-2-propylamino) propan-1-ol hydrochloride
byHPLC : 99.1%
Yield : 68%
m p : 206-208 °C
[a]D :-19.82°(5%inH20)
Optical purity by (HPLC) : 99.5 %
Spectroscopic interpretation:
The structure of the product, l-phenyl-2-(N-2-propylamino) propan-1-ol hydrochloride obtained was confirmed with the help of the following spectroscopic data. a) IR (cm1) (KBr)
O-H str. and N-H str. 3350-3000, aromatic C-H str. 3062, aliphatic C~H str.
2959, benzenoid bands 1604 and 1494, bands due to the gem-dimethyl group of /-propyl
moiety 1450, 1353, C-N str.1276, C-0 str. 1063, C-H oop bending of mono-substituted
benzene ring 744, 704.
b) !H NMR (DMSO-d6,300 MHz) (8H)
0.75 (3H, d, CH3-CH-CH-OH), 0.94 (6H, 2d, CH3-CH-CH3), 2.80 (2H, m, CH3-CH-CH -OH and CH3-CH-CH3), 4.58 (1H, d, -CH-OH), 5.10 (1H, bs, -OH), 7.25 (5H, m, aromatic protons).

c) 13C NMR (DMSO-d6,300 MHz) (8C)
14.45 (CH3-CH-CH-OH), 23.00 (CH3-CH-CH3), 44.30 (CH3-CH-CH3), 55.04 (CH3-CH-CH-OH), 73.37 (C6H5-CH-OH), 125.98-143.98 (aromatic carbons).
d) Mass spectrum (CI, methanol)
[MH]+ at m/z 194(100), [MH+-H20] at m/z 176(59), [(CH3)2CH-NH=CH--CH3]+at m/z 86(13).
Example-2
Preparation of (-) l-phenyl-2- (N-1-butylamino) propan-1-ol hydrochloride:
In a high-pressure hydrogenator, a solution of R(-)phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and lOg of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel w-Butylamine (24g, 0.33 mol) in toluene was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased (approx 2h), the reaction mixture was agitated for four more hours at the temperatufe maintained between 10-15 °C.The contents of the hydrogenator flask were filtered to remove the catalyst. The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether as solution, cooled to 0-5 °C and dry HC1 was bubbled through it. When the pH became 1.5 on the acidic side, HC1 gas was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from /-propyl alcohol.
Purity of (-)l-phenyl-2- (N-l-butylamino)propan-l-ol hydrochloride
by HPLC : 99.0%
Yield : 65%

mp : 218-220 °C
[a]D : -22.40° (5% in H20)
Optical purity by (HPLC) : 99.7 %
Spectroscopic interpretation:
The structure of the product as l-phenyl-2-(N-l-butylamino)propan-l-ol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm"1) (KBr)
O-H str. and N-H str. 3400-3200, aromatic C-H str. 2966, aliphatic C-H str.
2824, HN-Hstr. 2510, benzenoid bands 1555 and 1494, C-N str.1260, C-O str. 1066, C-H oop bending of mono-substituted benzene ring 740, 702.
b) !H NMR (DMSO-d6,300 MHz) (8H)
0.92(6H, m, -CH2-CH3, -NH-CH-CHj), 1.35 (2H, sextet, -CHrCH3), 1.69 (2H, quintet, -CH2-CH2-CH3), 3.00 (2H, t, -CH2-CH2-CH2-CH3), 5.22 (IH, m, -CH-CH3), 6.10 (IH, d, -CH-OH), 7.28-7.40 (5H, m, aromatic protons), 8.81 (2H, bs, N+H )•
c) ' 3C NMR (DMSO-d6,300 MHz) (5C)
9.11 (-CH2-CH3), 13.47 (-CH-CH3), 19.40 (-CH2-CH3), 27.49 (-CH2rCH2-CH3), 44.30 (-CH2-CH2-CH2-CH3), 58.24 (-CH-CH3), 69.22 (-CH-OH), 125.66-141.25 (aromatic carbons).
d) Mass spectrum (EI)
[M]+- at m/z 208(trace), [CH3CH2CH2CH2NH=CHCH3]at m/z 100(100), (C6H7)+
at m/z 79(20), (C6H5)+ at m/z 77(35), [CH3NH=CHCH3]at m/z 58(45), [CH3CH2CH2CH2]at m/z 57(35).

