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(R)-lansoprazole isopropyl amine salt and crystal form and preparation method thereof

A technology of lansoprazole isopropylamine salt and lansoprazole, applied in chemical instruments and methods, preparation of amino compounds, preparation of organic compounds, etc., can solve the problems of difficult operation, low stability of preparation products, and poor water solubility and other problems, to achieve the effect of simple and convenient operation, excellent physical and chemical properties, and high water solubility

Active Publication Date: 2013-01-16
SHANGHAI CHEMPARTNER CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is that (R)-lansoprazole has poor water solubility, poor stability, poor fluidity, sensitivity to humidity, strong hygroscopicity, and is applied in the preparation process, which makes the operation difficult and the production cost is higher. And the defect that preparation product stability is not high, and provide a kind of physicochemical property better, water-solubility is higher, hygroscopicity is lower, stability is higher, is beneficial to be applied to (R)-lansoprazole salt type of preparation technology And its crystal form and preparation method

Method used

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  • (R)-lansoprazole isopropyl amine salt and crystal form and preparation method thereof
  • (R)-lansoprazole isopropyl amine salt and crystal form and preparation method thereof
  • (R)-lansoprazole isopropyl amine salt and crystal form and preparation method thereof

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Embodiment 1

[0034] The preparation of embodiment 1 (R)-lansoprazole isopropylamine salt crystal form

[0035] (R)-lansoprazole (227.0mg) was dissolved in ethyl acetate (3mL), fully dissolved under heating to 60°C under magnetic stirring, and the sample solution was filtered with a 0.45um microporous membrane (nylon membrane), The filtrate was placed on a heating platform at 45° C., and a 1.15 molar ratio isopropylamine solution (61 uL) was slowly added thereto under magnetic stirring. After magnetic stirring for 20 min, 3.78 mL of anti-solvent n-heptane was slowly added to the boiling point at 37°C. Under magnetic stirring, the temperature of the sample was lowered to room temperature at a cooling rate of 4 °C / h, and a white precipitate was precipitated. The sample was suction filtered under reduced pressure to obtain a white solid, which was washed 3 times with n-heptane, and then the product was placed in a vacuum oven and dried under reduced pressure at 40°C to obtain the final produc...

Embodiment 2

[0036] The preparation of embodiment 2 (R)-lansoprazole isopropylamine salt crystal form

[0037] (R)-lansoprazole (250.0mg) was dissolved in methyl acetate (3mL), heated to 20°C under magnetic stirring and fully dissolved, the sample solution was filtered with a 0.22um microporous membrane (nylon membrane), The filtrate was placed on a heating platform at 20°C, and an equimolar ratio of isopropylamine solution (58.2 uL) was slowly added thereto under magnetic stirring. After magnetic stirring for 40 min, 3.6 mL of anti-solvent n-hexane was slowly added at 30 °C to the boiling point. Under magnetic stirring, the temperature of the sample was lowered to room temperature at a cooling rate of 4 °C / h, and a white precipitate was precipitated. The sample was suction-filtered under reduced pressure to obtain a white solid, which was washed three times with n-hexane, and then the product was placed in a vacuum oven and dried under reduced pressure at 40°C to obtain the final product...

Embodiment 3

[0038] The preparation of embodiment 3 (R)-lansoprazole isopropylamine salt crystal form

[0039](R)-lansoprazole (250.0mg) was dissolved in propyl acetate (3mL), fully dissolved under heating to 50°C under magnetic stirring, and the sample solution was filtered with a 0.8um microporous membrane (nylon membrane), The filtrate was placed on a heating platform at 50° C., and 5 times the amount of isopropylamine solution (290.75 uL) was slowly added under magnetic stirring. After magnetic stirring for 5 min, 3.9 mL of anti-solvent n-pentane was slowly added at 45 °C to the boiling point. Under magnetic stirring, the temperature of the sample was lowered to room temperature at a cooling rate of 4 °C / h, and a white precipitate was precipitated. The sample was suction filtered under reduced pressure to obtain a white solid, which was washed three times with n-pentane, and then the product was placed in a fume hood and dried under normal pressure to obtain the final product.

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Abstract

The invention discloses a (R)-lansoprazole isopropyl amine salt and a crystal form and a preparation method thereof. The (R)-lansoprazole isopropyl amine salt is shown in a formula 1. The crystal form has peaks in a spectrum of x-ray powder diffraction using a Cu-K alpha 1 radiation source at the diffraction angle 2 theta which is 6.08, 8.54, 10.89, 12.20, 13.91, 14.33, 15.17, 15.46, 16.09, 16.62, 17.52, 17.76, 18.38, 18.69, 19.08, 19.98, 20.30, 21.30, 21.81, 22.29, 23.37, 24.21, 24.58, 25.37, 25.91, 26.17, 26.74, 27.36, 27.70, 28.44, 29.15, 29.65, 30.88, 31.69, 32.78, 33.46, 33.84, 35.28, 37.49, 39.03 and 39.46, and the value error of the angle 2 theta ranges from minus 0.3 to plus 0.3. The preparation method comprises the following steps: under heating conditions, dissolving (R)-lansoprazole in an organic solvent, adding isopropyl amine, uniformly mixing, adding an antisolvent at the temperature of 30-45 DEG C to a cloud point, cooling, crystallizing, and separating an obtained crystalline solid. The (R)-lansoprazole isopropyl amine salt has better physicochemical properties, better flowability, better water solubility, lower hygroscopicity and higher stability and is favorable to application in preparation technologies.

Description

technical field [0001] The present invention relates to a kind of (R)-lansoprazole isopropylamine salt and its crystal form and preparation method. Background technique [0002] Lansoprazole was developed by Takeda Corporation of Japan in December, 1991, and was listed in Japan in 1992. It is the second proton pump inhibitor to be marketed after omeprazole. Compared with omeprazole, due to the introduction of fluorine atoms, the thermodynamics and oxidation stability of lansoprazole are increased, and the biological activity is greatly improved. [0003] The chemical name of lansoprazole is 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridyl]methyl]sulfinyl]-1H- Benzimidazole, the sulfur atom in its structure is a chiral center, so it has two optical isomers. Its dextral body (i.e. the chemical structure of (R)-lansoprazole is as follows: [0004] [0005] For the racemate of commercially available lansoprazole, the side effects of clinical reports mainly include heada...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C211/07C07C209/00A61K31/4439
Inventor 施斌张玉龙
Owner SHANGHAI CHEMPARTNER CO LTD