WO2006059332A1

WO2006059332A1 - Intermediates for the preparation of lercanidipine

Info

Publication number: WO2006059332A1
Application number: PCT/IL2005/001290
Authority: WO
Inventors: Zvulun Tomer
Original assignee: MOTIVAN Ltd
Current assignee: MOTIVAN Ltd
Priority date: 2004-12-02
Filing date: 2005-12-01
Publication date: 2006-06-08
Anticipated expiration: 2007-06-02
Also published as: EP1824824A1; IL165525A0

Abstract

Intermediates for the preparation of Lercanidipine comprising 1-halo-2-methyl-2-propyl methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-1-pyridine-3,5-dicarboxylate of the formula.

Description

INTERMEDIATES FOR THE PREPARATION OF LERCANIDIPINE

FIELD OF THE INVENTION

The invention is directed to novel intermediates for preparing Lercanidipine hydrochloride, to a processes for the manufacture of these intermediates and their use in preparing Lercanidipine. BACKGROUND OF THE INVENTION

Lercanidipine (methyl 1 , 1 ,N-trimethyl-N-(3 ,3-diphenylpropyl)-2- aminoethyl l,4-dmydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5- dicarboxylate) is a calcium channel blocker of the Dihydropyridine class used mainly in medicines as an antihypertensive medicament in the form of tablets or capsules. It is a highly lipophilic dihydropyridine with long duration of action and high vascular selectivity. Its mechanism of antihypertensive activity is attributed to a direct relaxant effect on vascular smooth muscle, which lowers total peripheral resistance. Lercanidipine has been described along with methods for making it in Israel Patents Nos. 74238 and 118143 and in U.S. Patents Nos. 4,705,797; 5,767,136; 4,968,832 and 5,696,139. Processes for preparing lercanidipine are described in U.S. Pats. Nos. 4,705,797, 4,705,797. US Pat. No. 5,912,351 describes a process for the preparation of lercanidipine hydrochloride by first preparing an intermediate by reacting 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 +1⁰ C. and subsequent esterification of the obtained acid chloride with 2,N-dimethyl-N-(3,3-diphenylpropyl)-l- amino-2-propyl alcohol at a temperature between -10 and 0° C. SUMMARY OF THE INVENTION

The invention related to a novel intermediates for the preparation of

(methyl 1 , 1 ,N-trimethyl-N-(3 ,3 -diphenylpropyl)-2-aminoethyl 1 ,4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride) which is known by its generic name Lercanidipine HCl, and their use in preparing Lercanidipine HCl.

The novel intermediates are l-Chloro-2-methyl-2-propyl methyl 1,4- dihydro-2,6-dimethyl-4-(3 -nitrophenyl)- 1 -pyridine-3 ,5-dicarboxylate and 1 -Bromo-2-methyl-2-ρropyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)-l-pyridine-3,5-dicarboxylate. These intermediates when reacted with N-methyl-3,3-diphenylpropylamine produce Lercanidipine.

The following examples illustrate the method of preparing the intermediates.

Example 1 l-Chloro-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)- 1 -pyridine-3 , 5 -dicarboxylate

31 g (0.26 moles) of thionyl chloride were added dropwise under stirring to a mixture of 78 g (0.235 moles) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid, 420 ml methylene dichloride and 110 ml dimethyl formamide kept at temperature of -2⁰C - +2° under nitrogen. After terminating the addition of the thionyl chloride the stirring was continued under nitrogen for a further hour. To the above mixture a solution of 26 g (0.24 moles) of l-chloro-2-methyl-2-propanol in 60 ml methylene dichloride was added dropwise while stirring under nitrogen at a temperature of -5⁰C - O⁰C. The stirring was continued for 3 hours at O⁰C, afterwards the mixture was allowed to stand for 24 hours at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in 1200 ml of ethylacetate. The organic solution was washed with saturated solution of sodium chloride and afterwards with a solution of 5% Na₂CO_3. The organic layer was separated and dried with Na₂SO₄. The organic solution was evaporated to 500 ml and allowed to stand at O⁰C for 24 hours. The l-Chloro-2-methyl-2-proρyl methyl 1,4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-l-pyridine-3,5-dicarboxylate thus obtained was filtered and dried at 5O⁰C under vacuum. The weight was 58 g ( 58 % yield) of about 98% purity as determined by HPLC analysis, shown in Figure 1.

The method for performing the HPLC was as follows:

HPLC: Merck-Hitachi with autosampler

Column: Symmetry C 18, 4,6 x 250mm (Waters)

Detector: UV 237nm

Mobile Phase: 60% Acetonitrile + 40% buffer pH 4.0

Flow rate: lml/min

Injection Volume: 20μl

Temparature: 3O⁰C

The buffer pH 4.0 was prepared by dissolving 5.14g potassium di- hydrogen phosphate and 2.4 ml triethylamine in 980 ml water with mixing. The pH of the solution was adjusted to 4.0 with phosphoric acid and distilled water was added to make 1 liter, and the solution was mixed.