Example: 3
Preparation of (-) l-phenyl-2- (N-1-cyclohexylamino) propan-1-ol hydrochloride:
In a high-pressure hydrogenator, a solution of R (-)- phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and lOg of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel cyclohexylamine (32g, 0.33 mol) in toluene was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased, the reaction mixture was agitated for four more hours at the temperature maintained between 10-15 °C. The contents of the hydrogenator flask were filtered to remove the catalyst. The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether as solution, cooled to 0-5 °C and dry HC1 gas was bubbled through it. When the pH became 1.5 on the acidic side, HC1 was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from /-propyl alcohol.
Purity of (-)l-phenyl-2- (N-l-cyclohexylamino)-propan-l-ol hydrochloride
by HPLC : 98.90%
Yield : 60%
mp : 218-222 °C
[a]D : -22.00° (5% in H20)
Optical purity by (HPLC) : 99.8 %
Spectroscopic interpretation:
The structure of the product, l-phenyl-2-(N-l-cyclohexylamino)-propan-l-ol hydrochloride was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
OH str. 3279, aromatic C-H str. 3028, aliphatic OH str. 2839, HN-Hstr.2702,
benzenoid bands 1603 and 1558, C-N str. 1356, C-O str. 1140, C-H oop bending of mono-substituted benzene ring 746,700.
b) ' H NMR (DMSO-d6,300 MHz) (8H)
0.99 (3H, d, -CH-CH3), 1.08-2.17 (1 OH, m, 5 -CHs groups of cyclohexyl ring), 3.13 (1H, m, -CH-NH-CH-), 3.41 (lH,m, -CH-CH3), 5.42 (lH,d, -CH-OH), 6.65 (lH,bs, -CH-OH), 7.25-7.42 (5H, m, aromatic protons), 8.60 (2H, very bs, NH2).
c) ,3C NMR (DMSO-d6,300 MHz) (5C)
9.72 (-CH-CH3), 24.01-53.21 (cyclohexyl ring carbons), 54.71 (-CH-CH3), 69.52 (-CH-OH), 125.76-141.31 (aromatic carbons).
d) Mass spectrum (EI)


i+.
[M] 'at m/z 234(absent),

NH=CH CH:

at m/z 126(100),


.+ . / n"\s^r\\ /r>K TT x+
N—CH CH:
at m/z 125 (10), (C6Hn) at m/z 83(20)? (C6H5) at m/z 77(18), (C5H8)+ at m/z 68(11), (C4H7)+ at m/z 55(46).
Example- 4
Preparation of (-) l-phenyl-2-(N-l-benzylamino) propan-1-ol hydrochloride:
In a high-pressure hydrogenator, a solution of R (-) phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and 5g of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel benzylamine (34.2g, 0.32 mol) in toluene was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased,

the reaction mixture was agitated for four more hours at the temperature maintained between 10°C and 15 °C. The contents of the hydrogenator flask were filtered to remove the catalyst. The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether as solution, cooled to 0-5 °C and dry HC1 gas was bubbled through it. When the pH became 1.5 on the acidic side, HC1 was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from /-propyl alcohol.
Purity of (-)l-phenyl-2-(N-l-benzylamino) propan-1-ol hydrochloride

by HPLC 99.46%
Yield 63%
mp 198-200 °C
[a]D -10.30°(5%inH2O)
Optical purity by (HPLC) 99.45 %
Spectroscopic interpretation:
The structure of the product, l-phenyl-2-(N-l-benzylamino) propan-1-ol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm"1) (KBr)
+ O-H str. 3348, aromatic C-H str. 2985, aliphatic C-H str. 2798, HN-H str.
2510, benzenoid bands 1576 and 1450, C-N str. 1259, C-0 str. 1067, C-H oop bending of mono-substituted benzene ring 738.
b) ' H NMR (DMSO-d6,300 MHz) (5H)
1.00 (3H, d, -CH-CHj), 4.30 (2H, s, -CHj- C6H5), 5.31 (m, 1H, -CH-CH3),
+
6.17 (d, 1H.-CH-OH), 7.25-7.70 (m, 10H, aromatic protons), 9.31 (bs, 2H, NH2).

c) 13C NMR (DMSO-d6,300 MHz) (6C)
9.13 (-CH-CH3), 47.56 (-CH2- C6H5), 58.21 (-CH-CH3)5 68.94 (-CH-OH), 125.59-141.24 (aromatic carbons).
d) Mass spectrum (EI)
+ [M]+* at m/z 242(absent), [C6H5CH2NH=CHCH3]at m/z 134(75), (C7H7)+ at
m/z 91(100), (C6H7)+ at m/z 79 (10), (C6H5)+ at m/z 77(12), (C5H5)+at m/z 65(11). Example- 5
Preparation of (-)-l-phenyl- (2-N-phenyIamino) propan-1-ol hydrochloride:
In a high-pressure hydrogenator, a solution of R (-) phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and 5g of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel aniline (30g, 0.33 mol) in toluene was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased (approx 2h), the reaction mixture was agitated for four more hours at the temperature maintained between 10°and 15 °C. The contents of the hydrogenator flask were filtered to remove the catalyst. The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether as solution, cooled to 0-5 °C and dry hydrochloride gas was bubbled through it. When the pH became 1.5 on the acidic side, HC1 was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from /-propyl alcohol.

