FIELD OF INVENTION:
The present invention directed to an improved process for the manufacture of isradipine(I) (international non-proprietary name) otherwise chemically known as 4-(4-benzofurazanyl)-l,4-dihydro-2, 6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester, as shown in Diagram 1, is used as an antihypertensive and antianginal drug. More particularly the present invention relates to the e manufacture of isradipine(I) of substantially high purity and relatively free from other impurities.
BACKGROUND OF THE PRESENT INVENTION
Isradipine(I) known as 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester having structural formula(I) is therapeutically used for cardiovascular diseases including angina, pectoris, hypertension and congestive heart failure. This is illustrated in Diagram 7.
Isradipine was disclosed in the German Patent DE294991 and US 446672.
The above two patents describes a general method for the prepation of 1,4 dihydropyridine derivative.
Preparation of benzodiazoles and their derivatives of general formula II is disclosed inGB0210323A, Lu0088342A9, EP00000150B1, AU0538515B2 and other related patents. This is illustrated in Diagram 8.
Wherein isradipine is referred to as Rl is CH3 and R2 -CH (CH3).
The procedure described in the above said patents for the production of isradipine(I), invariably leads to the formation of impurities a). 4-(4-

benzofurazayl)-1, 4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid
dimethyl ester(III) b). 4-(4-benzofurazayl)-l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid di-1-methylethyl ester(IV), as illustrated in Diagram 9, along with isradipine.
US 4466972 describes a method to produce compounds of general formula(I) in which 2,1,3- benzoxadiazole-4-carboxaldehyde(V) as illustrated in Diagram 10, alkyl acetoacetate and concentrated ammonia or beta amino ester are refluxed in ethanol. All these methods generates impurities above described impurities III &IV, which are very difficult to remove due structural similarity with isradipine (I). Thus all these procedure are not amenable for scale up, as they require chromatographic separation to get pure isradipine.
A single step synthesis of isradipine(I) is disclosed in CH 661270 in which
2,1,3- benzoxadiazole-4-carboxaldehyde(V) is reacted with
isopropylacetoacetate in the presence of acetic acid and piperidine in toluene. With out isolating the intermediate the reaction mixture is further reacted with methyl -p-aminocrotonate(VI), illustrated in Diagram 10. This crude product thus obtained after the distillation of toluene is recrystallized in ethanol to get pure isradipine (I). Since the intermediate is neither isolated nor purified, the method invariably end off giving higher amounts of impurities III and IV which is illustrated in Diagram 9.
A two-step synthesis was disclosed in WO 2005/005437A for the preparation of isradipine (I). The first step involves the reaction of 2,1,3- benzoxadiazole-4-carboxaldehyde (V) with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether to get an intermediate namely 2-acetyl-3-benzofuran-4yl-acrlic acid methyl ester(VII), illustrated in Diagram 10, with the yield 78% and the purity 93.4%. This intermediate is further purified by crystallizing the same with diisopropyl ether to get 2-acetyl-3-benzofuran-4-yl-

acrlic acid methyl ester(VII) of the purity 99.2% , the yield 61% containing of 2,1,3- benzoxadiazole-4-carboxaldehyde (V) 0.12%
The second step of the process involves the reaction of the purified 2-acetyl-3-benzofuran-4yl-acrylic acid methyl ester (VII) with isopropyl -(3-aminocrotanoate (VI) in absolute ethanol to get crude isradipine (I). The crude isradipine (I) thus obtained is further crystallized in ethanol to get isradipine (I)of the yield 67%, with the purity 99,5%, with the impurity III, 0.2% and impurity IV, 0.12%. Further purification using solvents like ethyl acetate followed by ethanol does not change the impurities level.
Thus the process suffer draw back of lower yield and the cumbersome purification process.
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a better and simple method for the production of isradipine (I) namely 4-(4-benzofurazanyl)-l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-methylethyl) ester, illustrated in Diagram 1.
Yet another objective of this invention is to produce isradipine(I) with very high quality and relatively free from impurities
Yet another objective of this invention is to provide a process produce for the key intermediate namely Z& E isomers of 2-benzo[2,l,3]-oxadiazole-4-ylmethylene-3-oxo-butyric acid methyl ester(VII), shown in Diagram 2, with very high purity free from other impurities
Detail description of the invention
The present invention is to provide a simple method for production of isradipine(I) consists of following three steps as shown in the scheme -1

