Novel preparation method for vitamin D class drug

A technology for compound and silyl ether protection, applied in the field of vitamin D drug synthesis, can solve the problems of cumbersome separation and purification of intermediates and products, inability to realize industrialization, low yield, etc., and achieves good reaction orientation selectivity and operation process The effect of short time and high yield

Inactive Publication Date: 2015-03-11
CHONGQING HUAPONT PHARMA
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0008] Using vitamin D2 as raw material through SO 2 Double bond protection and TBS protection, desulfurization with sodium bicarbonate, 1α-hydroxylation, and SO 2 Double bond protection, then oxidation and sodium bicarbonate desulfurization to obtain the intermediate, then Wittig reaction, chiral reduction, and finally light transformation and deprotection to obtain the compound of formula (I). The disadvantage of this method is that the yield is low and the intermediate It is cumbersome to separate and purify the product and cannot realize industrialization

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  • Novel preparation method for vitamin D class drug
  • Novel preparation method for vitamin D class drug
  • Novel preparation method for vitamin D class drug

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preparation example Construction

[0041] Part I Preparation of silyl ether protected calcipotriol

[0042] The preparation of silicon ether-protected calcipotriol is as follows: the compound shown in formula II and the compound shown in formula III are subjected to double bond coupling reaction under basic conditions to obtain the compound shown in formula IV. In the formula, R 1 , R 2 , R 3 The silicon ether protecting group is any one or more of dimethyl tert-butylsilane, triisopropylsilane, tert-butyldiisopropylsilane, triethylsilane and trimethylsilane. The above compounds are dissolved in organic solvents. The organic solvent includes any one or more of tetrahydrofuran, methyltetrahydrofuran, diethyl ether and toluene. In order to ensure that the reaction proceeds in an alkaline environment, alkaline reagents such as potassium dimethylsilylamide and potassium trimethylsilylamide can be added.

[0043]

Embodiment 1

[0044] Example 1 Preparation of silicon ether protected calcipotriol (compound of formula IV)

[0045] Under the protection of nitrogen, add 5ml of tetrahydrofuran and 5g of the compound of formula III into a 25ml dry single-necked bottle, cool to -80~-60℃, add 8ml of bis(trimethylsilyl) sodium amide solution dropwise, and control the temperature at -80~- After 0.5 hour at 60°C, slowly drop in a solution of 3g of the compound of formula II dissolved in 3ml of tetrahydrofuran, control the temperature at -80 to -60°C for 1 to 3 hours, and monitor by TLC (the developer is n-hexane: ethyl acetate = 30:1), After the reaction was completed, the temperature was raised to -5-5°C, and saturated ammonium chloride aqueous solution was added to the system to quench the reaction, and then extracted three times with ethyl acetate, the organic layer was washed twice with water, and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was added to (et...

Embodiment 2

[0046] Example 2 Preparation of silicon ether protected calcipotriol (compound of formula IV)

[0047] Under the protection of nitrogen, add 10ml of tetrahydrofuran and 2g of the compound of formula III to a 25ml dry single-necked bottle, cool to -80~0℃, add dropwise 4ml of bis(trimethylsilyl)potassium amide solution, and control the temperature at -80~-60 After 0.5 hours at ℃, slowly drop into the solution of 1.3g of the compound of formula II dissolved in 5ml of tetrahydrofuran, control the temperature at -80~-60℃ for 1~3 hours, and monitor the reaction by TLC (developing agent is n-hexane:ethyl acetate=30:1) After completion, the temperature was raised to -5-5°C, and saturated ammonium chloride aqueous solution was added to the system to quench the reaction, and then extracted three times with ethyl acetate, the organic layer was washed twice with water, and dried over anhydrous sodium sulfate. The residue obtained after concentration was added to (ethyl acetate:n-hexane=1:...

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Abstract

The invention discloses a novel synthesis method for a vitamin D class drug, namely a calcipotriol (formula I) compound. The novel synthesis method comprises the following steps: using a compound shown as a formula II and a compound shown as a formula III as raw materials, carrying out double-bond coupling reaction under a strong base action to obtain a compound shown as a formula IV, and then removing the compound shown as the formula IV from the protection of hydroxyl silyl ethers under the action of tetrabutyl ammonium fluoride to obtain the compound shown as the formula I. The operation is simple, the yield is high and the novel preparation method is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a synthesis method of vitamin D drugs. Background technique [0002] Calcipotriol has the effect of inhibiting cell proliferation and promoting cell differentiation, and has a certain immune and anti-inflammatory regulation effect. And the effect on calcium metabolism in the body is much lower than that of calcitriol. Calcipotriol therefore has the potential to treat skin diseases such as psoriasis characterized by epidermal dysplasia and incomplete differentiation. [0003] 1. Japanese patent JP 08325226 discloses a synthetic method, the route is as follows: [0004] [0005] Using the compound of formula (II) as a raw material and bromomethyltriphenylphosphine hydrobromide to carry out Wittig reaction in an alkaline environment and then deprotecting to obtain the compound of formula (V), and then carry out substitution ring closure with the compound of formula (VI) The c...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07C401/00
CPCY02P20/55
Inventor 唐朝军朱强
Owner CHONGQING HUAPONT PHARMA
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