Purity of (-)-l-phenyl-(2N-phenyl-amino) propan-1-ol hydrochloride

by HPLC 98.90%
Yield 65%
mp 179-181 °C
[a]D -18.40°(5%inH2O)
Optical purity by (HPLC) 99.5 %
Spectroscopic interpretation:
The structure of the product, l-phenyl-(2N-phenyl-amino) propan-1-ol hydrochloride was confirmed with the help of the following spectroscopic data.

a)

-1
IR(cnf)(KBr)
+ O-H str. 3329, HN-H str. 2486, 2459, benzenoid bands 1600 and 1557, C-N

str.1250, C-0 str. 1063, C-H oop bending of mono-substituted benzene ring 743, 696.

b)

!H NMR (DMSO-d6,200 MHz) (5H)
1.03 (3H, d, -CH-CHj), 3.79 (1H, m, -CH-CH3), 5.04 (1H, d, -CH-OH), 7.26-

7.69 (10H, m, aromatic protons).

c)

13C NMR (DMSO-d6,200 MHz) (8C)
8.22 (-CH-CH3), 60.72 (-CH-CH3), 67.77 (-CH-OH), 121.91-139.85

(aromatic carbons).
d) Mass spectrum (EI)
M+- at m/z 227(3), [CfiHsNH==CHCH,]at m/z 120(100), (C6H5)+ at m/z 77(20).

Example- 6
Preparation of (+)l-phenyl-2-(N-l-phenyIethylamino) propan-1-ol hydrochloride:
In a high-pressure hydrogenator, a solution of R (-) phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and lOg of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel (R)-(+) - phenylethylamine (40g, 0.33 mol) in toluene was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased(approx 2h), the reaction mixture was agitated for four more hours at the temperature maintained between 10°C and -15 °C. The contents of the hydrogenator flask were filtered to remove the catalyst. The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether as solution, cooled to 0-5 °C and dry hydrochloride gas was bubbled through it. When the pH became 1.5 on the acidic side, HC1 was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from i-propyl alcohol
Purity of (+)l-phenyl-2(N-l-phenylethyl-amino) propan-1-ol hydrochloride
by HPLC : 98.94%
Yield : 62%
m p : 204-208 °C
[a]D : +40.00° (5% in H20)
Optical purity by (HPLC) : 100.0 %
Spectroscopic interpretation:
The structure of the product, 1 -phenyl-2(N-l-phenylethyl-amino) propan-1-ol hydrochloride was confirmed with the help of the following spectroscopic data.

a)

-i
IR(cm')(KBr)
0-H str. 3389, HN-Hstr.2500, 2475, benzenoid bands 1584 and 1495, C-N

str.1250, OO str. 1065, C-H oop bending of mono-substituted benzene ring 746,704.

b)

*H NMR (DMSO-d6,200 MHz) (5H)
HO NH

0.93 (3H, d, /~A ), 1.71 (3H, d, C6H5-CH~CH3), 4.83 (1H, m,
Ph CH,
CH3-CH-CH-OH), 5.29 (1H, m, C6H5-CH-CH3), 6.21 (1H, d, C6H5-CH-OH), 6.99-7.87 (10H, m, aromatic protons), 9.49-9.75 (bd, 2H, ^H2)

13,
c)
C NMR (DMSO-d6, 200 MHz) (5C) 8.66 (HO-CH-CH-CH3),19.19 (C6H5-CH-CH3), 53.68 (CH3-CH-CH-OH), 55.41 (C6H5-CH-CH3), 66.16 (C6H5-CH-OH), 123.89-139.86 (aromatic carbons).

d)

