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Synthesis method of vitamin D analogue intermediate

A synthetic method and analog technology, applied in the field of vitamin D analog intermediates, can solve the problems of inability to directly hydroxylate, low yield, complicated operation, etc., and achieve the effect of shortening the production cycle and increasing the yield

Active Publication Date: 2019-09-06
南通华山药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Alfacalcidol is generally synthesized with vitamin D 3 As a starting material, alfacalcidol can be obtained by hydroxylating the 1-position, but due to structural hindrance, it cannot be directly hydroxylated. In the prior art, the 3-position and 5-position should be cyclized first, and then opened after hydroxylation. Ring, complex operation, long production cycle and low yield (such as Chen Yangsheng, etc., "China New Drug Impurities", Volume 14, No. 12, 2005, 1441-1443)

Method used

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  • Synthesis method of vitamin D analogue intermediate
  • Synthesis method of vitamin D analogue intermediate
  • Synthesis method of vitamin D analogue intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 trans vitamin D 3 preparation of

[0022]

[0023] 20 g vitamin D at room temperature 3 and 0.156g of diphenyldiselenide were added to a 1000ml flask, and then 500ml of cyclohexane was added to dissolve it. Irradiate with a 250-watt incandescent lamp, collect samples at 30 minutes, 60 minutes, 90 minutes and 120 minutes respectively, and analyze the reaction progress by HPLC. As shown in Table 1 below, the results indicated that the reaction was completed in 1.5 hours with a conversion rate of 66%.

[0024] Table 1 conversion rate table

[0025] time (min) Vitamin D 3 %

[0026] Subsequently, the reaction mixture was spun to dryness at 35°C, and pure trans-vitamin D was obtained by preparative liquid phase separation 3 , as an intermediate for the synthesis of alfacalcidol raw materials. unreacted vitamin D 3 After purification and separation, it can be recycled again.

Embodiment 2

[0027] The preparation of embodiment 2 trans-calcifediol

[0028]

[0029] Add 10g of calcifediol and 0.078g of diphenyldiselenide into a 1000ml flask at room temperature, then add 250ml of n-hexane and 250ml of ethyl acetate to dissolve. Irradiate with a 250-watt tungsten halogen lamp, collect samples at 30 minutes, 60 minutes, 90 minutes and 120 minutes respectively, and analyze the reaction progress by HPLC. As shown in Table 2 below, the results indicated that the reaction was completed in 1.5 hours with a conversion rate of 70%.

[0030] Table 2 conversion rate table

[0031] time (min) Calcidiol% Trans-calcifediol% 30 75 25 60 50 50 90 30 70 120 30 70

[0032] Subsequently, the reaction mixture was rotary evaporated to dryness at 35° C., and pure trans-calcifediol was obtained by preparative liquid phase separation, which was used as an intermediate for the synthesis of calcitriol raw materials. The unreacted calcifediol can...

Embodiment 3

[0033] Example 3 Preparation of Intermediate (IV).

[0034]

[0035] 10g vitamin D 3 , 0.55g of dibutylhydroxytoluene and 4.75g of imidazole were placed in the reaction flask and dissolved in 150ml of dichloromethane, and 5g of tert-butyldimethylsilyl chloride was dissolved in 25ml of dichloromethane, and slowly added dropwise to the above In the reaction bottle, stirring at room temperature, HPLC detection of vitamin D 3 The reaction is complete and intermediate (Ⅲ) is generated. After further purification by preparative liquid phase, pure intermediate (Ⅲ) was obtained

[0036] At room temperature, add 10 g of intermediate (Ⅲ), 0.085 g of dibenzyl diselenide and 0.054 g of diethyl diselenide into a 1000 ml flask, and then add 250 ml of cyclohexane and 250 ml of ethanol to dissolve. Irradiate with a 250-watt halogen lamp, collect samples at 30 minutes, 60 minutes, 120 minutes and 180 minutes, respectively, and analyze the reaction progress by HPLC. As shown in Table 3 b...

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Abstract

The invention discloses a synthesis method of a vitamin D analogue intermediate, and discloses a photochemical reaction method for preparing a revere intermediate (II) from a cis-form initiator (I). The intermediate prepared through the method can serve as the intermediate for synthesizing an active vitamin D analogue (such as alfacalcidol and calcitriol), the production cycle of active substancescan be shortened, and the yield is improved.

Description

technical field [0001] The present invention relates to a method for preparing a vitamin D analog intermediate, more particularly, the present invention relates to a method for photochemically synthesizing vitamin D 3 Methods for analog intermediates. Background technique [0002] Vitamin D 3 Analogues, such as alfacalcidol, are an important active metabolite of vitamin D3. It has the function of regulating the inorganic salt of bone, and its stability is similar to that of vitamin D 3 same. After oral administration, it is quickly absorbed by the gastrointestinal tract and enters the blood. After being hydroxylated at the 25th position by the action of liver microsomal 25-hydroxylase, active 1α, 25-hydroxyvitamin D is generated. 3 , Distributed in target tissues such as the intestinal tract and stomach, after binding to receptors, it can promote the intestinal absorption of calcium and phosphorus and increase the plasma calcium level. It can promote bone mineralization ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00
CPCC07C401/00C07C2602/08C07C2601/16
Inventor 施建飞钱建
Owner 南通华山药业有限公司
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