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Preparation method and application of falecalcitriol intermediate

A technology for an intermediate, calcidol, applied in the field of preparation of fluorocalcidol intermediates, can solve the problems of high cost, low safety and yield, expensive raw materials, etc., and achieves simplified reaction steps, reduced cost, and cost of raw materials. Inexpensive effect

Active Publication Date: 2020-12-08
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 purpose of the present invention is: for the synthesis of above-mentioned existing fluorocalcidol, raw materials are expensive, photoreaction ring-opening and thermal isomerization reaction are required or tert-butyllithium, sodium amalgam, or tri-n-butyltin hydride are required The phenomenon of dangerous test products such as carbon disulfide and carbon disulfide causes the problems of high cost, low safety and low yield. The present invention provides a preparation method and application of flucalcidol intermediates

Method used

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  • Preparation method and application of falecalcitriol intermediate
  • Preparation method and application of falecalcitriol intermediate
  • Preparation method and application of falecalcitriol intermediate

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Experimental program
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Embodiment 1

[0046] Embodiment 1: the preparation of compound 3

[0047] Add nickel chloride hexahydrate (81.8g, 343.9mmol) and zinc powder (22.4g, 343.9mmol) into a 500ml three-necked flask, add compound 2 (133.4g, 687.8mmol) and 200.0ml pyridine to the reaction system, and start stirring , the reaction system was green and turbid, replaced with inert gas three times, heated the reaction to 60°C-65°C for 30 minutes, stopped heating and lowered the temperature to 20°C-25°C, kept the temperature and used 100ml of compound 1 (30g, 68.8mmol) Pyridine was dissolved and added dropwise to the above reaction system, kept the temperature for 1.5h, filtered through diatomaceous earth, washed the filter cake with ethyl acetate, washed the organic phase with dilute hydrochloric acid, washed with saturated saline, dried, concentrated and passed through silica gel 15.6 g of compound 3 was obtained by column chromatography, with a yield of 45.0%.

Embodiment 2

[0048] Embodiment 2: the preparation of compound 4

[0049] Under the protection of argon, add compound 3 (5.0g, 9.9mmol) to a 100mL three-necked flask and dissolve it in 760.0ml of dichloromethane, add diisopropylethylamine (6.4g, 49.5mmol), cool down to 0°C and add Methoxychloromethane (4.0g, 49.5mmol), naturally warmed to room temperature, stirred for 48 hours, the reaction solution was added to aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried and concentrated to obtain the crude product, which was obtained by silica gel column chromatography 3.8 g of compound 4, yield 70.0%.

Embodiment 3

[0050] Embodiment 3: the preparation of compound 5

[0051]Compound 4 (8.0g, 14.6mmol) was added to a 250mL three-necked flask, 150.0ml (1854mmol) of tetrahydrofuran was added, a tetrahydrofuran solution of tetrabutylammonium fluoride trihydrate (23.0g, 72.9mmol) was added, and heated to reflux for 50 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, dried and concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain 4.6 g of compound 5 with a yield of 72.9%.

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Abstract

The invention discloses a preparation method and application of a falecalcitriol intermediate, and belongs to the field of organic chemistry. The preparation method comprises the following steps: step1, reacting a compound 1 with a compound 2 in an organic solvent 1 under the action of Lewis acid to obtain a compound 3; step 2, dissolving the intermediate compound 3 obtained in the step 1 in an organic solvent 2, and reacting with methoxychloromethane under an alkaline condition to obtain a compound 4; step 3, removing a silyl ether protecting group from the compound 4 in an organic solvent 3to obtain a compound 5; and step 4, dissolving the intermediate compound 5 obtained in the step 3 in an organic solvent 4, and carrying out an oxidation reaction to obtain a compound 6. The raw materials are cheap and easy to obtain, the reaction steps are simplified, the synthesis period is shortened, the preparation cost is reduced, large-scale preparation is easy, and the method is safer.

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 a flucalcidol intermediate and an application thereof. 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 calcit...

Claims

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Application Information

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IPC IPC(8): C07C45/29C07C49/517C07C41/52C07C43/30C07F7/18C07C401/00
CPCC07C45/292C07C49/517C07C41/52C07C43/30C07F7/1804C07F7/1892C07C401/00C07C2602/24Y02P20/55
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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