Mass spectrum (CI, methanol)



r+
MH

+

at m/z 256(100), [MH-H20] at m/z 238(33),



HO

H




+.
C6H5CH(OH)CH(CH3)NH2 at m/z 151(28),

Ph CH,

or [C6H5(CO)CH2CH3] ' at m/z

134(35), [C6H5-CH+(OH)] at m/z 107(12), [C6H5CHCH3] at m/z 105(22).
Example- 7
Preparation of (-)l-phenyl-2-(N-l-phenyIethylamino)propan-l-olhydrochIoride:
In a high-pressure hydrogenator, a solution of R-(-)- phenyl acetyl carbinol dissolved in toluene (40g, 0.26 mol), lOmL of water and lOg of 10% platinum on carbon catalyst were added. The hydrogenator was cooled to temperature below 10 °C. To this mixture in the hydrogenator vessel (S) - (-) - phenylethylamine (40g, 0.33 mol) in toluene

was added and then pressurized with hydrogen to 6 atm. After the uptake of hydrogen ceased(approx 2h), the reaction mixture was agitated for four more hours at the temperature maintained between 10°C and 15 °C The contents of the hydrogenator flask were filtered to remove the catalyst. The filtrate contained two layers (i.e.) toluene layer and water. The toluene layer was separated and dried over sodium sulphate (5g). The dried toluene layer was evaporated under reduced pressure. The residue was taken up in ether as solution, cooled to 0-5 °C and dry hydrochloride gas was bubbled through it. When the pH became 1.5 on the acidic side, hydrochloride gas was stopped and the white precipitate obtained was filtered and washed with ether. The white hydrochloride salt was recrystallised from /-propyl alcohol.
Purity of (-) l-phenyl-2(N-l-phenylethylamino) propan-1-ol hydrochloride
by HPLC : 98.34%
Yield : 67%
mp : 206-210 °C
[a]D : -40.00° (5% in H20)
Optical purity by (HPLC) : 100.0 %
Spectroscopic interpretation:
The structure of the product, l-phenyl-2(N-l-phenylethylamino) propan-1-ol hydrochloride was confirmed with the help of the following spectroscopic data.
a) IR (cm1) (KBr)
O-H str. and N-H str. 3400-3200, aromatic OH str. 2983, aliphatic OH str.
2827, HN-H str. 2504, benzenoid bands 1589 and 1496, ON str. 1214, OO str. 1066, C--H oop bending of monosubstituted benzene ring 746, 704.

b) *H NMR (DMSO-d6,200 MHz) (5H)
HO NH
0.92 (3H, d, C6H5-CH-CH3), 1.70 (3H, d, )~K ), 2.92 (bs, 1H,-CH-QH),
Fa CH,
4.81 (1H, m, CH3-CH-CH-OH), 5.26 (1H, m, C6H5-CH-CH3), 6.23 (1H, d, -CH-OH), 7.01-7.84 (10H, m, aromatic protons), 9.51 (2H, bd, NH2)-
c) 13C NMR (DMSO-d6,200 MHz) (5C)
10.01 (HO-CH-CH-CH3), 20.48 (C6H5-CH-CH3), 54.95 (CH3-CH-CH-OH), 56.57 (C6H5-CH-CH3), 67.49 (C6H5-CH-OH), 125.21-140.87 (aromatic carbons).
d) Mass spectrum (EI)
[M]+- at m/z 256(2), [C6H5(CH3)CHNH=CHCH3] at m/z 148(81),
+
[C6H5COCH=CH2]+- at m/z 132(4), [C6H5CHCH3] at m/z 105(100), (C6H5)+ at m/z 77(26).
ADVANTAGES OF PRESENT INVENTION
1. The products obtained in the present invention are new and not reported in the literature.
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.
4. The process described above gives highly enantioselective products.
5. The process leads to the new products in good yields.
We claim







1) New optically pure l-phenyl-2 (N-alkyl/aryl methylamino) propanol hydrochlorides
and the process for their preparation involving the preparation of imino derivative of R
(-)-phenyl acetyl carbinol with alkyl/aryl amines followed by asymmetric reduction using
noble metal catalyst in the presence of organic solvents, which comprises
i) adding of phenyl acetyl carbinol dissolved in org solvent in to a hydrogenator.
ii) adding of water and noble metal catalyst to the resulting solution of step(i)followed by cooling to a temperature in the range of 0° to 25°C
iii) adding of aryl/alkyl amine dissolved in organic solvent to the step-(ii) solution.
iv) passing the hydrogen in to the hydrogenator to maintain a pressure of latm to lOatm till consumption of hydrogen ceases, at a temp in the range from -30°c to +100°c preferably 10-15°Cfor a period of 15min to 10 hrs and further maintaining at a temperature in the range of-30°c to +100°c for a period ranging froml5min to 24hrs ..
v) filtering the solution to recover the catalyst and separating org layer and aq layer of the filtrate
vi) drying the solvent layer containing the product l-phenyl-2-(N-alkyl/arylamino) propanol obtained in step- 6 with salt drying agent before concentrating under vacuum
vii) adding of organic solvent to the resulting mass obtained in step-(vi) and acidifying by passing dry Hydrochloride gas to pH in the range 1.0 to 6.0 to obtain the crude (+/-)- l-phenyl-2-(N-alkyl/arylamino)propanol as HC1 salt
viii) recrystallising the crude product obtained in step-vii using organic solvent or water.
2) The new process as claimed in claim 1 where in R (-)-phenyl acetyl carbinol used in
step (i) may be selected from (+) or (-) or (+/-) phenyl acetyl carbinol s and the solvent
used is selected from organic solvents or water, preferably toluene.

