FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10,and Rule 13]
Title of the Invention
'TMOVEL PROCESS FOR THE PREPARATION OF LERCANIDIPINE"
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality : Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the invention

1593/MUM/2005
1 9 DEC 2005

NOVEL PROCESS FOR THE PREPARATION OF LERCANIDIPINE
FIELD OF THE INVENTION:
The present invention relates to new, improved and industrially viable process for the preparation of Lercanidipine or its pharmaceutically acceptable salts using novel derivatives of 2,N-dimethyl-N-(3,3-diphenylpropyl)-l-amino compounds and novel polymorphs of Lercanidipine hydrochloride, its process of preparation.
BACKGROUND OF THE INVENTION:
Lercanidipine hydrochloride, i.e., 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-,2-[(3,3-diphenylpropyl)methylamino]-1,1 -dimethyl ester, hydrochloride having the formula (I)

is an antagonist of type-L calcium channels, and has been found to be very active as an antihypertensive and is an useful agent for the treatment of angina and coronary diseases. Its mechanism of antihypertensive activity is attributed to a direct relaxant effect on vascular smooth muscle, which lowers total peripheral resistance.
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Lercanidipine hydrochloride (I) is disclosed in US4705797.
The preparation of said pharmaceutical agent can be obtained with different synthetic schemes. US4705797 discloses process for the preparation of Lercanidipine Hydrochloride as described according to the following scheme:

As per scheme-I crude lercanidipine is obtained as an oily residue that must be purified by flash chromatography using chloroform, containing increasing amounts of acetone, as the eluant. The solvent is then evaporated to dryness and remaining
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residue is dissolved in methanol adding a small excess of hydrochloric acid in ethanol. After evaporation of the solvent, the hemi-hydrated hydrochloride salt is prepared by treatment with diluted hydrochloric acid in the presence of sodium chloride.
A major disadvantage of the process of preparing lercanidipine, as it is described in US Patent No. 4705797, is that the disclosed cyclization reaction generates several by products, which results in a lower yield for the desired product. Moreover, the purification and isolation of lercanidipine from the reaction mixture is quite complex, since it requires numerous treatments with different solvents. Finally, the purification and isolation steps are difficult to perform on an industrial scale because of the absolute necessity of purifying the product by column chromatography.
Further, US Patent No. 5912351 describes an alternate process for the preparation of lercanidipine hydrochloride. It involves reaction of 1, 4-dihydro-2, 6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-carboxylic acid with thionyl chloride in dichloromethane and dimethylformamide at a temperature between-4 and +1 C and subsequent esterification of the obtained acid chloride with 2, N-dimethyl-N- (3, 3diphenylpropyl)-l-amino-2-propyl alcohol at a temperature between -10° and 0°C.
However, the disadvantage of the said process is the use of thionyl chloride as a reactant, which is difficult to handle on an industrial scale because of evolution of sulphur dioxide and hydrochloric gas from the reaction. Moreover it also requires special grade of equipment such as glass-lined reactor etc. Moreover, acid chloride of 1,4-dihydropyridine derivative used in the said process is hygroscopic and unstable.
Further WO/03/014084 discloses novel crystalline form I & II of Lercanidipine Hydrochloride and mixtures of Form I & II having predetermined and reproducible content of Form I & II & optionally other forms of Lercanidipine Hydrochloride such
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as amorphous. EP160044 ldiscloses crystalline form I of Lercanidipine Hydrochloride and a mixture of form I with amorphous and optionally form II. However both these prior art don't describe pure amorphous form (anhydrous or hemihydrate) of Lercanidipine Hydrochloride and its preparation.
Thus, there is a demand for a simpler, cost-effective, industrially viable process for synthesizing Lercanidipine with higher yields, while reducing number of process steps and avoiding use of harmful reagents, solvents and laborious separation methods such as column chromatography.
The Applicant has found simpler and cost-effective process for synthesizing Lercanidipine, avoiding use of hazardous materials, which is industrially viable and gives better yields.
