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Synthetic method of osteoporosis treatment drug 1 alpha-hydroxyitamin D3

A technology for hydroxyvitamins and osteoporosis, applied in drug combinations, bone diseases, organic chemistry, etc., can solve the problems of unavoidable loss of product isomers, cumbersome extraction process, inconvenient handling, etc., so as to save the extraction and cleaning of pyridine steps, save cooling energy consumption, and improve the yield

Inactive Publication Date: 2013-05-01
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the method generally adopted by various pharmaceutical manufacturers is vitamin D 3 As a raw material, alfacalcidol is obtained through 5-step reactions such as esterification, ring-closing, oxidation, ring-opening, and hydrolysis. The existing process uses pyridine as a solvent, but pyridine is miscible with water, and the extraction process of the product is very complicated and loses a large number of products
Diels-Alder reaction is used to separate cis and trans isomers in the 4th step reaction, which is inconvenient for post-processing treatment, and at the same time, a part of product isomers is inevitably lost, and the yield is low

Method used

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  • Synthetic method of osteoporosis treatment drug 1 alpha-hydroxyitamin D3
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Experimental program
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Effect test

Embodiment 1

[0034] Embodiment 1 (original technical solution)

[0035] Weigh 5.00g VD 3 (1a, 0.013mol), put it into a 200mL Erlenmeyer flask, add 30mL of pyridine, put it in an ice-water bath, add 7.14g (0.037mol) of p-toluenesulfonyl chloride into 30mL of pyridine to dissolve, add it to the Erlenmeyer flask several times, Shaking while adding, the color of the system darkened and turned bright yellow. After mixing, it was filled with argon gas for protection, sealed and protected from light, and placed in a refrigerator (at a temperature of about 4°C) for about 48 hours of reaction. Take out after the completion of TLC monitoring reaction, the solution is deep red, and there are colorless transparent needle-like crystals at the bottom. Transfer the liquid into a 500mL beaker, add a little ice cubes, add 100mL saturated NaHCO several times 3 Aqueous solution, stirring while adding, a large number of bubbles generated, adding ethyl acetate for extraction, then transferred to a 500mL sep...

Embodiment 2

[0037] An osteoporosis treatment drug 1α-hydroxyvitamin D 3 The synthetic method comprises the steps:

[0038] (1) Esterification: Vitamin D 3 (1a) and methanesulfonyl chloride were put into benzene, under the protection of nitrogen, adding pyridine and methylamine, at a temperature of 50 ℃, vitamin D 3 The hydroxyl group was subjected to an esterification reaction. After the reaction was monitored by TLC (4 hours), the solution was taken out, the solution was light red, and there were colorless transparent needle-like crystals at the bottom, which were washed twice with saturated sodium bicarbonate solution, and then washed with saturated aqueous sodium chloride solution. Twice, add anhydrous sodium sulfate to dry, filter, and distill under reduced pressure to obtain vitamin D 3 3-Hydroxyester (2a), yield nearly 100%; Vitamin D 3 , the mol ratio of methanesulfonyl chloride, pyridine and methylamine is 1:1.3:5.0:0.1;

[0039] (2) Cyclization: Using methanol as solvent, mix...

Embodiment 3

[0044] An osteoporosis treatment drug 1α-hydroxyvitamin D 3 The synthetic method comprises the steps:

[0045] (1) Esterification: Vitamin D 3 (1a) Put p-toluenesulfonyl chloride in toluene, under the protection of nitrogen, add pyridine and ethylamine, at 40 ° C, the vitamin D 3 The hydroxyl group was subjected to an esterification reaction. After the reaction was completed (4 hours and 15 minutes) by TLC, the solution was taken out, the solution was light red, and there were colorless transparent needle-like crystals at the bottom, washed twice with saturated sodium bicarbonate solution, and then washed with saturated sodium chloride Wash twice with aqueous solution, add anhydrous sodium sulfate to dry, filter, and distill under reduced pressure to obtain vitamin D 3 3-Hydroxyester (2a), yield nearly 100%; Vitamin D 3 , the mol ratio of p-toluenesulfonyl chloride, pyridine and ethylamine is 1:1.3:10.0:1.0;

[0046] (2) Cyclization: Using methanol as solvent, mix 1 mole o...

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Abstract

The invention discloses a synthetic method of an osteoporosis treatment drug 1 alpha-hydroxyitamin D3, which comprises the following steps: 1) esterfying; 2) cyclizing; 3) oxidizing; 4) opening ring; and 5) performing photochemical isomerization: dissolving a mixture of 5,6-cis 1 alpha-hydroxyitamin D3 and 5,6-trans 1 alpha-hydroxyitamin D3 in methanol with 20-200 parts by weight, adding a photosensitizer, reacting for 0.5-10 hours under irradiation of ultraviolet light to obtain 5,6-cis 1 alpha-hydroxyitamin D3 which is 1 alpha-hydroxyitamin D3; and performing recrystallization to obtain the 1 alpha-hydroxyitamin D3 acicular crystal. According to the invention, a fat-soluble solvent substitutes pyridine, an organic alkalescence catalyst is used, under the analogous yield condition, the reaction temperature changes to normal temperature from low temperature, the reaction time is short, the energy consumption is low, toxic substance pyridine with mass usage can be avoided, the steps for extracting and cleaning pyridine can be omitted, and the technology economy is enhanced.

Description

technical field [0001] The present invention relates to a synthesis method of osteoporosis medicine, in particular to a kind of osteoporosis medicine 1α-hydroxyvitamin D 3 (alfacalcidol) synthesis. Background technique [0002] Vitamin D 3 It is an essential fat-soluble vitamin for the growth, development, reproduction, maintenance of life and health of humans and animals. Its main physiological function is to promote the absorption of calcium and phosphorus in the intestine, ensure the sufficient supply of calcium and phosphorus in the body, promote the normal calcification of bones, and maintain the balance of blood calcium and blood phosphorus. It is clinically used to treat rickets, rickets, and hypothyroidism. embolism. [0003] but vitamin D 3 It has no physiological function itself, only in the conversion into 1α, 25-dihydroxyvitamin D 3 Only after that can it play a role. 1α, 25-Dihydroxyvitamin D 3 In addition to the known function of regulating calcium and p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00A61P19/10
Inventor 郭翔海丁浚元曾周靓子刘宁芝
Owner TIANJIN UNIV
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