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Process for preparing 1, 2, 3, 9-tetrahydro-9-methyl-3-[2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one

A technology of methylimidazole and dimethylformamide, which is applied in the field of antiemetic drug ondansetron and its pharmaceutically acceptable acid addition salt to achieve the effects of fast reaction time and reduction of by-products

Inactive Publication Date: 2005-09-07
BIOGAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reaction yield is only about 21%

Method used

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  • Process for preparing 1, 2, 3, 9-tetrahydro-9-methyl-3-[2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one
  • Process for preparing 1, 2, 3, 9-tetrahydro-9-methyl-3-[2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one
  • Process for preparing 1, 2, 3, 9-tetrahydro-9-methyl-3-[2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] 3-[(Dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (10 g, 34 mmol) and 2-form Kimidazole (16.8g, 205mmol, 6.0eq.) was suspended in a mixture of water (75ml) and dimethylformamide (37.5ml). The reaction mixture was heated to reflux (102-103 degrees Celsius) and stirred at this temperature for an additional 6 hours. The reaction mixture was cooled to 5-10 degrees Celsius and stirred at this temperature for half an hour. The precipitated crude ondansetron base was filtered and washed with cold water (3 x 90ml) and dried under vacuum at 60°C to give ondansetron base (9.68g, 96.4% yield ).

Embodiment 2

[0090] 3-[(Dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (12kg, 41mol) and 2-methyl Imidazole (20.2kg, 246mol, 6eq.) was suspended in a mixture of water (120L) and DMF (30L). The reaction mixture was heated to reflux (100-102 degrees Celsius) and stirred at this temperature for 5 hours. The reaction mixture was cooled to 5-10 degrees Celsius and stirred for half an hour. The precipitated crude ondansetron base was filtered and washed with cold water (2 x 110 L) and dried under vacuum at 60°C to give ondansetron base (10 kg, 83% yield) with 97.3% HPLC purity . The main impurity is exomethylenecarbazolone, reaching 2.6% of the crude ondansetron mixture.

[0091] Recrystallization of crude 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one

Embodiment 3

[0093] The crude ondansetron mixture (11.7 g), prepared as described in Example 2, was dissolved in methanol (468 ml) at 62°C. The resulting solution was stirred over charcoal (0.6 g) at 62°C for 15 minutes. And then filter out the charcoal. A portion of about 100 ml of methanol was distilled off under reduced pressure. The solution was then cooled to 0-5 degrees Celsius and stirred for 1 hour. The precipitated crystals were filtered off and washed twice with cold (0-5°C) methanol (7.3ml). The crystals were dried under reduced pressure at 65°C to afford ondansetron (ca. 81%, yield) with HPLC purity 99.6% and with 0.25% exomethylenecarbazolone contamination.

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Abstract

A process for preparing ondansetron by transamination of an ondansetron structural analog that can be readily prepared conveniently by a Mannich reaction is provided. The process represents an improvement upon known procedures for making ondansetron by transamination because of its rapid rate, selectivity and the ease with which the product can be isolated from the reaction mixture.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of Provisional Application Serial No. 60 / 376,323 (filed April 29, 2002, incorporated herein by reference) under 35 U.S.C. 1.119(e). technical field [0003] The present invention relates to the antiemetic drug ondansetron and its pharmaceutically acceptable acid addition salt, and more particularly to the post-processing steps for synthesizing ondansetron. Background technique [0004] The systematic chemical name of ondansetron is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole -4-one, and its molecular structure is [0005] [0006] It is the active ingredient in an FDA-approved antiemetic drug proposed for the treatment of nausea and vomiting associated with certain cancer chemotherapy and radiation treatments and for the prevention of postoperative nausea and / or vomiting. Ondansetron is commercially available as an orally disintegrating tablet ...

Claims

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Application Information

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IPC IPC(8): A61K31/4178A61P1/08C07D209/88C07D403/06
CPCC07D403/06C07D209/88A61P1/08C07D521/00
Inventor S·莫尔纳C·绍博E·梅斯扎洛斯索斯S·萨尔伊T·塔马斯
Owner BIOGAL PHARMA CO LTD
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