Thus, the present invention provides obvious benefits with respect to removing both the technical problems associated with prior art as well being simpler and economical, while at the same time achieving high purity and yield of the product with convenience to operate on a commercial scale.
SUMMARY OF THE INVENTION:
The present invention relates to new, improved and industrially viable process for the preparation of Lercanidipine hydrochloride using novel intermediate of amino phenyl derivatives of formula (III) with 1,4-dihydropyridine acid derivative.
CH3 Ph
CH3 CH3
(III) Wherein R is X, OS02R]
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X = CI, F, Br or I; R1 = alkyl (d to C4), phenyl, or 4-methyl phenyl.
The object of the present invention is to provide a process for synthesis of. Lercanidipine hydrochloride.
The second object of the instant invention is to provide a simpler and cost-effective process for synthesis of Lercanidipine hydrochloride.
Another object of the present invention is to provide an industrially viable process for synthesis of Lercanidipine hydrochloride.
Still another object of the present invention is to provide an improved process for synthesis of Lercanidipine hydrochloride, which gives better yield.
Yet another object of the present invention is to provide novel polymorphic forms of Lercanidipine hydrochloride.
In one general embodiment, the present invention provides a process for the preparation of lercanidipine hydrochloride of formula (I) as described herein below:
Which comprises the steps of:
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1) Esterification or halogenations of 2,N-Dimethyl-N-(3,3-diphenyl propyl)-l-amino-2-propanol (II)


With mesyl chloride (methane sulphonyl chloride) or Halogenating agent in an aprotic solvent optionally in presence of a base to obtain derivatives of 2,N-Dimethyl-N-(3,3-diphenyl propyl)-!-amino (III)

I) Adding solution of 2,6-dimethyl-5-methoxy carbonyl-4-(3-nitropheny 1)-1,4-dihydropyridine-3-carboxylic acid (IV)

in aprotic or aprotic solvent to an ester of formula III in presence of base; and 3) Isolating resultant lercanidipine or its Pharmaceutically acceptable salts
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates X-ray diffraction pattern of amorphous Form Tl of Lercanidipine hydrochloride obtained according to the present invention.
Fig. 2: This figure indicates Infrared Spectrum of amorphous Form Tl Lercanidipine hydrochloride obtained according to the present invention.
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Fig. 3: This figure indicates Differential Scaning Calorimetry of amorphous Form Tl Lercanidipine hydrochloride obtained according to the present invention.
DETAILED DESCRIPTION:
According to one general aspect of the present invention, there is provided a new, improved and industrially viable process for the preparation of Lercanidipine Hydrochloride, using intermediate of derivatives of amino phenyl compounds of formula III with 1,4-dihydropyridine acid derivative of formula (IV).
According to one aspect of the present invention, there is provided an efficient process for the preparation of Lercanidipine, which provides obvious benefits with respect to economics, generation of minimal effluents, lesser number of process steps, less reactor occupancy, higher purity of the product with convenience to operate on a commercial scale.
According to one another aspect of the present invention there is provided a new, improved and industrially viable process for the preparation of Lercanidipine Hydrochloride, using a novel intermediate of Sulphonic acid ester of amino alcohol of formula III
The present invention provides an improved process for preparing Lercanidipine Hydrochloride (I) as discussed herein: -
The process of the invention is illustrated by the following reaction scheme.
(A)
The 2,N-Dimethyl-N-(3,3-diphenyl propyl)- l-amino-2-propanol Formula (II)
is prepared according to a procedure known in the prior art (US 4705797)
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With Alkyl or aryl or substituted aryl sulphonyl halide in presence of Base in Chlorinated or non chlorinated aprotic solvent to obtained, Sulphonic acid ester of N-Dimethyl-N- (3,3-diphenyl propyl)-1-amino-2-propanol compound (ITIA) Wherein R = alkyl (CM), phenyl, p-tolyl and X = CI, Br, F, or I.
