FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
1. TITLE OF THE INVENTION:
Improved process for the synthesis of Lercanidipine Hydrochloride
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field of the Invention:
The present invention relates to an improved and efficient process for the synthesis of lercanidipine hydrochloride and its polymorphs.
Background of the Invention:
l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate also termed as Lercanidipine, Hydrochloride (I)

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which belongs to a group of drugs called calcium channel blockers, which act on the heart and blood vessels. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. Lercanidipine was first disclosed in patent US4705797, it discloses a process for the synthesis of lercanidipine as shown in Scheme-I.


According to the above scheme, amino alcohol (1) is esterified with diketene in toluene at 80°C and this reaction takes 2-3 hours for completion to form the corresponding acetoacetate (2) and the product needs to be purified using flash chromatography as the reaction generates many impurities as stated by the applicant. The compound (2) is further reacted with 3-nitrobenzaldehyde in chloroform in presence of HC1 at 15°C for 2 days to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3) and is purified using flash chromatography. (3) is further cyclised with methyl 3-aminocrotonate in isopropanol by heating at reflux temperature for 3.5 hours to give crude lercanidipine which is purified by flash chromatography using chloroform, containing increasing amounts of acetone, as the eluent. After evaporation of the solvent, the hydrochloride salt is prepared by treatment with diluted hydrochloric acid.
There are several shortcoming in the process of preparing lercanidipine, as it is described in US 4705797, and the disclosed reactions generates several by-products, and all the intermediates are purified using flash chromatography which results in a lower yield of the desired product. Also the purification and isolation of lercanidipine from the reaction mixture is difficult, since it requires numerous treatments with different solvents. Finally, the purification and isolation steps for lercanidipine are difficult to perform on an industrial scale because of the necessity of purifying the product by column chromatography.
The process described in US4705797 results in the formation of several by-products in all the stages, which requires cumbersome purification technique like column chromatography. The process results in Lercanidipine hydrochloride hemi hydrate, which is hygroscopic in nature. The overall yield of the process is 23%. These shortcomings make the process not suitable for industrial scale up.
Hence there is a need for an industrially suitable process that avoids the use of the hazardous reagent also eliminates the need for column purification.
US 4705797; US5767136; US 4968832; US5912351; and US5696139 describes process for preparing Lercanidipine and resolving it into individual enantiomers.
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WO 9635668 discloses an alternate process (Scheme-2) for the synthesis of lercanidioine
hydrochloride
which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity.
The process employs the use of a monocarboxylic acid (4) as a starting material which is
prepared by hydrolysis of its diester which results in dicarboxylic acid impurity and
further purification is required to isolate the intermediate (4).
