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Dexlansoprazole process and polymorphs

A dexlansoprazole and crystallization technology, applied in the field of preparing dexlansoprazole, can solve the problems such as yield loss, unenvironmental protection, uneconomical method and the like

Inactive Publication Date: 2011-02-16
DR REDDYS LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Existing methods for the preparation of crystalline dexlansoprazole involve repetitive crystallization operations requiring large amounts of solvents, which reduces its commercial viability and ultimately results in loss of yield, which in turn makes the process uneconomical and environmentally unfriendly

Method used

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  • Dexlansoprazole process and polymorphs
  • Dexlansoprazole process and polymorphs
  • Dexlansoprazole process and polymorphs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0358] Example 1: Preparation of 2-[(R)-[(4-nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole

[0359] Under a nitrogen atmosphere, 2-[[(4-nitro-3-methyl-2-pyridyl)methyl]thio]-1H-benzimidazole (10.2 g) and toluene (300 mL) were added to a round bottom flask and stirred at 25-35°C for 5-10 minutes. Water (0.09 mL) and (+)-diethyl tartrate (2.5 mL) were added and stirred at 25-35°C for 5-10 minutes. This mixture was heated to 65-70°C for 30 minutes. Titanium isopropoxide (11.68 mL) was added to the mixture at 65-70°C for 1-2 hours. The mixture was cooled to 15-20°C, then diisopropylethylamine (5.73 mL) was added and stirred for 5-10 minutes. The mixture was cooled to 0-5°C and cumene hydroperoxide (8.22 mL) was added over 20-30 minutes. The reaction mixture was maintained at 0-5°C for 4-5 hours. The mixture was extracted with 12.5% ​​piperidine solution (2 x 100 mL) and 12.5% ​​ammonia solution (2 x 100 mL), then the combined aqueous layers were washed with toluen...

Embodiment 2

[0360] Example 2: Preparation of 2-[(R)-[(4-nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole

[0361] 2-[[(4-Nitro-3-methyl-2-pyridyl)methyl]thio]-1H-benzimidazole (10.6 g) and toluene (300 mL) were charged in a Dean-Stark apparatus Place in a round bottom flask and stir for 5-10 minutes. The mixture was heated to 110°C and allowed to azeotropically reflux for 1-2 hours to completely remove the water. The mixture was cooled to 70°C, then water (0.36 mL), (+)-diethyltartrate (12.58 mL) and titanium isopropoxide (11.71 mL) were added and stirred at 65-70°C for 1 hour. The mixture was cooled to 15-25°C, and diisopropylethylamine (5.73 mL) was added, then the mixture was cooled to 0-5°C. At 0-5°C, cumene hydroperoxide (10.38 mL) was added within 30-45 minutes, and the mixture was maintained at 0-5°C for 4-5 hours. The reaction was quenched with 12.5% ​​piperidine (200 mL), and the organic and aqueous layers were separated. The organic layer was extracted with 12.5% ​...

Embodiment 3

[0362] Example 3: Optical Purification of 2-[(R)-[(4-nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole

[0363] 2-[(R)-[(4-Nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (5.0 g) and acetone (125 mL) were added to the round bottom flask and stir for 5-10 minutes. This mixture was heated to 50-55°C and maintained to completely dissolve 2-[(R)-[(4-nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzo imidazole. The solution was cooled to 25-35°C, further cooled to 5-10°C, then held at 5-10°C for 1-2 hours, then the solid formed was filtered and washed with acetone (10 mL). The filtrate was evaporated under reduced pressure at 40-45°C to give 3.2 g of the title compound. The chiral purity of the input material: 86.12%, the chiral purity of the product determined by HPLC was 99.49%, and the chemical purity of the product determined by HPLC was 98.14%.

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Abstract

Processes for the preparation of dexlansoprazole, an amorphous form of dexlansoprazole, a solid dispersion of amorphous dexlansoprazole and a pharmaceutically acceptable carrier, and processes for their preparation are provided. Also provided are crystalline compounds 2-[(R)-[(4-chloro-3-methyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and 2-[(R)-[(4-nitro-3-methyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, and methods for their preparation.

Description

technical field [0001] The present application relates to a method for preparing dexlansoprazole, amorphous dexlansoprazole and a method for preparing amorphous dexlansoprazole. The present application also relates to crystalline 2-[(R)-[(4-chloro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (hereinafter referred to as dexlansoprazole "4-chloro analogs") and 2-[(R)-[(4-nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (hereinafter referred to as Be the " 4-nitro analogue " of dexlansoprazole) and preparation method thereof. The present application also relates to a process for the preparation of crystalline dexlansoprazole. Background technique [0002] (R)-(+)-lansoprazole (with the officially adopted name "dexlansoprazole") is known chemically as (R)-2-[[[3-methyl-4-(2 , 2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole or (+)-(2)-[(R)-{[3-methyl -4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfinyl]-1H-benzimidazole, and can be represe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D235/24C07D235/28
CPCC07D401/12A61K9/1652B82Y5/00A61K47/48969A61K9/1635A61K47/6951A61P1/04
Inventor N·K·科拉N·曼内S·甘古拉U·尼兰A·纳雷德拉S·R·巴达姆S·V·帕蒂尔A·图马拉S·佩迪雷迪S·G·欣德A·西加拉S·V·穆杜努鲁M·K·图米迪
Owner DR REDDYS LAB LTD
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