(C): Reacting 2,6-dimethyl-5-methoxy carbonyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid of formula (IV)


with mesylate of N-Dimethyl-N-(3,3-diphenyl propyl)-1 -amino-2-propanol compound ( IIIA ) in presence of base in protic and aprotic solvent to obtained compound (I)
Reaction (B) can be carried out using by methane sulphonyl halide, p -Toluene sulphonyl chloride, or Benzene sulphonyl chloride using base selected from the group comprising of organic base, inorganic bases. Examples of organic and inorganic bases are Tri Ethyl Amine, Pyridine, sodium hydroxide and potassium hydroxide, sodium carbonates, and the like, at temperature ranging from about -15°C. to 60°C, preferably between -5°C. to 25°C, more preferably between 5°C. to 20°C, optionally in an inert gas atmosphere. The duration of the esterification reaction may be from 15 minutes to 5 hours depending on reagents used and measuring end point of reaction by analytical method such as TLC, HPLC and the like.
Surprisingly inventor have found that use of methane sulphonyl chloride may generates mesylate ester insitu as exemplified in copending application no.H64/MUM/2005 but leads to formation of chloro derivative (Formula 111(B)) instead of mesyl ester of formula III (A) as described herein. The structure elucidation of isolated chloro derivative is supported by the analytical techniques.
Reaction (C) as per the present invention can be carried out using in general by reacting compound (IIIA) with 2,6-dimethyl-5-methoxy carbonyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid of formula (IV) using base selected from the group comprising of organic base, inorganic bases. Examples of organic and inorganic bases are Tri Ethyl Amine, Pyridine, sodium hydroxide and potassium hydroxide, sodium carbonates, and the like, preferably potassium hydroxide, in a solvent to obtained compound (I) at temperature ranging from about -15°C to 90°C, preferably ranging from 0°C. to 40°C, more preferably ranging from 25°C. to 30°C. optionally in an inert gas atmosphere. The duration of the esterification reaction may
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be from 15 minutes to 5 hours. The duration of the condensation reaction may be from 15 minutes to 5 hours depending on reagents used and measuring end point of reaction by analytical method such as TLC, HPLC and the like.
According to an another aspect of the present invention there is provided a new, improved and industrially viable process for the preparation of Lercanidipine Hydrochloride, using a novel intermediate of 2-halo amino derivative of formula III wherein R=X
In an another aspect the present invention provides an improved process for preparing Lercanidipine Hydrochloride (I) as discussed herein: -
The process of the invention is illustrated by the following reaction scheme.
(A)
The 2,N-Dimethyl-N-(3,3-diphenyl propyl)- l-amino-2-propanol Formula (II)
is prepared according to a procedure known in the prior art (US 4705797)

HO Ph^3 (||)
* 3 y r
H
(V) OH
(VI)
(B')
Reacting 2,N-Dimethyl-N-(3,3-diphenyl propyl)-l-amino-2-propanol Formula ( II)
r -^ -Ph

Fh CM Ph
Dlchloromethane i ■.' 'Ph
CH3 CH,
J 3 ---3 ~- .3
(II) (IIIB)
With Halogenating agent in Chlorinated or non chlorinated aprotic solvent to obtained, of N-Dimethyl-N- (3,3-diphenyl propyl)- l-amino-2-halide compound (IIIB) Wherein X = CI, Br, F, or I. In a preferred embodiment X = chloride, R" = thionyl
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chloride, Phosphorous oxychloride, Oxaloylchloride, phosphorous trichloride or phosphorous pentachloride.
Reaction (B') can be carried out using by methane sulphonyl chloride, thionyl chloride, Phosphorous oxichloride, Oxaloylchloride, phosphorous trichloride or phosphorous pentachloride at temperature ranging from about 15°C. to 60°C, preferably between 20°C. to 45°C, more preferably between 25°C. to 40°C, optionally in an inert gas atmosphere. The duration of the esterification reaction may be from 15 minutes to 5 hours.