3) The new process as claimed in claims lto 2 wherein the catalyst used in step (ii) for reduction is chosen from noble metals, preferably platinum cooling the resulting solution to a temp range of 0° to 30°C preferably 10°C.
4) The new process as claimed in claims 1 to 3 where in amine used in step- (iii) may be selected from alkyl/aryl amines dissolved in solvent selected from non polar solvents preferably toluene.
5) The new process as claimed in claims 1 to 5 where in the hydrogenator in step-(iv) is pressurized using hydrogen in the range of latm to lOatm preferably 6atm till consumption of hydrogen ceases at a temperature in the range from -30°c to +100°c preferably 10°-15°C for a period of 15min to 10 hrs preferably 2h and is maintained further under stirring for a period of 15 min to lOhrs preferably 4h at a temp ranging from -30°C to 100°C preferably 10-15°C
6) The new process as claimed in claims 1 to 5 Wherein step(v) solution is filtered to recover the catalyst followed by separation of org layer containing the product from the aqueous layer of the filtrate.
7) The new process as claimed in claims 1 to 6 where in organic solvent layer in step (vi) containing the product is dried with solid drying agent preferably anhydrous sodium sulphate before concentrating under vacuum.
8) The new process as claimed in claims lto 7 where in the organic solvent in step (vii) added to the resulting mass in step - (vii) is selected from dialkyl/alicyclic ethers preferably diethyl ether and acidifying the resulting solution by passing dry hydrochloride gas to pH in the range 1.0 to 6.0 preferably 3.0 to obtain the crude (+/-)-l-phenyl-2- (N-alkyl/aryl amino) propanol hydrochloride.
9) The new process as claimed in claims 1 to 8 wherein the solvent used in step (viii) for recrystallisation is selected from organic solvents or water preferably isopropyl alcohol.




Documents:

1348-CHE-2007 AMENDED PAGES OF SPECIFICATION 03-06-2011.pdf

1348-CHE-2007 AMENDED CLAIMS 03-06-2011.pdf

1348-CHE-2007 FORM-13 03-06-2011.pdf

1348-CHE-2007 OTHER DOCUMENT 03-06-2011.pdf

1348-CHE-2007 AMENDED CLAIMS 14-09-2011.pdf

1348-CHE-2007 CORRESPONDENCE OTHERS 05-09-2011.pdf

1348-CHE-2007 CORRESPONDENCE OTHERS 14-09-2011.pdf

1348-CHE-2007 EXAMINATION REPORT REPLY RECEIVED 03-06-2011.pdf

1348-che-2007-abstract.pdf

1348-che-2007-claims.pdf

1348-che-2007-correspondnece-others.pdf

1348-che-2007-description(complete).pdf

1348-che-2007-form 1.pdf


Patent Number 249376
Indian Patent Application Number 1348/CHE/2007
PG Journal Number 42/2011
Publication Date 21-Oct-2011
Grant Date 18-Oct-2011
Date of Filing 25-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 MANASA" V.V KOIL STREET , CHINMAYA NAGAR CHENNAI-600092.
2 DR. DEVALLA VENKATA RAMANA NO 8. AYODHYA COLONY, VELACHERI, CHENNAI -600042
3 DR.PATHANGI SAMPATH SRINIVASAN NO 49/4 CAR STREET , TRIPLICANE ,CHENNAI-600005
4 BORKATTE NARASHIMA HITESH KUMAR NO.103 STREET ,A.P.BLOCK, 14TH SECTOR ,K.K. NAGAR , CHENNAI-600078
5 DR.BANUMATHI ARABINDOO NEW NO .25 (OLD NO.6/2),3RD STREET, PARAMESHWARI NAGAR, ADYAR ,CHENNAI-600020
PCT International Classification Number C07C215/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA