Field of Invention

[0001] This invention relates to the preparation and purification of monoesters of 4-aryl-1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, which are key intermediates in the preparation of dihydropyridine calcium channel blockers.

Background of the Invention and Prior Art

[0002] Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial pressure, and a number of diesters of 4-aryl-1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid are currently marketed worldwide as antihypertensive drugs.

[0003] The synthesis of symmetrical dihydropyridine diesters - such as nifedipine - is accomplished via the Hantzsch reaction (condensation of two equivalents of a β-dicarbonyl compound with one equivalent of an aldehyde in the presence of ammonia), whereas dihydropiridines of formula 1 , having two different ester moieties, have to be prepared by alternative routes.

2

X, Y are independently selected from hydrogen, halogen or nitro; R ₂ £ different from each other and selected from Ci-C ₄ alkyl or (CH ₂ ) _m -OR ₃ , where is 1 or 2, and R ₃ is selected from Ci-C ₄ alkyl or Ci-C ₄ acyl.

[0004] Preparation of compounds of formula 1 by derivatization of carboxylic acid intermediates of formula 2 has been described in both the scientific (J. Org. Chem. 2002, 67, 401 ; Tetrahedron Asymmetry 2001 , 12, 3251 ; J. Chem. Soc. Perkin Trans. 1 1993, 525; Chem. Pharm. Bull. 1993, 41, 1049; 1993, 41, 1060; 1991 , 39, 108) and patent (EP 1318147; EP 1 191021 ; US 6,350,762; US 6, 133,443; US 5,767, 131 ) literature; notably, both nimodipine (US 4,510,310) and clevidipine (US 5,856,346) are reported to be prepared in this manner. Similar considerations apply to other unsymmetrically substituted dihydropyridine drugs such as nisoldipine and nitrendipine.

[0005] Compounds of formula 2 are commonly prepared by basic hydrolysis of cyanoethyl esters of formula 3, which can be in turn prepared via the Knoevenagel-Fries modification of the Hantzsch reaction (condensation of one equivalent of a β-dicarbonyl compound with one equivalent of an aminocrotonate and one equivalent of an aldehyde). The synthesis of intermediates of formula 3 is discussed in detail by Ogawa {Chem. Pharm. Bull. 1993, 41, 108 and 1994, 42, 1579), and chromatographic purification is required for obtaining pure samples. The reversible nature of the initial steps of the Hantzsch dihydropyridine synthesis leads to the formation of compounds of formula 4 as a side-product, with as much as 6% of the symmetrical product being observed by Knaus (Org. Prep. Proced. Int. 1996, 28, 91 ). The applicant's experiments have shown similar results.

[0006] Upon hydrolysis, compounds of formula 4 generate diacids of formula 5, alkylation of which produces symmetrical diesters of formula 6 as a contaminant in the desired dihydropyridine. The structural similarities between compounds of formula 1 and those of formula 6 generally result in the latter being particularly undesirable impurities, as their removal is quite difficult and can only be accomplished by multiple crystallizations, at the cost of a significant reduction in yield and associated increase in cost and processing time.

[0007] Despite the problems posed by the formation of diesters of formula 4 during the Hantzsch reaction, no procedures other than column chromatography have thus far been proposed for the purification of intermediates of formulas 2 and/or 3.

[0008] It is an object of the present invention, to provide a novel synthesis of compounds of formula 1 , which involves fewer and simpler purification steps to produce material of pharmaceutical grade.

[0009] It is a further object to provide a novel process for purification of intermediates useful in the synthesis of heterosubstituted diesters of 4-aryl-1 ,4- dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid. Summary of the Invention

[0010] The present invention provides a simple and scalable process for the preparation of substituted dihydropyridine mono-acids of formula 2 of purity suitable for the preparation of API quality unsymmetrically substituted dihydropyridine calcium channel blocker drugs. It comprises a one-pot preparation of crude compound 2, followed by precipitation of its alkali metal salt, essentially free of diacid 5 and salts thereof. The carboxylic acid 2 may be regenerated by addition of strong acid such as phosphoric acid, and may be further purified by suspension in a mixture of acetone and heptane. Overall yield for the process is usually greater than 45%, and purity of the produced carboxylic acid 2 is usually greater than 97%.

[0011] Thus according to one aspect of the invention, there is provided a process of selectively recovering a substituted 1 ,4-dihydropyridine mono-acid of formula:

2 where X and Y are independently hydrogen, chloro or nitro; Ri is Ci - C ₄ alkyl or (CH ₂ )m-OR3 where m is 1 or 2 and R ₃ is Ci-C ₄ alkyl or Ci-C ₄ acyl, from a mixture thereof with the corresponding 2,5-diacid, which comprises adding to an aqueous solution of the mixture a source of alkali metal ions so as selectively to precipitate the alkali metal salt of the mono-acid to the substantial exclusion of the diacid and compounds thereof, and separating the precipitate so formed from the aqueous solution.

Description of the Preferred Embodiments

[0012] Suitable sources of alkali metal ions include sodium chloride, potassium chloride, lithium chloride, sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0013] Pronounced and unexpected differences in solubility were observed when concentrated solutions of sodium chloride or an alkaline metal hydroxide were added to solutions of compounds 2 and 5 in basic media. Whereas the acid 2 is precipitated as the corresponding carboxylate, the salt of diacid 5 stays in solution. In this manner, the level of impurity 5 in samples of compound 2 can be reliably reduced to below 0.5%, even when 5 was originally present in as much as 10%. [0014] The invention is exemplified by, but not limited to, preparation of clevidipine butyrate, in which case the mono-acid of formula 2 is 4-(2,3- dichlorophenyl)-1 ,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxyl ic acid. [0015] Preferably the free mono-acid is regenerated from its carboxylate (salt) after separation, by reaction with strong mineral acid, such as sulfuric acid, nitric acid, hydrochloric acid or phosphoric acid, with phosphoric acid being the preferred choice.