In a preferred embodiment, reactant used is methane sulphonyl chloride or Thionyl chloride. In a more preferred embodiment, reactant used is methane sulphonyl chloride.
(C): Reacting 2,6-dimethyl-5-methoxy carbonyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid of formula (IV)

with halide compound of N-Dimethyl-N-(3,3-diphenyl propyl)-1-amino compound ( NIB ) in presence of base in protic and aprotic solvent to obtained compound ( I)
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Reaction (C) as per the present invention can be carried out using in general by reacting compound (IITB) with 2,6-dimethyl-5-methoxy carbonyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid of formula (IV) using base selected from the group comprising of organic base, inorganic bases. Examples of organic and inorganic bases are Tri Ethyl Amine, Pyridine, sodium hydroxide and potassium hydroxide, sodium carbonates, and the like, preferably potassium hydroxide, in a solvent to obtained compound (I) at temperature ranging from about 15°C to 90°C, preferably ranging from 20°C. to 60°C, more preferably ranging from 25°C. to 35°C. optionally in an inert gas atmosphere. The duration of the esterification reaction may be from 15 minutes to 5 hours.
The solvent used in (B and B') is selected from the group comprising of ethers, esters, aromatic hydrocarbon, chlorinated or non-chlorinated Aprotic solvents or mixtures thereof.
The ethers that can be used as solvent are selected from the group comprising of diethyl ether, tetrahydrofuran, petroleum ether (60-80°C.) or mixtures thereof.
The esters that can be used as solvent are selected from the group comprising of methyl acetate, ethyl acetate, n-butyl acetate, n-propyl acetate or mixtures thereof.
The aromatic hydrocarbons that can be used as solvent are selected from the group comprising of benzene, toluene, xylene or mixtures thereof.
Chlorinated aprotic solvents that can be used as solvent are selected from the group comprising of Chloroform, chlorobenzene, Dichloromethane, Dichloroethane, 1,1,1-trichloroethane, or any mixture thereof.
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Non-chlorinated aprotic polar solvent that can be used as solvent are selected from the group comprising of Dimethylformamide, Dimethyl sulphoxide and dimethyl acetamide or any mixture thereof.
In a preferred embodiment, the solvent used in Reaction (B and B') is Dichloromethane.
The solvent used in (C and C) can be selected from the group comprising of protic and aprotic solvents or mixtures thereof.
Protic solvents that can be used as solvent are selected from the group comprising of Ethanol, Methanol Isopropyl alcohol, and tertbutanol or any mixture thereof.
Aprotic solvents that can be used as solvent are selected from the group comprising of Chloroform, tetrahydrofuran, and dioxane, Dimethylformamide.
In a preferred embodiment, the solvent used in Reaction (C and C) is Isopropyl Alcohol.
In an another embodiment the present invention provides a process for preparing the Lercanidipine Hydrochloride (I) as discussed herein: -
The process of the invention is illustrated by the following reaction scheme.
(A)
The 2,N-Dimethyl-N-(3,3-diphenyl propyl)-l-amino-2-propanol Formula( II) is prepared according to a procedure known in the prior art (US 4705797)
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With Halogenating agent in Chlorinated or non chlorinated aprotic solvent and then reacting insitu the halogenated compound so obtained with 2,6-dimethyl-5-methoxy carbonyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid of formula (IV) without isolation of formula III(B).
Reaction (B") can be carried out by using methane sulphonyl chloride, thionyl chloride, Phosphorous oxichloride, Oxaloylchloride, phosphorous trichloride or phosphorous pentachloride at temperature ranging from about 15°C. to 60°C, preferably between 20°C. to 45°C, more preferably between 25°C. to 40°C, optionally in an inert gas atmosphere. The duration of the reaction may be from 15 minutes to 5 hours.
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In a preferred embodiment, reactant used is methane sulphonyl chloride or Thionyl chloride. In a more preferred embodiment, reactant used is methane sulphonyl chloride.
