EP1824824A1 - Intermediates for the preparation of lercanidipine - Google Patents
Intermediates for the preparation of lercanidipineInfo
- Publication number
- EP1824824A1 EP1824824A1 EP05812950A EP05812950A EP1824824A1 EP 1824824 A1 EP1824824 A1 EP 1824824A1 EP 05812950 A EP05812950 A EP 05812950A EP 05812950 A EP05812950 A EP 05812950A EP 1824824 A1 EP1824824 A1 EP 1824824A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- dimethyl
- nitrophenyl
- pyridine
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- 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.
- 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 +1 0 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.
- the invention related to a novel intermediates for the preparation of
- Lercanidipine HCl (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.
- 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- ⁇ ropyl 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 method for performing the HPLC was as follows:
- 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 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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
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% 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 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
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL16552504A IL165525A0 (en) | 2004-12-02 | 2004-12-02 | Intermediates and a process for the manufacturing for antihypertensive dihydropyridine derivative suitable for pharmaceutical compositions |
| PCT/IL2005/001290 WO2006059332A1 (en) | 2004-12-02 | 2005-12-01 | Intermediates for the preparation of lercanidipine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1824824A1 true EP1824824A1 (en) | 2007-08-29 |
Family
ID=35945255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05812950A Withdrawn EP1824824A1 (en) | 2004-12-02 | 2005-12-01 | Intermediates for the preparation of lercanidipine |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1824824A1 (en) |
| IL (1) | IL165525A0 (en) |
| WO (1) | WO2006059332A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007031865A2 (en) * | 2005-09-16 | 2007-03-22 | Glenmark Pharmaceuticals Limited | Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof |
| CN102020602B (en) * | 2009-09-18 | 2013-12-25 | 深圳信立泰药业股份有限公司 | Crystal form of lercanidipine hydrochloride and preparation method thereof and crystal form-containing medicinal composition |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8403866D0 (en) * | 1984-02-14 | 1984-03-21 | Recordati Chem Pharm | Diphenylalkylaminoalkyl esters |
| US5767136A (en) * | 1995-05-12 | 1998-06-16 | Recordati, S.A. Chemical And Pharmaceutical Company | 1,4-Dihydropyridines useful for prevention or reduction of atherosclerotic lesions on arterial walls |
-
2004
- 2004-12-02 IL IL16552504A patent/IL165525A0/en unknown
-
2005
- 2005-12-01 WO PCT/IL2005/001290 patent/WO2006059332A1/en active Application Filing
- 2005-12-01 EP EP05812950A patent/EP1824824A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2006059332A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006059332A1 (en) | 2006-06-08 |
| IL165525A0 (en) | 2006-01-15 |
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