Synthesis of vitamin D2 derivatives

A vitamin and synthesis method technology, applied in the field of synthesis of vitamin D2 derivatives, can solve the problems of heavy metal residues, low oxidation activity of manganese dioxide, etc., and achieve the effects of mild conditions, improved atom utilization, and environmental friendliness

Inactive Publication Date: 2017-12-19
JIANGSU JIBEIER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The oxidation activity of manganese dioxide is low, and it is generally used for the oxidation of allylic hydroxyl groups
Pyridiniu...

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: DMP (1.315 g, 3.1 mmol) in dichloromethane (5 mL) was added dropwise to compound 1 (2 g, 3.1 mmol) in dichloromethane (20 mL) under argon protection at room temperature After the dropwise addition was completed, stirring was continued at room temperature for 2 hours. After the reaction was complete, 20 mL of saturated aqueous sodium bicarbonate was added, stirred at room temperature for 30 minutes, and filtered under reduced pressure. The filtrate was extracted three times with dichloromethane, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate for 2 hours. Suction filtration under reduced pressure, the filtrate was concentrated under reduced pressure, and column chromatography gave compound 2 (1.75 g, 88%) as a white solid.

Embodiment 2

[0025] Example 2: DMP (1.45 g, 3.41 mmol) in dichloromethane (5 mL) was added dropwise to compound 1 (2 g, 3.1 mmol) in dichloromethane (20 mL) under argon protection at room temperature After the dropwise addition was completed, stirring was continued at room temperature for 2 hours. After the reaction was complete, 20 mL of saturated aqueous sodium bicarbonate was added, stirred at room temperature for 30 minutes, and filtered under reduced pressure. The filtrate was extracted three times with dichloromethane, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate for 2 hours. Suction filtration under reduced pressure, the filtrate was concentrated under reduced pressure, and column chromatography gave compound 2 (1.83 g, 92%) as a white solid.

Embodiment 3

[0026] Example 3: DMP (1.45 g, 3.41 mmol) in dichloromethane (5 mL) was added dropwise to compound 1 (2 g, 3.1 mmol) in dichloromethane (20 mL) under argon protection at room temperature , After the dropwise addition was completed, the mixture was stirred under reflux at 40° C. for 2 hours. After the reaction was complete, 20 mL of saturated aqueous sodium bicarbonate was added, stirred at room temperature for 30 minutes, and filtered under reduced pressure. The filtrate was extracted three times with dichloromethane, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate for 2 hours. Suction filtration under reduced pressure, the filtrate was concentrated under reduced pressure, and column chromatography gave compound 2 (1.65 g, 83%) as a white solid.

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Abstract

The invention discloses a synthetic method for vitamin D2 derivatives. The synthesis of the key intermediate C-24 hydroxyl group for the commercially-available drugs tacalcitol and calcipotriol is basically prepared by using a NaBH4 reduction method. The NaBH4 reduction method has the disadvantages that target product yield is about 50% and the byproduct C-24 hydroxyl epimer alcohol has no value in use. According to the invention, a byproduct 1 or a byproduct 4 respectively produced in preparation of tacalcitol or calcipotriol is used as a starting material, a Dess-Martin reagent is used as an oxidation reagent, and a reaction is carried out in an organic solvent at 0 DEG C to 100 DEG C; after the reaction is completed, cooling to room temperature is carried out and then treatment is carried out so as to obtain an intermediate 2 or 5, respectively; and after treatment, the intermediate 2 or 5 is subjected to a reduction reaction so as to obtain a compound 3 or 6, respectively. Compared with the prior art, the synthetic method provided by the invention has the advantages that raw materials are easily available; reaction conditions are mild; post-treatment is simple; the utilization rate of atoms is increased; and pollution is reduced.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and mainly aims at a synthesis method of vitamin D2 derivatives. Background technique [0002] Tacalcitol and Calcipotriol are vitamin D derivatives, which were developed and produced by Teijin Pharmaceutical Co., Ltd. of Japan and Leo Denmark of Denmark respectively. The trade name of tacalcitol is Mengerfu, and its chemical name is (+)-(5Z,7E,22E,24R)-9,10-secocholesta-5,7,10(19)-triene-11α,3β,24 -triol. The trade name of calcipotriol is Dalux, and its chemical name is: (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-11α, 3β,24-triol. Studies have shown that the two drugs can enhance the absorption of calcium, and can also inhibit the proliferation and differentiation of certain cells, including epidermal keratinocytes, and are mainly used clinically for local treatment of psoriasis vulgaris. [0003] Since the synthesis route of tacalcitol and calcipotriol is relativ...

Claims

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Application Information

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IPC IPC(8): C07F7/18
CPCC07F7/1804C07F7/1892
Inventor 李召广张建海聂丽云钱玉琴
Owner JIANGSU JIBEIER PHARMA
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