The product has the following ¹H NMR Spectrum (300 MHz, CDCI₃): 8.11 (lH,m), 8.04 (lH,m), 7.64 (lH,d, J=7.5Hz), 7.37 (lH,t, J=8.1Hz), 3.64 (3H,s), 2.97 (lH,s) 2.90 (lH,s) 2.35 (3H,s) 2.34 (3H,s), 1.47 (3H,s), 1.44 (3H,s). Example 2 l-Bromo-2-methyl-2-propyl methyl l,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)- 1 -pyridine-3 ,5-dicarboxylate.

31 Gms (0.26 moles) of thionyl chloride were added dropwise under stirring to a mixture of 78 g (0.235 moles) of 2,6-dimethyl-5- methoxy carbony l-4-(3 -nitrophenyl)- 1 ,4-dihy dropyridine-3 -carboxylic acid, 420 ml methylene dichloride and 110 ml dimethyl formamide kept at temperature of -2⁰C - +2° under nitrogen. After terminating the addition of the thionyl chloride the stirring was continued under nitrogen for a further hour. To the above mixture a solution of 36.5 g (0.24 moles) of 1- bromo-2-methyl-2-propanol in 60 ml methylene dichloride was added dropwise while stirring under nitrogen at a temperature of -5⁰C - O⁰C. The stirring was continued for 3 hours at O⁰C, afterwards the mixture was allowed to stand for 24 hours at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in 1200 ml of ethylacetate. The organic solution was washed with saturated solution of sodium chloride and afterwards with a solution of 5% Na₂CO₃. The organic layer was separated and dried with Na₂SO₄. The organic solution was evaporated to 500 ml and allowed to stand at O⁰C for 24 hours. The 1 -bromo-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)- 1 -pyridine-3, 5 -dicarboxylate thus obtained was filtered and dried at 5O⁰C under vacuum. The weight was 59 g (53.6 % yield)

Following is an example of preparing Lercanidipine HCl using the intermediate of Example 1. Example 3

Methyl 1 , 1 ,N-trimethyl-N-f 3 ,3 -diphenylpropyl V 2-aminoethyl 1 ,4- dihydro-2,6-dimethyl-4-(3-nitrophenvπ-pyridine-3,5-dicarboxylate hydrochloride

A mixture of 44,6 g (0.105 moles) of l-Chloro-2-methyl-2-propyl methyl l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-l-pyridine-3,5-dicarboxylate and 40,2 g (0.107moles) of N methyl-3,3-diphenylpropylamine in 250 ml xylene in the presence of base, were refluxed under stirring and nitrogen for 10 hours. After cooling to 10-20⁰C the suspension was diluted with diethyl ether and the starting N methyl-3,3-diphenylpropylamine HCl. was separated by filtration. The filtrate was concentrated to about half of its volume and 3,95 g (0.108 moles) of gaseous HCl. was bubbled into the solution aasO-5°C under nitrogen. After 24 hours the suspension was filtered to give 45 g crude methyl l,l,N-trimethyl-N-(3,3- diphenylpropyl)-2-aminoethyl 1 ,4-dihydro-2,6-dimethyl-4-(3 - nitrophenyl)-pyridine-3 ,5-dicarboxylate hydrochloride (Lercanidipine HCL). The crude Lercanidipine HCl. is recrystallized from absolute ethanol to give pure Lercanidipine HCl. suitable for pharmaceutical purposes. Lercanidipine HCl. obtained thus may be formulated into tablets in a conventional manner.

The Lercanidipine HCl can be formulated into a medicine as is known in the art, preferably it is formulated as a tablet. The process of the invention is illustrated by the scheme in Figure 2.

Claims

CLAIMS:

1. l-Chloro-2-methyl-2-ρropyl methyl 1 ,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)- 1 -pyridine-3,5-dicarboxylate.

2. l-Bromo-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-l-pyridine-3,5-dicarboxylate.

3. Process for manufacturing l-Chloro-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 1 -pyridine- 3,5-dicarboxylate comprising: reacting thionyl chloride with l-Chloro-2-methyl-2-proρyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3 -nitrophenyl)- 1 - pyridine-3,5-dicarboxylate in suitable solvent at a temperature between - 4⁰C and + 2⁰C and in an inert atmosphere, adding to the reaction mixture l-chloro-2- methyl-2-propanol with stirring, allowing the resulting reaction mixture to stand at room temperature for a given time, washing and evaporating the solvent, and recrystallizing the product from a different solvent to produce l-Chloro-2-methyl-2-propyl methyl 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-l-pyridine-3,5-dicarboxylate.

4. Process for manufacturing l-Bromo-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 1 -pyridine- 3,5-dicarboxylate comprising: reacting thionyl chloride with l-Bromo-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3 -nitrophenyl)- 1 - pyridine-3,5-dicarboxylate in a suitable solvent at a temperature between - 4⁰C and + 2⁰C in an inert atmosphere, adding to the reaction mixture l-chloro-2-methyl-2-propanol with stirring, allowing the resulting reaction mixture to stand at room temperature for a given time, washing and evaporating the solvent, and recrystallizing the product from a different solvent to produce l-Bromo-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3 -nitrophenyl)- 1 - pyridine-3 ,5-dicarboxylate.

5. Process for manufacturing Lercanidipine and Lercanidipine HCl as disclosed the specification.

6. Lercanidipine and Lercanidipine HCl. prepared according to the process of claim 5.

7. Tablets for pharmaceutical use containing Lercanidipine HCl prepared by the method disclosed in the specifiction.