US 5,912,351 describe method for the preparation of anhydrous lercanidipine
hydrochloride.
WO03/014084 discloses novel crude forms A & B of lercanidipine and novel crystalline Forms I an II of lercanidipine hydrochloride obtained from above crude forms and method of their preparations. Crude Lercanidipine Hydrochloride Form A has a melting point of 150-152°C (on DSC) and it comprises about 3-4% ethyl acetate. Crude Lercanidipine Hydrochloride Form B has a melting point 131-135°C (on DSC) and it comprises about 0.3-0.7% ethyl acetate. It also describes Lercanidipine crystalline form I with XRD and having melting point of 197-201°C (on DSC). It further describes Lercanidipine crystalline form II with XRD and having melting point 207-211°C (on DSC). The invention also describes the mixture of Form I and Form II.
WO 03/014085 discloses solvates and new crystalline Polymorphic forms of Lercanidipine Hydrochloride forms III and IV and further provides method for synthesis of crystalline form (I) of Lercanidipine HC1 by de-solvating the solvates of anisole and tert butyl methyl ether with Lercanidipine HC1.
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There are very few processes described in the prior art for the synthesis of lercanidipine hydrochloride. As the technology evolves, new processes are reported, but no attempts were made in the past to develop an efficient and economical process for preparation of lercanidipine hydrochloride. Therefore the present inventors felt a need to develop a commercially useful process for preparation of lercanidipine hydrochloride in good yields with high purity by overcoming the short comings of prior art.
Brief Description of the Drawing:
The invention is illustrated by reference to the accompanying drawings described below Figure 1 shows powder X-ray diffractogram of the Form 'V crystalline polymorph of Lercanidipine Hydrochloride.
Summary of the invention:
According the present invention, there is provided an improved and cost-effective process for preparation of lercanidipine hydrochloride with good yield and high purity. In one aspect of the invention, the commercially available compound of formula (I) is purified by converting into its acid addition salt and further reacting the same with 2,2,6-trimethyl-1,3 dioxane-4-one, to obtain the product (II) with good purity.
In another aspect, the compound (II) is reacted with nitrobenzaldehyde in presence of
catalytic amount of base and a dehydrating agent to obtain the compound (III) in
substantially pure form.
In a further aspect, the compound (III) is cyclised with methyl-3-aminocrotanate in a
solvent selected such that the boiling point/reflux temperature is below 70C, in presence
of a dehydrating agent to give lecarnipidine, which is further converted to lercanipidine
hydrochloride.
Detailed Description of the Invention:
The present invention describes an improved and commercially useful process for the preparation of Lercanidipine hydrochloride. In particular, the invention describes the preparation of the precursor of lercanidipine hydrochloride having substantially good purity thereby increasing the yield of final product in a cost effective manner as compared to the processes disclosed in the prior art.
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Substantially pure as described in the application herein refers to compound having HPLC purity of more than 99%.
The present invention provides an improved process for synthesis of lercanidipine of formula given below or its pharmaceutically acceptable salts thereof

