WO2005023787A1 - Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde - Google Patents
Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde Download PDFInfo
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- WO2005023787A1 WO2005023787A1 PCT/IN2003/000305 IN0300305W WO2005023787A1 WO 2005023787 A1 WO2005023787 A1 WO 2005023787A1 IN 0300305 W IN0300305 W IN 0300305W WO 2005023787 A1 WO2005023787 A1 WO 2005023787A1
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- WIPO (PCT)
- Prior art keywords
- benzoxadiazole
- oxidation
- carboxaldehyde
- pcc
- methanol
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Definitions
- 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-Benzomrazanyl)-l,4-dihydro-2,6- dimemyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester l ⁇ iown as Isradipine.
- the present invention relates to the process for the manufacture 2,l,3-benzoxadiazole-4-carboxaldehyde from 2,1,3- benzoxadiazole-4-yl-methanol by oxidation using pyridinium chlorochromate (PCC) as oxidant.
- PCC pyridinium chlorochromate
- Isradipine is 4-(4-Benzofurazanyl)-l,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylic acid methyl 1-methylethyl ester having the chemical structure of formula (I).
- Isradipine is therapeutically indicated for treating cardiovascular diseases.
- the cardiovascular diseases include angina, pectoris, hypertension and congestive heart failure.
- 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- ⁇ -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 present invention consisted of the oxidation of 2,1,3 - benzoxadiazole-4-yl-methanol using pyridinium chlorochromate (PCC) as oxidant.
- PCC pyridinium chlorochromate
- 2,1 ,3- benzoxadiazole-4-yl-methanol is oxidised using pyridinium chlorochiOmate (PCC) as oxidant in a halogenated hydrocarbon solvent under suitable reaction conditions to get 2,l,3-benzoxadiazole-4- carboxaldehyde in good yield and purity.
- PCC pyridinium chlorochiOmate
- the present invention relates to an improved and novel method for the manufacture of 2,l,3-benzoxadiazole-4-carboxaldehyde, an intermediate for the preparation of 4-(4-Benzofurazanyl)-l,4-dihydro-2,6- dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester (herein after referred as Isradipine).
- Isradipine 4-(4-Benzofurazanyl)-l,4-dihydro-2,6- dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester
- Isradipine 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).
- PCC pyridinium chlorochromate
- Scheme - 1 Also described in the present invention
- pyridinium chlorochromate PCC
- 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,l ,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,l,3-benzoxadiazole-4-yl-methanol is reached to the desired level.
- PCC pyridinium chlorochromate
- 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.
- Example - 1 Preparation of 2,l,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,l,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.
- reaction mixture 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,l ,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).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
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 known as Isradipine. More particularly the present invention relates to the process for the manufacture 2,1,3-benzoxadiazole-4-carboxaldehyde from 2,1,3-benzoxadiazole-4-yl-methanol by oxidation using pyridinium chlorochromate (PCC) as oxidant.
Description
PROCESS FOR THE MANUFACTURE OF 2,1,3- BENZOXADIAZOLE-4-CARBOXALDEHYBE FIELD 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-Benzomrazanyl)-l,4-dihydro-2,6- dimemyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester lαiown as Isradipine. More particularly the present invention relates to the process for the manufacture 2,l,3-benzoxadiazole-4-carboxaldehyde from 2,1,3- benzoxadiazole-4-yl-methanol by oxidation using pyridinium chlorochromate (PCC) as oxidant. BACKGROUND OF THE INVENTION Isradipine is 4-(4-Benzofurazanyl)-l,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylic acid methyl 1-methylethyl ester having the chemical structure of formula (I).
( 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,l,3-benzoxadiazole-4- carboxaldehyde) having the structural formula (II).
