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Novel crystalline form of doxercalciferol and preparation method for novel crystalline form

A technology of docalciferol and its crystal form, which is applied in the new crystal form of docalciferol and its preparation field, can solve the problems of poor stereoselectivity, difficulty in separation and purification of final products, and low total yield of the route, and achieve easy operation , Conducive to large-scale industrial production, good physical and chemical properties

Active Publication Date: 2016-01-13
NANJING HERON PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The present inventors have researched and developed a synthetic calciferol for the disadvantages such as poor stereoselectivity, difficulty in separation and purification of the final product, and low overall yield of the route in the process route for the synthesis of calciferol in the prior art. The optimization process and improvement method of

Method used

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  • Novel crystalline form of doxercalciferol and preparation method for novel crystalline form
  • Novel crystalline form of doxercalciferol and preparation method for novel crystalline form
  • Novel crystalline form of doxercalciferol and preparation method for novel crystalline form

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Experimental program
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Embodiment 1

[0051] Embodiment 1 Preparation of new crystal form A of calciferol

[0052] (1) Vitamin D 2 (i.e. the compound of formula 2) about 15g was dissolved in 100mL of dichloromethane, cooled to -15 to -20°C, and SO was slowly introduced through the cylinder 2 Gas, heat preservation reaction for 1-2h, TLC monitors the reaction is complete, rotary evaporation to remove SO 2 Gas, to obtain a foamy yellow solid, 18.3g of the compound of formula 3;

[0053] (2) Add 18.3g of the compound of formula 3, add about 130mL of DMF, 11g of imidazole, 13g of tert-butyldimethylsilyl chloride, stir at room temperature for 2h, TLC monitors that the reaction is complete, add 300mL of water, extract with ethyl acetate (3*100mL) , combined the organic phases, washed the organic phases with 400 mL of saturated saline three times, dried and concentrated the organic phases to obtain a yellow oil, that is, about 22.1 g of the compound of formula 4;

[0054] (3) Dissolve about 22.1g of the compound of fo...

Embodiment 2

[0064]Embodiment 2 Preparation of New Crystal Form A of Calciferol

[0065] (1) Dissolve about 18g of vitamin D2 (that is, the compound of formula 2) in 120mL of dichloromethane, cool to -15 to -20°C, slowly introduce sulfur dioxide gas through the steel cylinder, keep warm for 1-2h, and monitor the reaction is complete by TLC , sulfur dioxide was removed by rotary evaporation to obtain a foamy yellow solid, 21.3g of the compound of formula 3;

[0066] (2) Add 21.3g of the compound of formula 3, add about 150mL of DMF, 13g of imidazole, 15g of tert-butyldimethylsilyl chloride, stir at room temperature for 2h, TLC monitors that the reaction is complete, add 300mL of water, extract with ethyl acetate (3*100mL) , combined the organic phases, washed the organic phases with 400 mL of saturated saline three times, dried and concentrated the organic phases to obtain a yellow oil, namely about 24.1 g of the compound of formula 4;

[0067] (3) Dissolve about 24.1g of the compound of f...

Embodiment 3

[0077] Embodiment 3 Preparation of new crystal form A of calciferol

[0078] The preparation of high-purity calciferol is the same as in Example 1, and the HPLC purity is 99.2%

[0079] Crystal preparation process:

[0080] a) At a temperature of 35-40°C, stir and dissolve 6.0 g of high-purity calciferol in a mixed solvent of butanone and ethanol; among them, 36 mL of butanone is 6 times that of calcidol, and ethanol is Doubling the amount of doxercalciferol is about 12mL;

[0081] b) Filtrate while it is hot, cool the filtrate to 10-15°C, slowly stir and crystallize for 5-10h;

[0082] c) The precipitated crystals were filtered and vacuum-dried at 25-30°C to obtain about 4.7 g of the new crystal form A of doxocalcidol, with an HPLC purity of 99.7%.

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a novel crystalline form A of doxercalciferol and a preparation method for the novel crystalline form A. The invention further comprises a pharmaceutical composition of the novel crystalline form A of doxercalciferol and an application of the composition for treating osteoporosis or secondary hyperparathyroidism. By virtue of Cu-Kalpha radiation, X-ray powder diffraction has diffraction peaks at positions where 2theta angles are 7.82, 8.51, 12.06, 13.01, 15.60, 17.05, 17.82, 18.71, 19.35, 20.06, 20.37, 20.62, 21.98, 22.68, 22.90, 23.81 and 24.79. The invention further discloses a technically improved scheme for preparing high purity doxercalciferol at the same time. The scheme is simple in step, easy to operate, short in consumed time and low in cost, and industrial large-scaled production is quite facilitated.

Description

technical field [0001] The invention belongs to the pharmaceutical field of vitamin D derivatives, and in particular relates to a new crystal form of docalciferol and a preparation method thereof. Background technique [0002] Vitamin D compounds can not only promote the absorption of calcium and phosphorus by bones, ensure sufficient supply of calcium and phosphorus in the body, and promote normal calcification of bones, but also have a wide range of biological effects, such as inhibiting cell proliferation, inducing cell differentiation, and regulating the body's immune system. The central role of vitamin D compounds in calcium metabolism, cell proliferation, and cell differentiation makes them promising candidates for the treatment of a variety of diseases, including cancer, osteoporosis, hyperparathyroidism, and psoriasis. Studies have shown that the 1-position of vitamin D compounds is replaced by α-hydroxyl to obtain 1α-hydroxyvitamin D compounds, which can better exer...

Claims

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Application Information

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IPC IPC(8): C07C401/00A61K31/592A61P19/10A61P5/20
Inventor 陆晨光丁伯祥闵涛袁尚徐丽石若鹏
Owner NANJING HERON PHARM CO LTD
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