FORM 2
THE PATENT ACT 1970
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A process for the preparation of dihydropyridine compounds.
2. APPLICANT(S)
(a) NAME: Emcure Pharmaceuticals Ltd.
(b) NATIONALITY: an Indian Company
(b) ADDRESS: 'Emcure House', T 184, M.I.D.C., Bhosari, Pune- 411026, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

DESCRIPTION
This invention relates to an improved method for the manufacture of dipine (dihydropyridine derivatives) molecules of high purity with substantially reduced impurities of byproducts and ease of manufacturing. Dipines have been synthesized in the known art through various methods. Several of the currently used synthesis schemes have limitations in that byproducts are produced during synthesis due to non-specific changes in the reactants. These byproducts are difficult to remove in subsequent purification steps, leading to increased impurity levels in the final products. These impurities can limit the use of the final products in pharmaceutical compounds. For example, when dipine molecules are synthesized by Knoevenagel condensation of a benzaldehyde with an acetoacetic ester, the intermediate benzylidene acetoacetic ester is formed, when hydrolyzed in acidic conditions said ester gives corresponding acid that is unstable and several byproducts are simultaneously formed, leading to increased impurities in the final product. To avoid the formation of these byproducts different chemical and purification schemes have been described in the prior art. However, several methods also have practical limitations and there is need for new improved methods for the synthesis of dipine class of compounds. Further there are limitations related to specific dipine molecules as some dipine molecules are relatively easy to synthesis than others due to the presence of different and bulky side chain moieties.
It is known to the skilled person in organic chemical synthesis that in order to obtain highly pure final products, it is a good strategy to avoid formation of byproducts than develop purification methods to remove impurities from the final products. The principal object of this invention relates to an improved method of preparation of dipine molecules for use in pharmaceutical compositions with improved impurity profiles for the impurities due to byproducts of hydrolysis of intermediate benzylidene acetoacetic esters. Another object of this invention relates to the use of new intermediates (t-butylacetoacetate and a chloromethyl ether) previously not used, and new chemistry that significantly increases the utility of the invention in industrial applications.

Accordingly the invention is disclosed in the general Scheme 1 with a reaction sequence for the preparation of clevidipine as an example of the utility of the invention in Scheme 2. In the first scheme moieties R1-4 are: R1 is selected from the group consisting of [2-benzyl(methyl)amino]aminoethyl, 3-R-hydroxy-1-(phenylmethyl)-piperidine, 2-oxopropyl, 2-methoxyethyl, 2-(4-diphenylmethyl)-piperazin-1-yl]ethyl, 99 % by HPLC.

Example 3: Hydrolysis of t-butyl 2,3-dichlorobenzylidene ester in dichloroacetic acid
To a solution of methyl 2,3-dichlorobenzylidene ester (5.0 g, 1.0 mol) in MDC in round bottom flask is added dichloroacetic acid (15.62 g, 4.24 mol) and stirred at 25 °C for 4 h. The sample is checked by TLC for hydrolysis of the ester. No hydrolysis of the ester is detected and more than 60% of the reaction mass remained unchanged after further incubation for 2 h and the reaction discarded.
Example 4: Hydrolysis of t-butyl 2,3-dichlorobenzylidene ester in trichloroacetic acid
To a solution of methyl 2,3-dichlorobenzylidene ester (5.0 g, 1.0 mol) in MDC in round bottom flask is added trichloroacetic acid (19.79 g, 4.24 mol) and stirred at 25 °C for 4 h. The sample is checked by TLC for hydrolysis of the ester, some hydrolysis of the ester is observed. The reaction is further run for 40 °C for 3 h. Hydrolysis of some more of the ester is observed; however, subsequent recovery of the pure product is difficult from the reaction mass due to large amounts of impurities as the reaction does not proceed to full completion.
Example 5: Hydrolysis of methyl 2,3-dichlorobenzylidene ester in TFA
To a solution of methyl 2,3-dichlorobenzyiidene ester (2.0 g, 1.0 mol) in MDC (10 mL) is added trifluoroacetic acid (3.52 g, 4.24 mol) and stirred at 25 °C for 3 h. The sample is checked with TLC for hydrolysis of the ester. MDC is distilled out under vacuum at 45 °C. The residue is charged with water (50 mL) and MDC (50 mL) mixture and stirred for 30 min. After further separating of ester and acid fractions in water/ MDC layers, MDC layer is treated with sodium butyrate. MDC layer is concentrated under vacuum at 40 °C to obtain oily mass of the ester of 0.8 g. Mass and NMR detected this oily liquid as Z isomer of the ester (E isomer of the ester is solid; starting material) no product of hydrolysis or other byproducts of the methyl ester obtained.
Example 6: Hydrolysis of methyl 2,3-dichlorobenzylidene ester in NaOH
To a solution of methyl 2,3-dichlorobenzylidene ester (2.0 g, 1.0 mol) in water

