Preparation method of calcifediol intermediate A ring

A technology for calcifediol and intermediates, which is applied in the field of preparation of the A-ring of calcifediol intermediates, can solve the problems of long synthesis routes, difficulty in realizing mass production, etc., and achieves a short synthesis route, simple operation and mild conditions. Effect

Inactive Publication Date: 2021-11-16
甘肃皓天医药科技有限责任公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The same synthetic route is lengthy and difficult to achieve mass production

Method used

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  • Preparation method of calcifediol intermediate A ring
  • Preparation method of calcifediol intermediate A ring
  • Preparation method of calcifediol intermediate A ring

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] A preparation method of calcifediol intermediate A ring, the synthetic route is described in the following formula:

[0040]

[0041] The specific preparation method is:

[0042] Preparation of compound Ⅲ-1

[0043] In the synthetic route shown in step 1, the solvent is tetrahydrofuran.

[0044] Under argon protection, compound II-1 (269.00g, 1.53mol) was dissolved in 1000mL tetrahydrofuran in a 2000mL three-neck flask, cooled to -70°C, and n-butyllithium (611.50ml, 1.53mol) was added dropwise, and stirred for 60min. Add compound I (50.00 g, 0.51 mol), and then add boron trifluoride ether (80.00 g, 0.56 mol), and continue stirring for 60 min. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried and concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain Compound III-1 (120 g) with a yield of 85.7%.

[0045] Preparation of compound Ⅳ-1

[0046] Under...

Embodiment 2

[0054] A preparation method of calcifediol intermediate A ring, the synthetic route is described in the following formula:

[0055]

[0056] The specific preparation method is:

[0057] Preparation of compound Ⅲ-2

[0058] Under the protection of argon, compound II-2 (257.04g, 1.84mol) was dissolved in 1000mL ether in a 2000mL three-necked flask, cooled to -78°C, and n-butyllithium (736.00ml, 1.84mol) was added dropwise, and stirred for 50min. Add compound I (60.00 g, 0.61 mol), and then add boron trifluoride ether (86.90 g, 0.61 mol), and stir for 60 min. Saturated aqueous sodium bicarbonate solution was added, the organic phase was separated, dried and concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain Compound III-2 (120.50 g), with a yield of 82.8%.

[0059] Preparation of compound Ⅳ-2

[0060] Under the protection of argon, compound III-2 (120.00g, 0.50mol) was dissolved in 1200mL dichloromethane in a 2000mL thr...

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Abstract

The invention discloses a preparation method of a calcifediol intermediate ring A, and belongs to the technical field of organic chemistry. A compound III, a compound IV and a compound V are respectively obtained by taking a compound I as an initial raw material according to a synthesis route through a process shown in a reaction formula, and a key intermediate VII is finally obtained. The synthesis process adopts conventional organic chemical reactions, the raw materials are low in cost and easy to obtain, the process is simple, the synthesis route is short, the yield is high, the product quality is stable, large-scale production is easily achieved, and the method has good economic benefits and wide application prospects.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and is applicable to the preparation of pharmaceutical intermediates, in particular to a method for preparing ring A of a calcifediol intermediate. Background technique [0002] Calcifediol is vitamin D in the human body 3 (VD 3 ) in liver VD 3 Transformed under the action of hydroxylase, it is sensitive to air, heat and light, easily soluble in polar organic solvents such as ethanol, and insoluble in water. Developed and marketed by Upjohn Company of the United States in the 1980s, it is used to treat various chronic bone disorders such as osteoporosis in the elderly, as well as metabolic bone diseases related to chronic renal failure. It has broad application prospects, and its chemical structure is shown in Formula 1. [0003] [0004] According to the synthetic routes reported so far, the chemical synthesis methods of calcifediol mainly include the following types. One is to p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07C41/24C07C43/196
CPCC07F7/1804C07F7/1892C07C41/24C07C41/30C07C41/18C07C41/26C07C41/22C07C43/196C07C43/178C07C43/14
Inventor 魏鹏飞王鹏博李毅薛吉军朱军龙
Owner 甘肃皓天医药科技有限责任公司
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