which process comprises reacting substantially pure compound (I) with 2,2,6-trimethyl-
1,3 dioxane-4-one

to yield substantially purel,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-amino ethyl
acetoacetate (II)

which is reacted further with 3-nitro benzaldehyde under conditions herein described to yield substantially pure l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-
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acetyl 3-nitro cinnamate (III)


which is finally reacted with methyl 3-amino crotonate to yield Lercanidipine hydrochloride in substantially pure form.
A process according to the present invention of preparing lercanidipine hydrochloride can thus be represented by the following reaction scheme

Lercanidipine HCI
In one embodiment of the present invention, compound (I), which is commercially available with low purity, is purified using simple process by converting (I) to its acid addition salt and isolating a substantially pure compound (I) thereby obtaining the
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compound (II) with good yield and purity in the subsequent process step. The preferred acid for preparing the salt is selected from oxalic acid, mandelic acid tartaric acid, citric acid, fumaric acid preferably salicylic acid.
Typically the compound (I) is purified by refluxing with salicylic acid in a suitable organic solvent selected from alcohols, ethyl acetate, toluene, and acetone preferably isopropyl alcohol and isolating a substantially pure salicylate salt of compound (I).
In another embodiment of the present invention the compound (I) is reacted with 2,2,6-trimethyl-1,3 dioxane-4-one using a non polar solvent and the reaction is carried out in distillation mode giving rise to substantially pure l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-amino ethyl acetoacetate (II).
Typically the compound (I) is reacted with 2,2,6-trimethyl-l,3 dioxane-4-one in toluene at temperature of about 105-110°C in distillation mode and certain amount of distillate is collected during the reaction, the reaction goes to completion in about 30 mins and avoids the formation of impurities. The reaction is worked up using standard techniques to give substantially pure compound (II).
In a further embodiment of the present invention the compound (II) is reacted with 3-nitrobenzaldehyde in presence of catalytic amount of base and a dehydrating agent, preferably molecular sieves to give substantially pure l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (III).
Typically the compound (II) is reacted with 3-nitrobenzaldehyde in presence of catalytic amount of piperidine and acetic acid and dried molecular sieves by refluxing in dichloromethane for about 5-6 hours. The reaction is worked up using standard techniques to give substantially pure compound (III).
In yet another embodiment of the present invention the compound (III) is cyclised with methyl 3-aminocrotonate in a solvent mixtures selected such that the boiling point/reflux temperature or the reaction temperature is below 70°C and in presence of a dehydrating agent to give lercanidpine hydrochloride. The solvent is selected from group comprising
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C1-C4 alcohols, methyl isobutyl ketone, acetone, toluene, THF or mixtures thereof. The reaction is preferably carried out using methanol as solvent and at temperature below 70°C.
Typically compound (III) is cyclised with methyl 3-aminocrotonate in methanol and in presence of a dehydrating agent preferably molecular sieves by heating at a temperature of about 60-65°C for about 7-8 hrs. The reaction mass is filtered hot and the filtrate is concentrated to residue. The residue is dissolved in dichloromethane, washed with water and stirred with IN HC1 and followed by brine solution. The separated organic layer is concentrated to residue. The residue is then dissolved in methyl isobutyl ketone and stirred at 25-30°C till complete precipitation of product. The solid is filtered and slurried in methyl isobutyl ketone and filtered. The product is dried under vacuum at 85°C to give Lercanidipine Hydrochloride.
In yet another embodiment, the present invention describes the use of methyl isobutyl ketone for enhancing the purity of Lercanidipine hydrochloride. Methyl isobutyl ketone selectively eliminates the impurities formed during the reaction by facilitating the crystallization of lercanidipine hydrochloride in the form of a solvate. Typically a MIBK solvate of lercanidipine hydrochloride contains 0.5% to 6% MIBK. Desolvation of lercanidipine hydrochloride MIBK solvate can be done by drying at elevated temperature or suspending in a non-volatile solvent for sufficient period of time to effect desolvation.
According to the present invention there is further provided crystalline Lercanidipine hydrochloride hereinafter referred to as Form V, which is substantially non-hygroscopic and has good flow characteristic.
Crystalline Lercanidipine Hydrochloride Form V according to the present invention can be prepared by drying the methyl isobutyl ketone solvate at about 85°C under vacuum.
Crystalline Lercanidipine Hydrochloride Form V according to the present invention is further characterized by having a melting point of about 174-180°C
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Crystalline Lercanidipine Hydrochloride Form V according to the present invention is further characterized by X-ray powder diffraction spectrum as shown in Fig 1.
Crystalline Lercanidipine Hydrochloride Form V is further characterized by having characteristic peaks (2 0°) at 10.660, 11.460, 11.720, 13.337, 14.483, 15.060, 16.480, 16.962, 17.180, 17.838, 19.352, 19.799, 20.240, 20.502, 21.339, 21.859, 22.420, 24.560, 25.081, 25.582, 27.282, 28.839, 29.999, 35.939 ± 0.2 0°.
Further characteristic data for crystalline Lercanidipine Hydrochloride Form V according to the present invention as obtained by X-ray powder diffraction spectrum measured on a Rigaku Miniflex advance X-ray powder diffractometer having a copper-k-a radiation is
shown in Table 1.
Table-I

