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Crystal form of 3-(4-(1,1,1,3,3,3-hexafluoro-tert-butyl ester)benzyl)-2-keto-2H-benzopyran-4-sodium alkoxide, and preparation thereof

A technology of benzopyran and crystal form, which is applied to medical preparations containing active ingredients, blood diseases, extracellular fluid diseases, etc. Medicinal requirements and other issues, to achieve the effect of low cost, simple and easy-to-obtain solvent, and good stability

Active Publication Date: 2018-04-20
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The inventor conducted further research and found that the white solid obtained by using this method becomes a white milky object when it encounters air. Detecting, it is measured that there are characteristic peaks ( Figure 7 )
[0007] In addition, the preparation method of the salt in the patent WO2005100336 is freeze-drying, which is not suitable for industrial scale-up production operations

Method used

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  • Crystal form of 3-(4-(1,1,1,3,3,3-hexafluoro-tert-butyl ester)benzyl)-2-keto-2H-benzopyran-4-sodium alkoxide, and preparation thereof
  • Crystal form of 3-(4-(1,1,1,3,3,3-hexafluoro-tert-butyl ester)benzyl)-2-keto-2H-benzopyran-4-sodium alkoxide, and preparation thereof
  • Crystal form of 3-(4-(1,1,1,3,3,3-hexafluoro-tert-butyl ester)benzyl)-2-keto-2H-benzopyran-4-sodium alkoxide, and preparation thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Example 1: 3-(4-(1,1,1,3,3,3-hexafluorotert-butylcarboethoxy)benzyl)-2-keto-2H-benzopyran-4-ol sodium crystal Form A preparation method

[0037]2g of 4-hydroxy-2-keto-3-(4-(1,1,1,3,3,3-hexafluoro-tert-butylcarboxylate) benzyl)-2H-benzopyran (4.3mmol) Dissolve 0.46g of sodium tert-butoxide (4.7mmol) in 30ml of acetone, react at -30 to 30°C for 3h, filter, evaporate the filtrate to dryness to obtain a pale yellow solid, dissolve it in 6ml of ethyl acetate, raise the temperature to 40°C, and add 40ml of Isooctane was crystallized to obtain crystal form A, and the sodium content was 95%-110% as detected by atomic method.

Embodiment 2

[0038] Example 2: 3-(4-(1,1,1,3,3,3-hexafluorotert-butylcarboethoxy)benzyl)-2-keto-2H-benzopyran-4-ol sodium crystal Form A preparation method

[0039] 3g of 4-hydroxy-2-keto-3-(4-(1,1,1,3,3,3-hexafluoro-tert-butylcarboxylate) benzyl)-2H-benzopyran (6.5mmol) Dissolve 0.31g of sodium hydroxide (7.8mmol) in 30ml of tetrahydrofuran, react at -30 to 30°C for 3 hours, filter, and evaporate the filtrate to dryness to obtain a light yellow solid, which is dissolved in 30ml of ethyl acetate, and crystallized by dropping 50ml of isooctane. The temperature was raised to 70° C. to obtain the crystal form A, and the sodium content was 95% to 110% as detected by the atomic method.

Embodiment 3

[0040] Example 3: 3-(4-(1,1,1,3,3,3-hexafluorotert-butylcarboethoxy)benzyl)-2-keto-2H-benzopyran-4-ol sodium crystal Form A preparation method

[0041] 5g of 4-hydroxy-2-keto-3-(4-(1,1,1,3,3,3-hexafluoro-tert-butylcarboxylate) benzyl)-2H-benzopyran (6.5mmol) Dissolve 0.48g of sodium hydroxide (7.8mmol) in 30ml of ethyl acetate, react at -30 to 30°C for 3h, filter, evaporate the filtrate to dryness to obtain a pale yellow solid, dissolve it in 30ml of methyl isobutyl ketone, and drop in 50ml of isobutyl ketone Octane was crystallized, and the temperature was raised to 100° C. to obtain crystal form A. The sodium content was 95% to 110% as detected by atomic method.

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Abstract

The present invention relates to the crystal form of a new anticoagulant 3-(4-(1,1,1,3,3,3-hexafluoro-tert-butyl ester)benzyl)-2-keto-2H-benzopyran-4-sodium alkoxide (tecarfarin), and a preparation method thereof. According to the present invention, the crystal form has characteristics of good stability, easy manufacturing, easy treatment, easy storage, good treatment effect and simple preparationmethod, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical crystallization, and in particular relates to a novel anticoagulant drug 3-(4-(1,1,1,3,3,3-hexafluorotert-butylcarboxy)benzyl)-2-keto- Crystal form of sodium 2H-benzopyran-4-olate (ticarfarin sodium) and its preparation method. Background technique [0002] 3-(4-(1,1,1,3,3,3-hexafluoro-tert-butylcarboethoxy)benzyl)-2-keto-2H-benzopyran-4-ol (ticafarin, Tecarfarin) is an analogue of warfarin, with the same mechanism of action as warfarin, and is a new oral vitamin K epoxide reductase inhibitor. Its structural formula is: [0003] [0004] Armetheon obtained authorization from ARYx Therapeutics of the United States in 2012 to develop ticarfarin for anticoagulation therapy. For patients with atrial fibrillation, patients with prosthetic valves or long-term renal insufficiency, existing oral anticoagulants are contraindicated. Ticafarin can not only be used for anticoagulant treatmen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/56A61K31/366A61P7/02
CPCC07B2200/13C07D311/56
Inventor 朱永强杨杨刘佳
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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