The solvent used in B" is selected from the group comprising of ethers, esters, aromatic hydrocarbon, chlorinated or non-chlorinated Aprotic solvents or mixtures thereof.
The ethers that can be used as solvent are selected from the group comprising of diethyl ether, tetrahydrofuran, petroleum ether (60-80°C.) or mixtures thereof.
The esters that can be used as solvent are selected from the group comprising of methyl acetate, ethyl acetate, n-butyl acetate, n-propyl acetate or mixtures thereof.
The aromatic hydrocarbons that can be used as solvent are selected from the group comprising of benzene, toluene, xylene or mixtures thereof.
Chlorinated aprotic solvents that can be used as solvent are selected from the group comprising of Chloroform, chlorobenzene, Dichloromethane, Dichloroethane, 1,1,1-trichloroethane, or any mixture thereof.
Non-chlorinated aprotic polar solvent that can be used as solvent are selected from the group comprising of Dimethylformamide, Dimethylsulphoxide and dimethyl acetamide or any mixture thereof.
In a preferred embodiment, the solvent used in Reaction ( B") is Dichloromethane.
In yet another aspect of the present invention there is provided a novel polymorphic form of Lercanidipine hydrochloride e.g. amorphous form.
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Polymorphism is the occurrence of distinct crystalline forms of a single compound, and have the same molecular formula, but each polymorph may have distinct physical properties. A single compound may give rise to a variety of polymorphic forms, whose physical properties may be distinct and different, such as different solubility profiles, different melting point temperatures and different x-ray diffraction peaks. Due to differing solubility profiles of polymorphs, the identification of pharmaceutical polymorphs is essential for preparing pharmaceutical dosage forms with predictable solubility profiles. Polymorphic forms can be distinguished from each other by various analytical techniques, for example, by x-ray diffraction and infrared spectroscopic techniques.
Crystallization of Lercanidipine hydrochloride is carried out in different solvents / solvent combinations. In one embodiment of the invention, the crystallization is carried out in an organic solvent or water or mixtures thereof. In another embodiment, the organic solvent is an alcohol; ester; tetrahydrofuran; acetonitrile; acetone; dimethyl formamide; toluene or 1,4-dioxane. In another embodiment, the alcohol is selected from the group consisting of methanol, ethanol and isopropyl alcohol. In a further embodiment, the ester is selected from the group consisting of ethylacetate and n-butyl acetate. In yet another embodiment, the solvent used for crystallization is acetonitrile and methanol. In another embodiment, the solvent used is ethyl acetate and methanol. In another embodiment, the solvent used is tetrahydrofuran and methanol. In a still further embodiment, the solvent used is isopropyl alcohol and dimethylformamide. In another embodiment, the solvent used is acetone and dimethylformamide. In another embodiment, the solvent used is toluene and methanol. In a further embodiment, the solvent used is 1,4-dioxane and methanol.
The polymorph of Lercanidipine Hydrochloride in the present invention can be prepared either by a) dissolving Lercanidipine Hydrochloride in a solvent and optionally adding antisolvent b) dissolving Lercanidipine Hydrochloride in solvent
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and adding antisolvent either after distilling the solvent or without distilling the solvent or c) using spray drying process.
In a preferred embodiment, the solvent used is methanol and n-hexane.
The different crystallization experiments carried out in the various solvent(s)/solvent combinations as described above yielded different polymorphic forms of Lercanidipine hydrochloride, characterized by powder x-ray diffraction pattern, DSC, and infra-red spectrum.
While the present invention has been described in term of it's specific embodiments, certain modifications & equivalents will be apparent to scope of the instant invention.
In the following section, embodiments are described by way of examples to illustrate the process of invention; however this does not limit the scope of the present invention. Several variants of these examples would be evident to person's skill in the art.
PREPARATORY EXAMPLES:
Example -1
Preparation of N-(2-chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-
methylamine.