Diffraction angles (20°) Relative Intensity (IAO)
7.060 6.0
4.422 14.3
10.660 24.5
11.460 37.9
11.720 35.0
12.859 11.9
13.337 21.8
14.483 15.4
15.060 100
15.739 15.7
16.480 26.2
16.962 37.4
17.180 50.3
17.838 42.9
19.352 20.9
19.799 58.9
20.240 25.4
20.502 34.2
21.339 39.2
21.859 16.5
22.420 41.7
23.622 5.9
23.935 7.1
24.560 33.3
25.081 21.6
25.582 17.8
26.855 5.9
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27.282 10.4
28.839 19.3
29.999 17.6
30.619 8.5
31.179 4.5
33.159 5.5
33.258 6.3
33.806 4.0
35.381 6.9
35.820 8.2
35.939 10.1
38.837 3.9
38.980 4.8
The nature of the invention, its object and advantages are explained hereunder in greater detail in relation to non-limiting exemplary embodiments.
Examples Example 1
Preparation of l-(3,3-diphenyl-N-methylpropylamino)-2-methyl-2-propanol salicylate (I)
l-(3,3-diphenyl-N-methylpropylamino)-2-methyl-2-propanol base (I) ( 500 gm.) was stirred in 3500 ml of isopropyl alcohol and solution of salicylic acid in isopropyl alcohol (255 gms dissolved in 2.0 ltrs isopropyl alcohol) was added and stirred for 30 min at 27°C. The reaction mass was then refluxed to get clear solution. The solution was cooled gradually to 27 °C to obtain white precipitate. The resulting solid of l-(3,3-diphenyl-N-methylpropylamino)~2-methyl-2-propanol salicylate salt was filtered and dried under vacuum at 50-60°C for 8 hrs. to get 600 gms of the titled compound having an HPLC Purity of about 99%.
Example 2
Preparation of l,l-N-trimethyl-N-(3,3-diphenylpropyl)-2-amino ethyl acetoacetate (II).
l-(3,3-diphenyl-N-methylpropylamino)-2-methyl-2-propanol base (I) (100 gms) was obtained by basifying its salicylate salt (147 gms) using 5 % sodium carbonate solution.
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The l-(3,3-diphenyl-N-methyl propyl amino) -2-methyl-2-propanol base was dissolved in toluene 1.5 ltrs. was reacted with 2,2,6-trimethyl -1,3 dioxane -4-one (34 ml) at 105°C-110°C in distillation mode for 30 min. to recover about 250 ml of distillate. The reaction mass was then cooled to about 20°C and about 750 ml 1 N HC1 was added to the reaction mass and stirred for 30 min. The reaction mass was allowed to settle and the above toluene layer was separated. The reaction mass was again stirred with 500 ml of toluene and allowed to settle. The upper toluene layer was separated. The aqueous reaction mass was basified using 50% aqueous sodium carbonate solution below 20°C and extracted with dichloromethane 3X 500ml. The organic layer was dried and evaporated under vacuum to obtain 80 gms of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-amino ethyl acetoacetate (II). having HPLC Purity of about 99%.
Example 3
Preparation of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-
nitrocinnamate Hydrochloride (III)
3-nitrobenzaldehyde (32 gms) and l-N-trimethyl-N-(3,3-diphenyl propyl)-2-amino ethyl acetoacetate base (II) (800 gms) was stirred in 2.0 ltrs. of dichloromethane, piperidine (6ml) and acetic acid (4 ml) was added to the reaction mass under inert atmosphere. 200 gms of Dried Molecular sieves Type 4A° was added to the reaction mass and refluxed for 5-6 hrs. The reaction mass was filtered hot through celite bed. The filtrate was evaporated under vacuum to residue. The residue was dissolved in toluene (350 ml) and cooled to 20°C. To the reaction mass about 800 ml of IN HC1 was added and stirred for 30 min and allowed to settle. The toluene layer was separated. The reaction mass was again stirred with 500 ml toluene and settled. The toluene layer was separated and discarded. The reaction mass was then extracted with 3X500 ml dichloromethane. The dichloromethane layer was dried and concentrated to residue at a temperature below 40°C to get 120 gms of (III) having HPLC purity of about 99.1%, Yield : 85 %.
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l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl-a-acetyl 3-nitrocinnamate
Hydrochloride (III) (120gms) was dissolved in 2.0 ltrs. of methanol, 26 gms of methyl-3-amino crotonate and 50 gms of dried molecular sieves type 4A0 was added and the reaction mass was refluxed 8-9hrs . The reaction mass was filtered hot through celite bed. The filtrate was evaporated under vacuum to residue. The residue was dissolved in 1000 ml of dichloromethane. The organic layer was successively washed with water, IN HC1 and brine solution. The organic layer was dried over sodium sulfate and concentrated to residue. The residue was dissolved in 1.6 ltrs. methyl isobutyl ketone and stirred until complete precipitation of lercanidipine Hydrochloride was observed. The solid was filtered and slurried in 1000 ml of methyl isobutyl ketone. The product was dried under vacuum at 85°C to give lercanidipine hydrochloride having HPLC purity 99.5% melting point 174-180°C.
Example 4
Preparation of Lercanidipine Hydrochloride
Dated this 9th day of August 2006