(10 mL) is added under stirring NaOH (0.44 g, 1.5 mol) and heated at 40 °C for 2 h. The sample is checked with TLC for the presence of the ester / acid. Methanol is distilied out under vacuum at 45 °C. The residue is charged with water (40 mL) and MDC (40 mL) mixture and stirred for 30 min and pH is adjusted to 1.0 by HCI. After further separating of ester and acid fractions in water/ MDC layers, MDC layer is treated with sodium butyrate. MDC layer is concentrated under vacuum at 40 °C to obtain solid mass of the ester of 0.1 g (more than 95% consumed in the reaction). Mass and NMR give no clear results due to the presence of many non-specific byproducts of hydrolysis the methyl ester. Similar degradation of happens in the case of isopropyl 2,3-dichlorobenzylidene and t-butyl 2,3-dichlorobenzylidene esters.
Example 7: Hydrolysis of isopropyl 2,3-dichlorobenzylidene ester in TFA
To a solution of 2,3-dichlorobenzaldehyde (25.0 g, 1.0 mo!) in isopropyl acetoacetate (21.62 g, 1.05 mol) is added piperidine (0.6 g, 0.05 mol) and acetic acid (0.43 g, 0.05 mol). The solution is heated at 40-45 °C and stirred for 9 h, and then sample is checked by TLC for completion of the reaction leading to formation of t-butyl 2,3-dichlorobenzylidene ester. To the residue is added methylene dichroride (125 mL) and trifluroacetic acid (69.1 g, 4.24 mol), and reaction is stirred for 4 h at room temperature, sample is checked by TLC for completion of the reaction leading to formation of 2,3-dichlorobenzylidene acid. However, hydrolysis of isopropyl group does not proceed.

5. CLAIMS:
1. A process for the preparation of a compound of the formula 6, comprising the steps of:
Formula 6

(a) reacting a benzaldehyde of the formula 2 Formula 2

in which R3 and R4 are independently selected from the group consisting of hydrogen, chloro, bromo,
butylacetoacetate in the presence of an amine leading to formation of a compound of formula 3;

Formula 3

(b) hydrolysis of a compound of formula 3 using a carboxylic acid leading to the formation and isolation of a stable compound of formula 4; Formula 4

(c) condensation of a compound of formula 4 with a chloromethyl ether of formula 5 Formula 5

in which R1 are selected from the group consisting of
[2-benzyl(methyl)amino]aminoethyl, 3-R-hydroxy-1 -
(phenylmethyl)-piperidine, 2-oxopropyl, 2-
methoxyethyl, 2-(4-diphenylmethyl)-piperazin-1 -
yl]ethyl, (E)-3-phenylprop-2-enyl, (3R)-1-,

benzylpyrrolidin-3-yl, and [{3, 3-diphenylpropyl) (methy!)-amino]-1, 1-dimethyl ethyl groups, leading to the formation of a compound of formula 6; and Formula 6

(d) condensation of a compound of formula 6 with a compound of formula 7 Formula 7

leading to the formation of a compound of formula 1 in which R2 are selected from the group of consisting of methyl, ethyl, an ether and ester groups, alternatively wherein a compound prepared by any of the processes a)-d) is converted to an optical isomer thereof by known reactions.
2. A method for the manufacture of a compound of the formula 1 according to claim 1, and said method having one of the reactants t-butylacetoacetate and a chloromethyl ether of formula 5.
3. A method for the manufacture of a compound of the formula 1 according to claim 1, and said method having trifluoroacetic acid for hydrolysis of t-butyl group.

Formula 1

4- A pharmaceutical composition comprising an effective
amount of a compound according to claim 2.
5 A pharmaceutical composition according to claim 3 in a unit dosage form.
6 A pharmaceutical composition according to claim 3 comprising a compound prepared according to claims 1 to 2 in association with a pharmaceutically acceptable carrier and/or an inactive compound and/or another active compound.
7. A method for modulating the blood pressure in a host
Comprising administering to a host in need of such
treatment an effective amount of a compound according to claim 2.
8. A method of the manufacture of a pharmaceutical composition consisting of a compound of formula 1 as in claim 2 prepared according to claim 1.
9. A compound of formula 4 according to claim 1 that is stable at room temperature and easy to isolate and store.
10. A process for preparing a compound of formula 6 and 1 substantially as described with reference to the examples.