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Preparation method of right-handed lansoprazole crystal form

A dexlansoprazole crystal and a technology for dexlansoprazole are applied in the field of preparation of dexlansoprazole crystal forms, and can solve the problem that the consumption of the solvent is too large, the solvent recovery is difficult, and n-heptane The problem of large dosage, etc., can achieve the effect of reducing solvent consumption, high production efficiency and low environmental pollution.

Inactive Publication Date: 2017-01-04
成都尚药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the precipitated crystals are unstable
And when adopting ethyl acetate-n-heptane system, the consumption of n-heptane is too large, and the boiling point difference of ethyl acetate and n-heptane is not big simultaneously, makes solvent recovery difficulty bigger, and yield is lower
The solubility of R-lansoprazole in dichloromethane is not large, it needs nearly 10ml / g of dichloromethane to dissolve, and the solvent consumption is too large

Method used

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  • Preparation method of right-handed lansoprazole crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) 10g lansoprazole hydrate (1.5 crystalline waters) after the purification is dissolved in 50ml ethyl acetate, adds saturated sodium bicarbonate solution, stirs, separates phases, and the aqueous phase is extracted once with ethyl acetate again, Combine the organic phases, add anhydrous sodium sulfate and activated carbon to the organic phase, stir, filter, and wash with ethyl acetate.

[0030] (2) Combine the filtrate and washing liquid, and slowly add 100ml of isopropyl ether under stirring at room temperature, then add seed crystal A, and stir.

[0031] (3) When the solution is cooled to 0-10°C, solids will precipitate out soon. Stir at this temperature for 0.5-1 h.

[0032] (4) Suction filtration, the filter cake is washed with an appropriate amount of isopropyl ether.

[0033] (5) The product was vacuum-dried at 40° C. for 24 h.

[0034] Obtained 8.2 g of dense white crystals with a yield of 81%. Melting point: 142-143°C.

[0035] figure 1 Be the XRD figure...

Embodiment 2

[0040] (1) 20g lansoprazole hydrate (1.5 crystalline waters) after the purification is dissolved in 100ml ethyl acetate, adds saturated sodium bicarbonate solution, stirs, separates phases, and the aqueous phase is extracted once with ethyl acetate again, Combine the organic phases, add anhydrous sodium sulfate and activated carbon to the organic phase, stir, filter, and wash with ethyl acetate.

[0041] (2) Combine the filtrate and washing liquid, and slowly add 100ml of isopropyl ether under stirring at room temperature, then add seed crystal A, and stir.

[0042] (3) When the solution is cooled to 5°C, a solid precipitates out soon. Stir at this temperature for 0.8h.

[0043] (4) Suction filtration, the filter cake is washed with an appropriate amount of isopropyl ether.

[0044] (5) The product was vacuum-dried at 40° C. for 24 hours to obtain 16.5 g of dense white crystals with a yield of 82.5%.

Embodiment 3

[0046] (1) 30g lansoprazole hydrate (1.5 crystal waters) after the purification is dissolved in 150ml ethyl acetate, adds saturated sodium bicarbonate solution, stirs, separates phases, and the aqueous phase is extracted once with ethyl acetate again, Combine the organic phases, add anhydrous sodium sulfate and activated carbon to the organic phase, stir, filter, and wash with ethyl acetate.

[0047] (2) Combine the filtrate and washing liquid, and slowly add 100ml of isopropyl ether under stirring at room temperature, then add seed crystal A, and stir.

[0048] (3) When the solution is cooled to 3°C, a solid precipitates out soon. Stir at this temperature for 1 h.

[0049] (4) Suction filtration, the filter cake is washed with an appropriate amount of isopropyl ether.

[0050] (5) The product was vacuum-dried at 40° C. for 24 h. 23.8 g of dense white crystals were obtained, with a yield of 79.3%.

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Abstract

The invention provides a preparation method of a right-handed lansoprazole crystal form. The preparation method is carried out in an ethyl acetate-isopropyl ether system. The preparation method comprises the following steps: (1) dissolving a purified lansoprazole hydrate in five times of mass / volume ratio of ethyl acetate, adding an appropriate amount of saturated sodium bicarbonate solution, stirring for 10 min, carrying phase separation, adding an appropriate amount of anhydrous sodium sulfate and 0.2g of active carbon into an organic phase, stirring for 30 min, filtering, and washing with ethyl acetate; (2) merging filtrate and washing liquor, slowly adding isopropyl ether two times of the volume of the ethyl acetate, adding a crystal seed A, and stirring for 10 min; (3) cooling to 0 to 10 DEG C, and precipitating solids; (4) performing suction filtration, and washing a filter cake with isopropyl ether; and (5) drying in vacuum for 2h at 40 DEG C, thus obtaining white crystals with relatively large density. By adopting the preparation method, the defect in the original patent that a great amount of solvent is consumed by using a methylene dichloride-isopropyl ether system can be overcome, an obtained crystal form is high in melt point, large in bulk density and high in stability, and the preparation method is small in environmental pollution during the preparation process, simple in operation, high in production efficiency and suitable for mass production.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a preparation method of dexlansoprazole crystal form. Background technique [0002] Dexlansoprazole is a proton pump inhibitor that acts specifically and noncompetitively on H + / K + -ATPase, treatment of peptic ulcer. U.S. FDA approved on January 30, 2009 the esophagitis treatment new drug dexlansoprazole (generic name Dexlansoprazole) that Japan's Takeda Pharmaceutical Company researches and develops listing. The drug is an enantiomer of the proton pump inhibitor lansoprazole, also known as dexlansoprazole, and is used to treat heartburn and varying degrees of erosive esophagus associated with non-erosive gastroesophageal reflux disease inflammation. According to literature review, the biopharmaceutical classification of dexlansoprazole is BCS Ⅱ. Therefore, need to improve the bioavailability of its preparation by improving the dissolubility of dexlansoprazole. Changing the crysta...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/13
Inventor 张会潘小峰
Owner 成都尚药科技有限公司
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