The patents EP 0000150 and US 4,460,972 described a process for the preparation of Isradipine, 2,l,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-β-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-β-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,l,3-benzoxadiazole-4- carboxaldehyde , The product 2,l,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-methy 1-2, 1 ,3- benzoxadiazole by successive reactions.. Bromination of 4-methy 1-2, 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,l,3-benzoxadiazole-4- 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 Mn02 presents limitations to scaling up of the process. Also the oxidation of 2,l,3-benzoxadiazole-4-yl-
methanol using activated Mn02 was inconsistent as the reaction time, product quality and yield are extremely dependent on the quality of activated Mn02. 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,l,3-benzoxadiazole-4-carboxaldehyde. To achieve the said object, in the instant invention 2,1 ,3- benzoxadiazole-4-yl-methanol is oxidised using pyridinium chlorochiOmate (PCC) as oxidant in a halogenated hydrocarbon solvent under suitable reaction conditions to get 2,l,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,l,3-benzoxadiazole-4-carboxaldehyde, an intermediate for the preparation of 4-(4-Benzofurazanyl)-l,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-carboxalde yde 2,1 ,3-benzoxadiazole-4-yl-methanol Scheme - 1
The oxidation of 2, l ,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,l ,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,l,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,l,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,l,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,l ,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%)
Claims
1. A process for the manufacture of 2, 1 ,3-benzoxadiazole-4- carboxaldehyde comprising: - oxidizing 2,1 ,3-benzoxadiazole-4-yl-methanol 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 between -5° 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,l,3-benzoxadiazole-4-yl-methanol 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 ,3-benzoxadiazole-4-carboxaldehyde 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.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003269482A AU2003269482A1 (en) | 2003-09-10 | 2003-09-10 | Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde |
| PCT/IN2003/000305 WO2005023787A1 (en) | 2003-09-10 | 2003-09-10 | Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000305 WO2005023787A1 (en) | 2003-09-10 | 2003-09-10 | Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde |
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| Publication Number | Publication Date |
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| WO2005023787A1 true WO2005023787A1 (en) | 2005-03-17 |
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| PCT/IN2003/000305 WO2005023787A1 (en) | 2003-09-10 | 2003-09-10 | Process for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde |
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| AU (1) | AU2003269482A1 (en) |
| WO (1) | WO2005023787A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276547A (en) * | 2011-05-04 | 2011-12-14 | 山东省医药工业研究所 | Preparation method of isradipine key intermediate 4-formoxylbenzofuran |
| CN102942534A (en) * | 2012-12-13 | 2013-02-27 | 牟英迪 | Preparation of drug intermediate 4-formoxyl benzofuroxan |
| CN103319432A (en) * | 2013-06-28 | 2013-09-25 | 江苏倍达医药科技有限公司 | Method for synthesizing isradipine medicament midbody 4-formyl benzo furazan |
| WO2014209595A1 (en) * | 2013-06-28 | 2014-12-31 | Archer Daniels Midland Company | Tetrahydrofuran-2,5-dicarbaldehydes (diformyl-tetrahydrofuran, dfthf) and process for making the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2103203A (en) * | 1978-12-18 | 1983-02-16 | Sandoz Ltd | 1,4-dihydropyridines, their preparation and pharmaceutical compositions containing them |
-
2003
- 2003-09-10 WO PCT/IN2003/000305 patent/WO2005023787A1/en active Application Filing
- 2003-09-10 AU AU2003269482A patent/AU2003269482A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2103203A (en) * | 1978-12-18 | 1983-02-16 | Sandoz Ltd | 1,4-dihydropyridines, their preparation and pharmaceutical compositions containing them |
Non-Patent Citations (2)
| Title |
|---|
| DATABASE CAPLUS [online] GASCO ET AL: "Benzofurazanyl- and benzofuroxanyl-1,4-dihydropyridines: synthesis, structure and calcium entry blocker activity", XP002979042, accession no. STN Database accession no. 1996:137301 * |
| EUROPEAN J. OF MEDICINAL CHEMISTRY, vol. 31, no. 1, 1996, pages 3 - 10 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276547A (en) * | 2011-05-04 | 2011-12-14 | 山东省医药工业研究所 | Preparation method of isradipine key intermediate 4-formoxylbenzofuran |
| CN102942534A (en) * | 2012-12-13 | 2013-02-27 | 牟英迪 | Preparation of drug intermediate 4-formoxyl benzofuroxan |
| CN103319432A (en) * | 2013-06-28 | 2013-09-25 | 江苏倍达医药科技有限公司 | Method for synthesizing isradipine medicament midbody 4-formyl benzo furazan |
| WO2014209595A1 (en) * | 2013-06-28 | 2014-12-31 | Archer Daniels Midland Company | Tetrahydrofuran-2,5-dicarbaldehydes (diformyl-tetrahydrofuran, dfthf) and process for making the same |
| CN103319432B (en) * | 2013-06-28 | 2015-02-18 | 江苏倍达医药科技有限公司 | Method for synthesizing isradipine medicament midbody 4-formyl benzo furazan |
| CN105324030A (en) * | 2013-06-28 | 2016-02-10 | 阿彻丹尼尔斯米德兰德公司 | Tetrahydrofuran-2,5-dicarbaldehydes (diformyl-tetrahydrofuran, DFTHF) and process for making the same |
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| Publication number | Publication date |
|---|---|
| AU2003269482A1 (en) | 2005-03-29 |
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