Stage-01
In the stage-01, which is illustrated through Diagram 4, 3-aminocrotonoic acid isopropyl ester (VI), as shown in Diagram 3, is prepared by treating 3-aminocrotonoic acid isobutyl ester with ammonium acetate in a solvent or of mixture of solvent from a group consisting of alkane C4 to CIO, more preferably heptane. The reaction was carried out with continuous removal of water at temperature 60-120°C more preferably 80-100°C The crude product was isolated by the filtration of excess ammonium acetate, followed distillation heptane. Then the crude product was fractionally distilled to get pure 3-aminocrotonic acid isopropyl ester (VI) under vacuum
In the stage-02, which is illustrated through Diagram 5, 2,1,3- benzoxadiazole-4-carboxaldehyde (V) is reacted with methyl acetoacetate in the presence of acetic acid and di-(n-butyl)amine in a or mixture of halogenated solvents from a group consisting methylene dichloride, chloroform , EDC, chlorobenzene. more preferably methylene chloride . The reaction is carried out preferably at 25°C to 100°C, more preferably at the reflux temperature of methylene chloride with removal of water formed in the reaction. After complete removal of halogenated solvent, the residue is treated with a mixture of heptane to get product Z&E isomers of 2-benzo [2,l,3]-oxadiazole-4-yl methylene-3-oxo-butyric acid methyl ester (VII) with very high purity 99% and yield. Ratio of isomer is in range of 51.5-53.53 : 49.0-45.49 with RRT 2 & 2.645 with reference to aldehyde. This isomeric mixture is used as such for further reaction. These isomers are isolated by column chromotography further characterized by NMR 86 L.C-MS.
E- isomer RRT at 2, NMR in CDC13 -COCH3- as singlet at 6 2.52; -COOCH3 as singlet at 8 3.84; -C=CH- as singlet at 8 7.968; aromatic C5-protons as doublet at 87.92-7.97, C6 protons as doublet at 87.58-7.6 and C7 protons as mutiplet at 87.45-7.5. LC -MS showed M+H -247.

Z- isomer RRT at 2.645, NMR in CDC13 -COCH3- as singlet at 6 2.46; -COOCH3 as singlet at 8 3.9; -C=CH- as singlet at 8 8.04; aromatic C5-protons as doublet at 87.87-7.9, C6 protons as doublet at 87.5-7.52 and C7 protons as mutiplet at 67.41-7.45. LC -MS showed M+H -247.
In stage-03, as shown in Diagram 6, the mixture of Z&E isomers of 2-benzo [2,l,3]-oxadiazole-4-yl methylene-3-oxo-butyric acid methyl ester (VII) is reacted with 3-aminocrotonoic acid isopropyl ester(VI) in a solvent or a mixture of solvent from a group consisting of alkane C4 to CIO with dialkyl ether of glycols, more preferably dimethoxyethane and heptane
The reaction is carried out at temperature 30-120 °C more preferably 80-95°C. Further after completion of reaction, the crude precipitated product is filtered, dissolved in dimethoxymethane, treated with charcoal filtered and cooled to 10-15°C. The product crystallized thus was filtered and dried.
DESCRIPTION OP THE PREPARED ENBODIMENTS
The scope of the preferred embodiments of the present invention is further illustrated by following non-limiting examples:
EXAMPLE-01
Preparation of 3-aminocrotonoic acid isopropyl ester (VI).
A mixture of lOOgm (0.693 mole) of isopropylacetoacetate, 75gm (0.973mole) ammonium acetate and 500ml heptane is heated to 80-100°C for 5 to 10 hours. Water formed during the reaction was separated by azeotropic distillation using dean stark apparatus. The ammonium acetate remain un-reacted was isolated by cooling and filtering the mass. Then the heptane is distill out completely at reduced pressure to obtained crude product which was purified by fractional distillation to yield 66 gm pure product (66.45%) of GC purity 99.9%.