[0016] The relatively low solubility of the salts of carboxylic acid 2 in water leads to volumetrically inefficient processes, which may be deemed unsuitable for scale-up. Accordingly, a preferred embodiment of the process of the present invention uses one or more Ci-C ₄ lower alcohols as co-solvent to address this problem; the salts of compound 2 are very soluble in such alcohols, but the efficiency of the precipitation is not affected by the presence of the organic solvent. Methanol is particularly preferred. As an additional benefit, use of alcohols also results in the precipitation of a more easily filterable solid. Further purification of the separated solid can be effected by washing with acetone/heptane mixture.

[0017] Availability of a method for the purification of mono-carboxylic acid 2 reduces or even eliminates the need for the purification of reaction intermediates, thus allowing the development of a one-pot procedure for the synthesis of this intermediate 2. The synthetic procedure is particularly suitable for large scale manufacturing; it is volumetrically efficient and does not involve chromatography, temperature extremes or solvent exchanges, with the product being isolated by filtration.

[0018] Following purification, the mono-acid is alkylated to introduce the desired second, unsymmetrical ester group, in the known way. In the case of preparation of clevidipine butyrate, this involves reaction with chloromethyl butyrate. [0019] The invention is further described, for illustrative purposes, in the following specific, non-limiting experimental examples.

Specific Description of the Most Preferred Embodiment

Example 1 - Synthesis of crude 5-methoxycarbonyl-4-(2,3-dichlorophenyl)-2,6- dimethyl-1 ,4-dihydropyridine-3-carboxylic acid

[0020] The starting materials 2,2,6-trimethyl-4/-/-1 ,3-dioxin-4-one (89.2g, 0.63 mol) and 3-hydroxypropionitrile (44.6g, 0.63 mol) were heated in an oil bath at 120°C for 3h, during which acetone (the reaction byproduct) was distilled off. The reaction mixture was cooled to room temperature, and isopropanol (570ml_), methyl 3-aminocrotonate (65.7g, 0.57 mol) and 2,3-dichlorobenzaldehyde (100.0g, 0.57 mol) were added. The reaction mixture was heated to reflux, and some of the isopropanol (340m L) was distilled off. The reaction mixture was then cooled in an ice-water bath and dichloromethane (230m L) and a solution of NaOH (28.7g, 0.72 mol) in water (290ml_) were added. After stirring at room temperature for several hours, the reaction mixture was diluted with water and the layers were separated. The aqueous phase was extracted once more with dichloromethane, after which it was cooled in an ice-water bath and phosphoric acid (85%, 25ml_) was added. After precipitation and stirring, the solids were collected by filtration and washed with water. Drying under high vacuum at 40°C gave carboxylic acid 2 as a yellow powder (126 g, 62% yield). Analysis by HPLC indicates a purity of 89.23%, with 3.17% of diacid 5 present.

Example 2 - Purification of 5-methoxycarbonyl-4-(2,3-dichlorophenyl)-2,6- dimethyl-1 ,4-dihydropyridine-3-carboxylic acid

[0021] The crude carboxylic acid 2 from Example 1 (126g, 0.35 mol) was dissolved in a mixture of methanol (230ml_) and a solution of NaOH (34. Og, 0.85 mol) in water (230ml_). The solution was extracted with dichloromethane, and brine was added to the aqueous layer. The solids were collected by filtration and then re-suspended in water and stirred vigorously for 2h, after which the reaction mixture was cooled in an ice-water bath and phosphoric acid (85%, 21 ml_) was added. The solids were collected by filtration and washed with water. After drying under vacuum at 40°C, compound 2 was suspended in a 1 : 1 mixture of acetone and heptane and vigorously stirred for 2h. The solids were collected by filtration and washed with heptane. Drying under high vacuum at 40°C gave carboxylic acid 2 as a beige powder (95 g, 75% yield, 46%overall yield). Analysis by HPLC indicates a purity of 97.28%, with 0.13% of diacid 5 present.

Example 3 - Synthesis of 3-butanoyloxymethoxycarbonyl-5-methoxycarbonyl-4- (2,3-dichlorophenyl)-2,6-dimethyl-1 ,4-dihydropyridine [0022] Purified carboxylic acid 2 (5.00g, 14 mmol) and potassium carbonate (1 .94g, 14 mmol) were suspended in a mixture of 1 ,4-dioxane (25ml_) and water (1 .25ml_). Chloromethyl butyrate (3.26g, 24 mmol) was added and the reaction mixture was refluxed for 4h. The reaction mixture was cooled to room temperature, and heptane (17ml_) and silica gel were added. The solids were filtered off and washed with a mixture of 1 ,4-dioxane and heptane. Isopropanol (20ml_) and water (75ml_) were added to the combined filtrates. The resulting solution was stirred at room temperature and the formed solids were collected by filtration and washed with a mixture of water and isopropanol followed by heptane. Drying for 48h under high vacuum at 40°C gave the title compound as an off-white powder (4.20g, 66% yield). Analysis by HPLC indicates a purity of 99.03%, with no impurity 6 being detected.