To a solution of lOOgms of 2,N -Dimethyl-N-(3,3-diphenyl propyl)- l-amino-2-propanol(II), 1.3L of dichloromethane, 44gms of triethyl amine, add solution of Methane sulphonyl chloride in dichloromethane (42.4gm. in 0.2L) at 20°-25°C. in 2-2.5hrs. .Stir the reaction mass at 20°- 25°C for 4 hours. Check the content of 2,N-Dimethyl-N-(3,3-Diphenylpropyl)-l-Amino-2-Propanol by HPLC. Charge water at 20°-25°C and stir for 20 minutes and separate layers. Wash the Dichloromethane
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layer with 5 % aq. sodium bicarbonate solution (1.0 L) , water (1.0L) at 25-30°C
respectively. Take Dichloromethane layer and charge Na2SO4(10gm) at 25-30°C.
Filter the solution through cotton cloth and wash the bed with Dichloromethane.
Remove the excess solvent (Dichloromethane) under vacuum below 30°C to give a
heavy oil of N-(2-chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-methylamine
(Yield: 100gms;94%)
1H NMR: 7.330-7.397(8H, m); 7.225-7.284(2H, m); 4.054(1H, t); 2.647(2H, s); 2.548(2H, t); 2.293-2.350(2H, q); 2.462(3H, s); 1.577(6H, s) IR: 1492.8, 1451.3 (Ar.OC), 1107.1 (C-N stretching), 700.1 (C-Cl stretching) Elemental analysis: Carbon - 75.02%, Nitrogen - 4.07%, Hydrogen - 8.39%
Example - 2
Preparation of 3,5-PyridinedicarboxyIic acid, l,4-dihydro-2,6-dimethyl-4-(3-
nitrophenyl)-,2-l{3,3-diphenylpropyl)methylamino|-l,l-diniethyI ester,
hydrochloride [ Lercanidipine hydrochloride) ] (I)
To a stirred solution of 80 gm of 2,6-Dimethyl-5-methoxy carbonyl-4-(3-Nitrophenyl)-l,4-dihydropyridine-3-carboxylicacid, Isopropyl alcohol (0.8L), 20gm of powdered potassium hydroxide, charge solution of N-(2-chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-methylamine in Isopropyl alcohol (lOOgms in 0.2L IPA) under stirring. Stir the reaction mass at 25°-30°C. for 3 hrs. Check the absence of N-(2-Chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-methylamine by TLC. Distill out Isopropyl alcohol completely under vacuum below 50°C. Charge ethyl acetate (2.0L) & Water (1.0L). Stir for 30 min. & separate the layers. Wash the ethyl acetate layer with 1.5 L of 10% Na2C03 solution in three parts at 25°-30°C followed by washing of organic layer charge with brine solution(0.5L) and 1.5 L of 10% HCL in three separate parts followed by brine solution (0.5L) and finally treatment of NaSO4(20gm) to an organic layer. Filter the solution over cotton cloth and wash the bed with ethylacetate( 0.05 L). Charge 0.01 kg of activated charcoal at 25-30°C. Stir at 25-30°C for 30.0 min. Filter the solution over hyflow bed (0.020 kg of hyflow
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slurry in 0.150 L of ethylacetate) Distill out ethyl acetate under vacuum below 50°C. Charge ethylacetate (1.0L) to the reaction mass at 50-55°C and stir at 50-55°C for 30 mins. Cool to 25°-30°C and seed the reaction mass with Lercanidipine Hydrochloride crystals. Stir for 16hrs. at 25°-30°C. Filter the reaction mass and wash the cake with Ethylacetate(0.02L). Suck dried and stir the wet material in ethylacetate (0.8L) for 30.0 min. and filter the material. Wash the bed with Ethylacetate (0.02L). Suck dried for 1 hr and dry the material under vaccum at 30-35°C for 8 hrs till constant weight is attained. (Yield: 95 gm; 47%)
Example -3