A mixture of 2,l,3-benzoxadiazole-4-carboxaldehyde 50 gm (0.337 mole), methylacetoacetate 48gm (0.41mole), di-n-butylamine 7.5gm (0.058 mole) and acetic acid 7.5 gm (0.12 mole) was refluxed in methylene chloride 465gm for 7 to 9 hours. After completion of reaction, reaction mass was cooled and washed with water. Methylene chloride was distilled off at reduced pressure. To the gummy residue, hexane was added and stirred for 30min. The formed powered product was isolated by filtration, washed with water and dried to gave 78gm yield 94% of HPLC purity 99%. (sum of Z&E isomers - with the ratio 51.5-47.5) NMR in CDC13 -COCH3-at 8 2.47&2.52 as two separate singlets in the ratio of 4:3; -COOCH3 at 6 3.84&3.91as two separate singlets in the ratio of 3:4; -C=CH- at 8 7.968&8.041as two separate singlets in the ratio of 4:3: out of aromatic protons one H at 67.87-7.92 as multiplet, second & third H as broad multiplets 8 7.2 -7.59. LC -MS of both peaks showed M+H -247 confirming the products are isomers

Isopropyl ester of 3-aminocrotonoic acid (VI) 33gm (0.23 mole) and 2-benzo [2,l,3]-oxadiazole-4-ylmethylene-3-oxo-butyric acid methyl ester (VII) 55 gm (0.223 mole) was heated to 80 to 85°C in a solvent mixture of heptane 30 gm and dimethoxyethane 36gm for 3hr. After completion of reaction, the reaction mixture was cooled and product was filtered out from the reaction mixture. The crude product was dissolved in 72gm of dimethoxyethane. The solution was heated to 60-65°C, treated with activated charcoal and filtered. The filtered

solution was then cooled slowly 10-15°C to crystallize, The product namely 4-
(4-benzofurazanyl)-l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid
methyl 1-methylethyl ester(I) was filtered and dried. Yield is 61gm ( mole 74%) with purity of 99.8% to 99.9% by HPLC, m pt 168°C.
The product was further characterized by IR, NMR and Mass spectroscopy.

WE CLAIM:
1. A method for the manufacture of 4-(4-benzofurazanyl)-l,4-dihydro-2,6-
dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester(I), isradipine
comprise of the following inventions
a) Preparation Z&E isomers of 2-benzo [2,l,3]-oxadiazole-4-ylmethylene-3-oxo-butyric acid methyl ester(VII) with the purity more than 99% by reacting 2,1,3-benzoxadiazole-4-carboxaldehyde(V) with methyl acetoacetate in the presence of acetic acid and dibutyl amine in halogenated solvents
b) Preparation of 3-aminocrotonoic acid isopropyl ester(VI) by the reaction of isopropyl acetoacetate with ammonium acetate in or of mixture of C3-C8 alkane with continuous removal of water at temperature range from 50-120°C
C) Preparation of isradipine(l) namely 4-(4-benzofurazanyl)-l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester by the reaction of 2-benzo [2,l,3]-oxadiazole-4-yl methylene-3-oxo-butyric acid methyl ester(VII) with 3-aminocrotonoic acid isopropyl ester(VI) a solvent or a mixture of solvent from a group consisting of alkane C4 to CIO with dialkyl ether of glycols.
2. The process according to the claim 1a. the most preferred solvent is
dichloromethane
3. The process according to the claim l.a the most preferred temperature is the
reflux temperature of dichloromethane
4. The process according to the claim l.a the molar ratio of dibutyl amine to
2,l>3-benzoxadiazole-4-carboxaldehyde islO to25 mole%, most preferred
ratio 17 mole %

5. The process according to the claim l.a the molar ratio of acetic acid to
dibutyl amine is in the range of 1-3 and more preferably 2.068
6. The process according to the claim l.a. the ratio mixture Z&E is 1:1 more
exactly 46-49 to 54 -51
7. The process according to the claim Lb, alkane or of mixture of alkane from a
group consisting of alkane C4 to C10, more preferably heptane.
8. The process according to the claim l.b in the reaction was carried out with
continuous removal of water at temperature 60-120°C more preferably 80-
100°C
9. The process according to the claim I.e. the 1:1 mixture of solvent is
dimethoxy ethane and heptane by volume
10. The process according to the claim I.e. the most preferred temperature is
80 to 85°C