SUBRAMANIAM S S (IN)
SWAMINATHAN VENKATRAMAN (IN)
CHANDIRAN THAKASHINA MOORTY (IN)
SUBRAMANIAM S S (IN)
SWAMINATHAN VENKATRAMAN (IN)
| GB2103203A | 1983-02-16 |
| 1. | A process for the manufacture of 2,1, 3benzoxadiazole4 carboxaldehyde comprising: oxidizing 2,1, 3benzoxadiazole4ylmethanol using pyridinium chlorochromate (PCC) as an oxidant. |
| 2. | A process as claimed in claim 1 wherein oxidation is carried out in the presence of a halogenated hydrocarbon solvent. |
| 3. | A process as claimed in claim 1 wherein the amount of pyridinium chlorochromate (PCC) used for the oxidation is about 1.0 moles to 2.0 moles. |
| 4. | A process as claimed in claim 3 wherein the amount of pyridinium chlorochromate (PCC) used for the oxidation is about 1.1 moles to 1.2 moles. |
| 5. | A process as claimed in claim 2 wherein the solvent is dichloromethane. |
| 6. | A process as claimed in claim 1 wherein the oxidation step is carried out at a temperature ranging between5° C to about 20 °C for about 2 to 5 hours and continued at a temperature of about 20° C to 45 °C till the oxidation of 2, 1, 3benzoxadiazole4ylmethanol has reached the desired level. |
| 7. | A process as claimed in claim 6 wherein the oxidation step is carried out at a temperature ranging between 0° C to about 5 °C for about 2 to 3 hours. |
| 8. | A process as claimed in claim 1 further comprising the step of separating 2, 1, 3benzoxadiazole4carboxaldehyde from the reaction mixture. |
| 9. | A process as claimed in claim 8 wherein the separation step comprises: allowing the reaction mixture to settle down in the bottom of the reactor and removing the clear solution filtering the solution through a bed of silica gel to remove the dissolved and suspended chromium salts, washing the filtrate with oxalic acid for removing final traces the chromium salt from the mother liquor washing and concentrating the mother liquor and precipitating the product. |
| 10. | A process as claimed in claim 9 wherein bed of silica gel is prepared by sandwiching the silica gel bed between a hyflo super cell bed. |
| 11. | A process as claimed in claim 9 wherein the concentrate is precipitated using hexane. |
BACKGROUND OF THE INVENTION Isradipine is 4- (4-Benzofurazanyl)-1, 4-dihydro-2,6-dimethyl-3, 5- pyridinedicarboxylic acid methyl 1-methylethyl ester having the chemical structure of formula (I). <BR> <P>(I)
Isradipine is therapeutically indicated for treating cardiovascular diseases. The cardiovascular diseases include angina, pectoris, hypertension and congestive heart failure.
Number of methods for the preparation of Isradipine is described in the literature. All the methods suggested for the preparation of Isradipine proceeds through a key intermediate (2, 1, 3-benzoxadiazole-4- carboxaldehyde) having the structural formula (II).
(II) The patents EP 0000150 and US 4,460, 972 described a process for the preparation of Isradipine, 2, 1, 3-benzoxadiazole-4-carboxaldehyde is reacted together with methyl acetoacetate, isopropyl acetoacetate, and ammonia in ethanol to get a crude product. The crude product was then purified by column chromatography to get pure isradipine.
A modified process was described in GB 2103203. The process described in this patent involved the reaction of 2,1, 3-benzoxadiazole-4- carboxaldehyde with isopropyl acetoacetate and methyl-ß-aminocrotonate in ethanol to get Isradipne.
A single step process for the preparation of Isradipine was described in CH 661270. This procedure involves first reacting 2,1, 3- benzoxadiazole-4-carboxaldehyde with isopropyl acetoacetate, followed by
further reaction with methyl-B-aminocrotonate in refluxing tolune to get Isradipine.
Process for the preparation of this key raw material was described in CH 661270 and CH 661728. The described process starts from 2,1, 3- benzoxadiazole, which was metalated using butyl lithium and diisopropylamine in THF. The metalated intermediate was then formylated using N, N-dimethylformamide to get 2, 1, 3-benzoxadiazole-4- carboxaldehyde, The product 2, 1, 3-benzoxadiazole-4-carboxaldehyde was isolated from the reaction mixture after extensive work up and purification process.
Gasco et al. , European Journal of Medicinal Chemistry (1996), 31 (1), 3-10 described another process for the preparation of 2,1, 3- benzoxadiazole-4-carboxaldehyde starting from 4-methyl-2,1, 3- benzoxadiazole by successive reactions.. Bromination of 4-methyl-2,1, 3- benzoxadiazole with N-bromosuccinamide in the presence of peroxide gives 4-bromomethyl-2, 1, 3-benzoxadiazole, which was hydrolysed with carbonate to get 2,1, 3-benzoxadiazole-4-yl-methanol. Oxidation of 2,1, 3- benzoxadiazole-4-yl-methanol using activated Mn02 gives 2,1, 3- benzoxadiazole-4-carboxaldehyde.
Both the process described in the above mentioned literature references for the preparation 2, 1, 3-benzoxadiazole-4-carboxaldehyde are rather difficult for scale-up. The first process described in CH 661270 and CH 661728 involves a use of butyl lithium and extensive work-up followed by purification steps to prepare 2, 1, 3-benzoxadiazole-4- <BR> <BR> carboxaldehyde. In the second process described by Gasco et al. , the final step of the preparation involves the oxidation of 2,1, 3-benzoxadiazole-4- yl-methanol using activated Mn02. Non-availability of the commercial quantities of consistent quality activated MnO2 presents limitations to scaling up of the process. Also the oxidation of 2, 1, 3-benzoxadiazole-4-yl-
methanol using activated NffiO, was inconsistent as the reaction time, product quality and yield are extremely dependent on the quality of activated Mono.
