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Preparation method and application of intermediate for preparing fluocalcitol

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

Active Publication Date: 2020-11-20
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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  • Preparation method and application of intermediate for preparing fluocalcitol
  • Preparation method and application of intermediate for preparing fluocalcitol
  • Preparation method and application of intermediate for preparing fluocalcitol

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Experimental program
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Effect test

Embodiment 1

[0061] Embodiment 1: the preparation of compound 3

[0062] Add compound 1 (30.0g, 258.4mmol, 0.861mol / L) and n-hexane (300ml) into a 2000ml three-necked flask, cool the reaction down to -60°C to -65°C, dropwise add lithium diisopropylamide (258.4ml, 258.4 mmol), keep the temperature and react for 30min, slowly add the saturated n-hexane solution (260.0ml) of compound 2 dropwise, keep the temperature and react 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 n-hexane solution of hexafluoroacetone: drop the trihydrate of hexafluoroacetone into concentrated sulfuric acid, and absorb the generated gas with n-hexane (-20°C to -40°C) until saturated.

Embodiment 2

[0063] Embodiment 2: the preparation of compound 4

[0064] Under argon protection, compound 3 (35.0g, 124.1mmol) was added to a 500mL three-necked flask, then dichloromethane (300.0ml) was added, diisopropylethylamine (48.1g, 372.3mmol) was added, and the temperature was lowered to 0 Add methoxychloromethane (19.8g, 248.2mmol) at ℃, naturally warm up to room temperature, stir for 36 hours, add the reaction solution into aqueous sodium bicarbonate solution, extract with ethyl acetate, dry and concentrate to obtain the crude product, which is subjected to silica gel column chromatography 28.3 g of compound 4 was obtained, with a yield of 70.0%.

Embodiment 3

[0065] Embodiment 3: the preparation of compound 5

[0066] Compound 4 (28.0g, 85.8mmol) was added to a 500mL three-neck flask, tetrahydrofuran (280.0ml) was added, the temperature was lowered to -5°C to 0°C, and lithium aluminum hydride (3.3g, 85.8mmol) was added in batches while maintaining the temperature. The mixture was reacted at high temperature for 1 hour, quenched by adding aqueous sodium hydroxide solution, extracted with ethyl acetate, dried and concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain 15.8 g of compound 5 with a yield of 72.0%.

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Abstract

The invention discloses a preparation method and application of an intermediate for preparing fluocalcitol, and belongs to the field of organic chemistry. The preparation method comprises the following steps: by taking a compound 1 as an initial raw material, carrying out addition reaction, tertiary hydroxyl protection, ester group reduction and iodination on the compound 1 and a compound 2 to obtain a compound 6, reacting the compound 6 with triphenylphosphine to form a quaternary phosphonium salt, carrying out Wittg reaction on the quaternary phosphonium salt and a compound 8 to obtain an olefin compound 9, reducing, removing a silyl ether protection group and oxidizing to obtain an intermediate 12; the raw materials are cheap and easy to obtain, the reaction steps are simplified, the preparation cost is reduced, the yield is high, and the product quality is easy to control; use of dangerous samples such as tert-butyl lithium, sodium amalgam, tri-n-butyl hydrogen stannate and carbondisulfide is avoided, the preparation risk is reduced, and large-scale preparation is easy.

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 and application of an intermediate used to prepare flucalcidol. Background technique [0002] Fluocciferol is a vitamin D analogue, 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 shows stronger biological activity than calcitriol. In the in vitro test, the activation effect of flucalcidol and calcitriol on the vitamin D responsive gene of rat osteoblast cell line ROB-C26 was compared. 6h after adding vitamin D, the expression level of 1α, 25(OH)2-D3-24 hydroxylase mRNA was detected, and it was found that the effect of this product is 10 times stronger than that of ...

Claims

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Application Information

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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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