CA2701087A1

CA2701087A1 - Preparation of clevidipine butyrate ring the same

Info

Publication number: CA2701087A1
Application number: CA 2701087
Authority: CA
Inventors: Fabio E. S. Souza; Ming PAN
Original assignee: Alphora Research Inc
Current assignee: Alphora Research Inc
Priority date: 2010-04-12
Filing date: 2010-04-12
Publication date: 2011-10-12
Also published as: WO2011127599A1

Abstract

Clevidipine butyrate, O3-(butanoyloxymethyl)-O5-methyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, is prepared by the alkylation of 4-(2,3-dichiorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid tetramethylammonium hydroxide, with chloromethyl butyrate.

Description

PREPARATION OF CLEVIDIPINE BUTYRATE
RING THE SAME

Field of the Invention [0001] This invention relates to clevidipine butyrate, a pharmaceutically active dihydropyridine calcium channel blocker used as a fast acting intravenous anti hypertensive in critical care settings, and processes for its preparation.
Background of the Invention [0002] The synthesis of clevidipine butyrate, 03-(butanoyloxymethyl)-05-methyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, is disclosed in patents US 5,856,346 and US 6,350,877 and comprises the alkylation of carboxylic acid 1, 4-(2,3-d ichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid, with chloromethyl butyrate:

CI a C0 00 O 0 i McO2C I I OH + " -OC- 0~0 02Me H H
1 Clevidipine [0003] Compound 1 is prepared by basic hydrolysis of cyanoethyl ester 2, which can be in turn prepared via the Hantzsch reaction (condensation of two moles of a (3-dicarbonyl compound with one mole of an aldehyde in the presence of ammonia, to form a dihydropyridine), or the corresponding Knoevenagel-Fries modification.

(Cl ~

NC,-,--,o C02Me I I
N
H

1 75907-17(KB) [0004] Preparation of clevidipine as reported in US patents 5,856,346 and 6,350,877 involves reacting a salt of 1 - either generated in situ or pre-formed -with chloromethyl butyrate. The salt of 1 is generated by reaction with an inorganic base, so that the cation is an inorganic cation (specifically sodium or potassium). Depending on reaction conditions, yields range from 66-90%, with purity ranging from 98.8-99.6%, with the best results being reported to be obtained when pre-formed salt of I is employed. However, pre-forming and isolating the salt of I add additional steps to the process, with adverse effects on costs and yields.

[0005] It is an object of the present invention to provide a novel process for the preparation of clevidipine butyrate.

Summary of the Invention [0006] The process according to the present invention uses tetramethylammonium hydroxide (TMAH), an organic base, to generate a salt of compound I wherein the cation is Me4N+ which is alkylated. Yield and purity of the crude material produced are typically greater than 80% and 99.3%, respectively. Use of TMAH eliminates the need to pre-form salt 1. Moreover, the procedure of the invention is robust with respect to the tolerance of high levels of impurities. Starting materials of purity as low as 92.5% can be used, and a pharmaceutically acceptable product obtained.

[0007] Thus according to the present invention, from one aspect, there is provided a process of preparing clevidipine butyrate, which comprises reacting an acid of formula 1:

2 75907-17(KB) CI

Me02C
I I OH
N
H

with tetramethylammonium hydroxide and chloromethyl butyrate.

Description of the Preferred Embodiments [0008] The free acid form of compound 1 is suitably prepared by basic hydrolysis of cyanoethyl ester 2, described above. Then the free acid can be reacted with solid TMAH, optionally in the form of a hydrate, in dioxane solvent. It is also preferred to add a small amount of water, e.g. 2-10% v/v, to the reaction, so as to obtain crude material of suitable quality.

[0009] This reaction to produce the tetramethylammonium salt of compound I
can be conducted at room temperature, with stirring. After substantial completion of the reaction, the chloromethyl butyrate is preferably added to the same reaction vessel, without recovering the carboxylate. The alkylation process proceeds under reflux conditions. When the reaction is complete, the reaction mixture is allowed to cool to some degree, and the organic phase containing the desired solid product is subjected to filtration to recover the solids. After suitable washing and drying, crude clevidipine butyrate is obtained.

[0010] It is preferred according to the invention to subject the crude product to crystallization from a solution in mixed dichioromethane/heptane solvent. This step not only eliminates most of the impurities, but also significantly improves the colour of the final product, so as to yield an off-white solid. Repeating this crystallization step will produce a white solid. A final crystallization from isopropanol/water is also preferably conducted, for further removal of impurities.

[0011] The invention is further described, for illustrative purposes, in the following specific experimental example.

3 75907-17(KB) Specific Description of the Most Preferred Embodiment [0012] To free acid compound 1, 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (50.0g, 140 mmol) and solid Me4NOH=5H2O (30.5g, 168 mmol) were added dioxane (250mL) and water (12.5mL), and the resulting suspension was stirred at room temperature for 45 min. Chloromethyl butyrate (33.0g, 242 mmol) was added and the reaction mixture was refluxed for 5h. Once the reaction was complete, heptane (250mL) was added.

[0013] The aqueous layer was removed, and silica gel was added to the organic phase. The suspension was stirred for 30 min., after which the solids were removed by filtration and washed with a 1:1 mixture of heptane and dioxane.
The filtrate and wash were combined, and isopropanol (250mL) and deionized water (750mL) were added. After agitating for 18h, the solids were collected by filtration, washed with a mixture of isopropanol and deionized water, then with heptane. The crude clevidipine butyrate was dried under high vacuum at 40 C
until constant weight (54.0g, 118 mmol, 84% yield) was achieved.

[0014] Crude clevidipine butyrate (50.0g, 110 mmol) was dissolved in dichioromethane (200mL) and heptane (800mL) was added to the solution. After stirring for 2h, the solids were collected by filtration and washed with a mixture of dichloromethane and heptane, followed by heptane. The clevidipine butyrate was then dried under high vacuum at 40 C for 16h to give an off-white solid (40.5g, 89 mmol, 81 % yield).

[0015] For the final crystallization, clevidipine butyrate (40.0g, 88 mmol) was dissolved in hot isopropanol (400mL). With the solution still hot, deionized water (400mL) was added and the mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with a mixture of deionized water and isopropanol, followed by heptane. Drying under high vacuum at 40 C gave clevidipine butyrate as an off white solid (36.6g, 80 mmol, 91% yield).

4 75907-17(KB)

Claims

1. A process of preparing clevidipine butyrate, which comprises reacting a carboxylic acid of formula 1:

with tetramethylammonium hydroxide and chloromethyl butyrate.

2 The process of claim 1, wherein the process is conducted in dioxane/water solvent.

3. The process of claim 2 wherein the dioxane:water v/v ratio is from about 90:10 to 98:2.

4. The process of claim 1 wherein crude clevidipine butyrate is recovered from the reaction mixture, and subsequently crystallized from a mixed solvent system comprising dichloromethane and heptane.

5. The process of claim 4 wherein the clevidipine butyrate product is subjected to a final recrystallization from isopropanol/water.