The present invention consisted of the oxidation of 2,1, 3- benzoxadiazole-4-yl-methanol using pyridinium chlorochromate (PCC) as oxidant. This present invention is able of overcome the problems associated with the process described in the earlier literature.
SUMMARY OF THE INVENTION The object of the present invention is to provide simplified process for the manufacture of 2, 1, 3-benzoxadiazole-4-carboxaldehyde.
To achieve the said object, in the instant invention 2,1, 3- benzoxadiazole-4-yl-methanol is oxidised using pyridinium chlorochromate (PCC) as oxidant in a halogenated hydrocarbon solvent under suitable reaction conditions to get 2, 1, 3-benzoxadiazole-4- carboxaldehyde in good yield and purity.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved and novel method for the manufacture of 2, 1, 3-benzoxadiazole-4-carboxaldehyde, an intermediate for the preparation of 4- (4-Benzofurazanyl)-1, 4-dihydro-2,6- dimethyl-3, 5-pyridinedicarboxylic acid methyl 1-methylethyl ester (herein after referred as Isradipine). In the present invention 2,1, 3- benzoxadiazole-4-yl-methanol is oxidized, using pyridinium chlorochromate (PCC) as an oxidant, in a halogenated hydrocarbon solvent under suitable reaction conditions (Scheme-1). Also described in the present invention is a method of carrying out the said reaction, and a method of separation of the product from the reaction mixture.
2, 1, 3-benzoxadiazole-4-carboxaldehyde 2, 1, 3-benzoxadiazole-4-yl-methanol Scheme-1 The oxidation of 2, 1, 3-benzoxadiazole-4-yl-methanol is carried out using pyridinium chlorochromate (PCC) as oxidant. This reagent has very good selectivity for the oxidation of the alcohol to aldehyde and the oxidation proceeds with small amount of over oxidation of the aldehyde to the corresponding carboxylic acid. The amount of pyridinium chlorochromate (PCC) used for the oxidation is 1.0 moles to 2. 0 moles and preferably 1. 1 moles to 1. 2 moles. The oxidation is performed by adding the solution of 2,1, 3-benzoxadiazole-4-yl-methanol dissolved in a suitable solvent, in to the pyridinium chlorochromate (PCC), suspended in a suitable solvent. Suitable solvents for this process is are halogenated hydrocarbons, and preferably dichloromethane.
The addition of 2, 1, 3-benzoxadiazole-4-yl-methanol solution in to the solution of pyridinium chlorochromate (PCC) could be carried out at- 5 to 20°C over a period of 2 to 5 hr, preferably at 0 to 5°C over a period of 2 to 3 hr. The oxidation is continued after the addition of 2,1, 3- benzoxadiazole-4-yl-methanol in to pyridinium chlorochromate (PCC) at 20 to 45°C till the oxidation of 2, 1, 3-benzoxadiazole-4-yl-methanol is reached to the desired level.
The oxidation reaction is accompanied with the separation of the chromium salts sludge in the reaction mixture. The sludge separating out of the solution is very thick and it hampers the stirring of the reaction mixture during the oxidation reaction. To avoid this stirring problem the stirrer height is properly adjusted to accommodate the sludge well bellow the stirrer level in the reactor.
The reaction mixture is allowed to settle after completion of the oxidation to allow the chromium salts sludge to settle in the bottom of the reactor and the clear solution is siphoned out. The solution then is filtered through a bed of silica gel, preferably prepared by sandwiching the silica gel bed between a hyflo super cell bed. This filtration removes the dissolved and suspended chromium salts from the reaction mixture. The filtrate is washed with oxalic acid solution to remove final traces of the chromium salt from the mother liquor containing the product. The mother liquor is then washed with water, and concentrated. Hexane is added in to the concentrate to precipitate the product.
The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention thereto.
Example-1 Preparation of 2, 1, 3-benzoxadiazole-4-carboxaldehyde Pyridinium chlorochromate (160 g, 0.74 mole) was suspended in dichloromethane (300 ml) and stirred at 25-28 °C for 10 min and then cooled in a ice bath to 0 °C. When the temperature reaches 0 °C added 2, 1, 3-benzoxadiazole-4-yl-methanol (100 g, 0.66 mole) dissolved in dichloromethane (275 ml) drop by drop in to the suspension using an addition funnel. When the addition is over, the reaction mixture was stirred at 25-30 °C and maintained for 2 hours. A sample is then removed from the reaction mixture and analysed by qualitative HPLC. The reaction is continued till the 2, 1, 3-benzoxadiazole-4-yl-methanol is less then 1 %.
Upon reaction completion, the reaction mixture was allowed to settle for 30 min and then filtered through hyflo-silica gel bed prepared by sandwiching Hyflo-silica gel-hyflo (25g-200g-25g). The bed is subsequently washed with three volumes of dichloromethane (3 x 200 ml).
The filtrate obtained is washed first with 10% aqueous oxalic acid (100
ml), and then with water (200 ml, 100 ml). The organic layer is then subjected to distillation to remove dichloromethane. The concentrate was then treated with hexane (200 ml) and cooled to 5°C to precipitate the product. The product is filtered, washed with hexane (100 ml) and dried to obtain the titled product (80 g, purity by HPLC = 98. 2%)