Preparation method of maxacalcitol

A technology of maxacalcitol and methanol, applied in the direction of organic chemistry, can solve the problems of cumbersome chemical synthesis steps, lengthy chemical reaction steps, and low yield

Pending Publication Date: 2022-06-24
HANGZHOU XIASHA BIOCHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Although the above method avoids the use of 1α-hydroxyepiandrosterone raw materials, the preparation of the A ring intermediate requires cumbersome chemical synthesis steps, and the yield is extremely low; the preparation of the C / D ring intermediate requires the use of more expensive vitamin D2 Steroid raw materials are prepared by oxidative cracking and other methods, the chemical reaction steps are lengthy, the yield is low, and the cost is high, which does not conform to the principle of green chemistry

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  • Preparation method of maxacalcitol
  • Preparation method of maxacalcitol
  • Preparation method of maxacalcitol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] A kind of preparation method of maxacalcidol, concrete process is such as figure 1 As shown, the specific process is:

[0036] S1. Preparation of (3R)-tert-butyldimethylsiloxane-androst-5en-17 ketone (acylation I): 20 g of dehydroepiandrosterone was dissolved in 200 mL of tetrahydrofuran, at 37 ° C, and 9.5g of imidazole and 15.8g of tert-butyldimethylsilyl chloride were added for reflux reaction, and after 3 hours of reaction, the solvent was distilled off under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride solution, dehydrated, and evaporated to obtain 28.05g of white solid. That is (3R)-tert-butyldimethylsiloxane-androst-5-ene-17 ketone, denoted as compound 18, and the reaction process is as follows:

[0037] C 19 H 28 O 2 +C 6 H 15 ClSi+C 3 H 4 N 2 →C 25 H 42 O 2 Si+C 3 H 5 N 2 Cl;

[0038] Preparation of S2, (17Z,3R)-tert-butyldimethylsiloxane-androst-5,17-diene (Grignard reaction I): keep the temperature at 5...

Embodiment 2

[0086] A preparation method of maxacalcitol, the concrete technological process is:

[0087] Preparation of S1, (3R)-tert-butyldimethylsiloxane-androst-5en-17 ketone: dissolve 20 g of dehydroepiandrosterone in 200 mL of tetrahydrofuran, and add 15.0 g of imidazole and 21.9 g of tert-butyl 28.0g of white solid was obtained, which was (3R)-tert-butyldimethylsiloxane after refluxing reaction with dimethylsilyl chloride, distillation under reduced pressure, extraction with ethyl acetate, washing with saturated sodium chloride water, dehydration, and evaporation of the solvent. -Androst-5en-17one, denoted as compound 18.

[0088] Preparation of S2, (17Z,3R)-tert-butyldimethylsiloxane-androst-5,17-diene: add 28.0 g of compound 18 and 77.19 g of ethyltriphenylphosphonium bromide to 200 mL of tetrahydrofuran solvent , 98.0g potassium tert-butoxide refluxed for reaction, extracted with petroleum ether, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, concent...

Embodiment 3

[0104] A preparation method of maxacalcitol, the concrete technological process is:

[0105] Preparation of S1, (3R)-tert-butyldimethylsiloxane-androst-5en-17 ketone: 20.0 g of dehydroepiandrosterone was dissolved in 400 mL of tetrahydrofuran, and 7.03 g of imidazole and 11.42 g of tert-butyl were added 26.2g of white solid was obtained, which was (3R)-tert-butyldimethylsilicon Oxy-androst-5en-17one, denoted as compound 18.

[0106] Preparation of S2, (17Z,3R)-tert-butyldimethylsiloxane-androst-5,17-diene: add 26.0g compound 18 and 35.78g ethyltriphenylphosphonium bromide to 260mL tetrahydrofuran solvent , 10.81g potassium tert-butoxide was refluxed for reaction, extracted with petroleum ether, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, concentrated in vacuo to obtain a yellowish solid, and purified by recrystallization to obtain 22.1g (17Z,3R)-tertiary Butyldimethylsiloxane-androsta-5,17-diene, denoted as compound 19.

[0107] Preparation o...

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PUM

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Abstract

The invention relates to a synthesis method of a medicine, in particular to a preparation method of maxacalcitol. The maxacalcitol is prepared by taking dehydroepiandrosterone as an initial raw material through acylation, Grignard reaction, oxidation, saponification, hydroxyl protection, epoxidation, reduction, elimination, NBS bromination / dehydrobromination, deprotection and illumination ring opening, the operation is simple, the yield is high, and the maxacalcitol is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing a medicine, in particular to a method for preparing maxacalcitol. Background technique [0002] Maxacalcidol is a vitamin D3 derivative with antiproliferative activity and has a weak hypercalcemia-inducing effect. It is a third-generation active vitamin D3 drug developed by Chinese and foreign pharmaceutical companies and has been intensively developed in Japan. Maxacalcidol has a certain affinity for VDR located in human epidermal keratinocytes, which is lower than that of calciferol, but maxacalcidol can penetrate into the nucleus to play a physiological role. Maxacalcidol has excellent effects on inducing the differentiation of epidermal keratinocytes and inhibiting the proliferation of epidermal keratinocytes. protein expression and improve its epidermal hypertrophy. After applying maxacalcitol ointment to the affected area, it can delay the DNA synthesis and mitotic rate in keratinocytes, promo...

Claims

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Application Information

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IPC IPC(8): C07C401/00
CPCC07C401/00C07C2601/14C07C2602/08
Inventor 吴江浩楼靖靖邵振宝金晓烽
Owner HANGZHOU XIASHA BIOCHEM TECH
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