A new crystalline form of docalciferol and its preparation method

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

Active Publication Date: 2018-02-13
NANJING HERON PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 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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  • A new crystalline form of docalciferol and its preparation method
  • A new crystalline form of docalciferol and its preparation method
  • A new crystalline form of docalciferol and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of new crystal form A of degree-calcidol

[0053] (1) Put vitamin D 2 (The compound of formula 2) Dissolve about 15g in 100mL of dichloromethane, cool to -15 to -20°C, and slowly pass SO through a steel bottle 2 Gas, keep the reaction for 1-2h, TLC monitors the reaction to be complete, rotary evaporation to remove SO 2 Gas to obtain a foamy yellow solid, 18.3 g of the compound of formula 3;

[0054] (2) Add 18.3 g of the compound of formula 3 to about 130 mL of DMF, 11 g of imidazole, 13 g of tert-butyldimethylchlorosilane, and stir at room temperature for 2 hours. TLC monitors that the reaction is complete. Add 300 mL of water and extract with ethyl acetate (3*100 mL) , Combine the organic phases, wash the organic phase three times with 400 mL of saturated brine, dry and concentrate the organic phase to obtain a yellow oil, that is, about 22.1 g of the compound of formula 4;

[0055] (3) Dissolve about 22.1g of the compound of formula 4 in a mixture of 2...

Embodiment 2

[0065] Example 2 Preparation of new crystal form A of calcidiol

[0066] (1) Dissolve about 18g of vitamin D2 (compound of formula 2) in 120mL of dichloromethane, cool to -15 to -20°C, slowly inject sulfur dioxide gas through a steel bottle, keep the reaction for 1-2h, and TLC monitor the reaction to be complete , Rotary evaporation to remove sulfur dioxide to obtain a foamy yellow solid, 21.3g of the compound of formula 3;

[0067] (2) Add 21.3g of compound of formula 3, add about 150mL DMF, 13g imidazole, 15g tert-butyldimethylchlorosilane, stir at room temperature for 2h, TLC monitor the reaction is complete, add 300mL water, and extract with ethyl acetate (3*100mL) , Combine the organic phases, wash the organic phase three times with 400 mL of saturated brine, dry and concentrate the organic phase to obtain a yellow oil, that is, about 24.1 g of the compound of formula 4;

[0068] (3) Dissolve about 24.1g of the compound of formula 4 in a mixture of 250mL ethanol and 15mL water,...

Embodiment 3

[0078] Example 3 Preparation of new crystal form A of calcidiol

[0079] The preparation of high-purity docalcidol is the same as in Example 1, and the HPLC purity is 99.2%

[0080] Crystal preparation process:

[0081] a) At a temperature of 35-40℃, stir and dissolve 6.0g of high-purity docalciferol in a mixed solvent of butanone and ethanol; among them, butanone is 6 times the amount of docalciferol, about 36mL, and ethanol is 2 times the amount of Ducalcidol is about 12mL;

[0082] b) Filter while it is hot, cool the filtrate to 10-15°C, stir slowly and crystallize for 5-10 hours;

[0083] c) The precipitated crystals are filtered and dried in a vacuum at 25-30°C to obtain about 4.7 g of new crystal form A of calcidiol, with a purity of 99.7% by HPLC.

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a new crystal form A of docalciferol and a preparation method thereof. The invention also relates to a pharmaceutical composition containing the new crystal form A of docalciferol and its role in the treatment of osteoporosis Hyperparathyroidism or secondary hyperparathyroidism. The new crystal form A of docalciferol, using Cu-Kα radiation, X-ray powder diffraction at 2θ angles at 7.82, 8.51, 12.06, 13.01, 15.60, 17.05, 17.82, 18.71, 19.35, 20.06, There are diffraction peaks at 20.37, 20.62, 21.98, 22.68, 22.90, 23.81, and 24.79. At the same time, the invention also discloses a process improvement scheme for preparing high-purity doxercalciferol, which has simple steps, easy operation, short time consumption and low cost, and is very beneficial to large-scale industrial production.

Description

Technical field [0001] The invention belongs to the pharmaceutical field of vitamin D derivatives, and specifically relates to a new crystal form of docalcidol and a preparation method thereof. Background technique [0002] Vitamin D compounds can not only promote the absorption of calcium and phosphorus by the bones, ensure the adequate supply of calcium and phosphorus in the body, promote the 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 it a promising candidate for the treatment of various diseases including cancer, osteoporosis, hyperparathyroidism and psoriasis. Studies have shown that the 1-position of vitamin D compounds is substituted by α hydroxy to obtain 1α-hydroxy vitamin D compounds, which can better exert their ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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