Purification of crude lercanidipine hydrochloride
Charge Crude Lercanidipine hydrochloride (0.1 Kg) and Absolute Ethanol (0.3L) at 25-30°C. Heat to 75-80 ° C in 20.0 min. and Stir at 75-80 ° C for 5.0 min to get clear solution. Filter the solution over hyflow bed (0.01 Kg hyflow slurry prepared in 0.02 It of absolute Ethanol) and Wash with absolute Ethanol (0.025 L). Cool to 25-30°C and seed with Lercanidipine hydrochloride (0.0002 Kg) obtained in example 2 above and stir at 25-30°C for 16 hrs. Filter the material and wash the bed with Chilled absolute Ethanol (0.025 L, 0-5°C) and Suck dry the material for 1 hr. Take the wet material and charge absolute Ethanol (0.3 L) at 25-30°C and Heat up to 75-80° C in 20.0 min. Stir at 75-80° C for 5.0 min to get clear solution. Filter the solution over hyflow bed (0.01 Kg hyflow slurry prepared in 0.02 It of absolute Ethanol). Wash the bed with absolute Ethanol (0.025 L) and Cool to 25-30°C and seed with Lercanidipine hydrochloride (0.0002 Kg). Stir at 25-30°C for 16 hrs. and Filter the material and wash the bed with Chilled absolute Ethanol ( 0.025 L, 0-5°C). Suck dry the material for 1 hr and dry the material in vaccum oven under vaccum at 30- 35°C for 8 hrs to get Ethanol below 3000 ppm by residual solvent test. HPLC Purity: -99.9% Yield: 75 gm (75%)
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Example -4
Preparation of N-(2-chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-
methylamine (IIIB)
To a solution of 3.5gm of 2,N -Dimethyl-N-(3,3-diphenyl propyl)-l-amino-2-propanol(II), prepared as described in US Patent 4705797, is reacted with thionyl chloride in presence of methylenechloride for 5 hrs. at reflux tempearature to get N-(2-chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-methylamine (8.5 gm) (Yield: 80%)
Example - 5
Preparation of 3,5-Pyridinedicarboxylic acid, l,4-dihydro-2,6-dimethyl-4-(3-
nitrophenyl)-,2-[(3,3-diphenylpropyl)methyIamino]-l,l-dimethyl ester,
hydrochloride [ Lercanidipine hydrochloride) ] (I)
N-(2-chloro-2-methylpropyl)-N-(3,3-diphenylpropyl)-N-methylamine (HIB)(8.5gm) is reacted with 2,6-Dimethyl-5-methoxy carbonyl-4-(3-Nitrophenyl)-l,4-dihydropyridine-3-carboxylicacid in presence of triethylamine and isopropyl alcohol at 30° to 35° for 2 hr to get Lercanidipine Hydrochloride (8.0gm). (Yield: 47.3%)
Example - 6
Preparation of Amorphous Form of Lercanidipine Hydrochloride
Charge Lercanidipine hydrochloride (10.0 g) and Methanol (30.0 ml) at 25-30DC. and stir for 15.0 min to get clear solution. Filter the solution over hyflow bed(5.0 g of Hyflow is prepared in 30.0 ml of Methanol). Distill out Methanol completely under vacuum at 40-45°C and keep the mass under vacuum at 40-45°C for 30.0 min. Charge n-Hexane (50.0 ml) at 25-30°C. and stir for 30.0 min. Filter the solution and wash the bed with 20.0 ml of n-Hexane and finally dry the material under vacuum below 35°C for 8 hrs. (Dry Wt. 9.5 gm; Yield: 95%)
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ABSTRACT:
The present invention relates to new, improved and industrially viable process for the preparation of Lercanidipine or its pharmaceutically acceptable salts using novel derivatives of 2JN-dimethyl-N-(3,3-diphenylpropyl)-l-amino compounds and novel polymorphs of Lercanidipine hydrochloride, its process of preparation.