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The preparation method and application of the intermediate for the preparation of flucalcidol

A technology for intermediates and calcidol, applied in the field of preparation of intermediates, can solve the problems of low safety, high cost, expensive raw materials and the like, and achieve the effects of simplifying reaction steps, high yield and reducing cost

Active Publication Date: 2022-06-17
甘肃皓天医药科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The object of the present invention is to be aimed at above-mentioned existing fluoccidol synthetic raw material is expensive, needs photoreaction ring-opening and thermal isomerization reaction or needs to use tert-butyllithium, sodium amalgam, or tri-n-butyltin hydrogen and The phenomenon of dangerous samples such as carbon disulfide leads to the problems of high cost and low safety. The invention provides a preparation method and application of an intermediate for the preparation of fluorocalcidol.

Method used

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  • The preparation method and application of the intermediate for the preparation of flucalcidol
  • The preparation method and application of the intermediate for the preparation of flucalcidol
  • The preparation method and application of the intermediate for the preparation of flucalcidol

Examples

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Embodiment 1

[0060] Example 1: Preparation of Compound 3

[0061] In a 2000ml there-necked flask, add compound 1 (30.0g, 258.4mmol, 0.861mol / L), n-hexane (300ml), cool the reaction to -60°C to -65°C, dropwise add lithium diisopropylamine (258.4ml, 258.4 mmol), keep the temperature reaction for 30min, slowly add the n-hexane saturated solution (260.0ml) of compound 2 dropwise, keep the temperature reaction for 1h, quench the reaction with saturated aqueous ammonium chloride solution, separate the organic phase, dry and concentrate to obtain 36.4g compound 3. The yield is 50.0%. Preparation of saturated hexafluoroacetone in n-hexane solution: drop the trihydrate of hexafluoroacetone into concentrated sulfuric acid, and absorb the generated gas with n-hexane (-20°C to -40°C) until saturation.

Embodiment 2

[0062] Example 2: Preparation of Compound 4

[0063] Under argon protection, compound 3 (35.0g, 124.1mmol) was added in a 500mL there-necked flask, then dichloromethane (300.0ml) was added, diisopropylethylamine (48.1g, 372.3mmol) was added, and the temperature was lowered to 0 ℃ was added methoxychloromethane (19.8g, 248.2mmol), the temperature was naturally raised to room temperature, stirred for 36 hours, the reaction solution was added to the aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried and concentrated to obtain the crude product, which was subjected to silica gel column chromatography 28.3 g of compound 4 were obtained with a yield of 70.0%.

Embodiment 3

[0064] Example 3: Preparation of Compound 5

[0065] Compound 4 (28.0g, 85.8mmol) was added to a 500mL there-necked flask, tetrahydrofuran (280.0ml) was added, cooled to -5°C to 0°C, and lithium aluminum hydride (3.3g, 85.8mmol) was added in batches while maintaining the temperature. The temperature was reacted for 1 hour, the reaction was quenched by adding sodium hydroxide aqueous solution, extracted with ethyl acetate, dried and concentrated to obtain a crude product, and 15.8 g of compound 5 was obtained by silica gel column chromatography with a yield of 72.0%.

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Abstract

The invention discloses a preparation method and application of an intermediate used for preparing flucalcidol, and belongs to the field of organic chemistry. Compound 1 is used as a starting material, and compound 2 undergoes addition reaction, tertiary hydroxyl protection, ester group reduction, and iodine Compound 6 was obtained by substitution, compound 6 was formed into quaternary phosphonium salt with triphenylphosphine, and compound 8 was reacted with Wittg to obtain alkene compound 9, which was then reduced to remove the silicon ether protecting group and oxidized to obtain intermediate 12. The raw material of the present invention is cheap and easy to obtain, the reaction steps are simplified, the cost of preparation is reduced, the yield is high, and the product quality is easy to control; avoiding the use of dangerous samples such as tert-butyllithium, sodium amalgam, tri-n-butyltin hydrogen, carbon disulfide, etc. , which reduces the risk of preparation and is easy to scale up the preparation;

Description

technical field [0001] The invention belongs to the field of organic chemistry, and relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of an intermediate for preparing fluorocalcidol and its application. Background technique [0002] Fluorocalcidol is a vitamin D analog, which can be used to treat calcium metabolism disorders such as osteoporosis and hyperparathyroidism, and has a therapeutic effect on secondary hyperparathyroidism in patients with chronic renal failure receiving hemodialysis. In a variety of biological detection systems, it showed stronger biological activity than calcitriol. In vitro experiments, the activation effects of fluorocalcidol and calcitriol on vitamin D-responsive gene in rat osteoblast cell line ROB-C26 were compared. The mRNA expression level of 1α, 25(OH)2-D3-24 hydroxylase was detected 6 hours after the addition of vitamin D, and it was found that the effect of this product was 10 times s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/517C07C45/29C07C401/00
CPCC07C45/292C07C401/00C07C41/26C07F7/1892C07F9/5442C07C41/22C07C67/31C07C67/343C07C2602/08C07C43/126C07C69/708C07C69/675C07C49/517C07C43/137Y02P20/55
Inventor 魏鹏飞薛吉军李毅常德山肖明兴
Owner 甘肃皓天医药科技有限责任公司
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