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Preparation method of eldecalcitol A ring intermediate

A technology of idecalcidol and intermediates, which is applied in chemical instruments and methods, organic chemistry, bulk chemical production and other directions, can solve the problems of long synthesis route, high production cost, high difficulty and the like, and achieves simple preparation method, Inexpensive raw materials and mild reaction conditions

Active Publication Date: 2020-12-18
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

However, the introduction of the 2-position side chain through tert-butyl ester requires the use of lithium aluminum hydrogen reduction, which has a great potential safety hazard
[0016] In summary, in the prior art, the synthesis route of the A ring of the idecalcitol intermediate is long, difficult, and low in purity, so the production cost is high

Method used

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  • Preparation method of eldecalcitol A ring intermediate
  • Preparation method of eldecalcitol A ring intermediate
  • Preparation method of eldecalcitol A ring intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] This embodiment provides a kind of preparation method of idecalcitol A ring intermediate, and synthetic route is as follows figure 1 shown, including the following steps:

[0043] (1) Preparation of Compound II

[0044] Compound I (100.0g, 288.9mmoL) was dissolved in 500.0mL of methanol and 50.0mL of water in a 1000mL three-necked flask, hydrochloric acid (216.7g, 433.3mmoL) was added at room temperature, stirred at room temperature for 15 hours, and the reaction solution was concentrated and dried to obtain The crude product was subjected to column chromatography with ethyl acetate and n-heptane to obtain compound II (60.2 g) with a yield of 67.9%.

[0045] (2) Preparation of Compound III

[0046] Dissolve compound II (60.0g, 196.0mmoL) in 500.0mL of N,N-dimethylformamide in a 1000mL three-neck flask, cool down to -5°C-0°C, add imidazole (53.3g, 783.9mmoL), Add tert-butyldimethylsilyl chloride (88.2g, 588.0mmoL) in batches, heat up to room temperature and stir for 1...

Embodiment 2

[0051] (1) Preparation of Compound II

[0052] Compound I (100.0g, 288.9mmoL) was dissolved in 500.0mL ethanol in a 1000mL three-necked flask, 50mL of 10% sulfuric acid solution was added at room temperature, stirred at room temperature for 11 hours, the reaction solution was concentrated and dried to obtain the crude product, which was washed with ethyl acetate and n-heptane column chromatography to obtain compound II (59.0 g) with a yield of 65%.

[0053] (2) Preparation of Compound III

[0054]Dissolve compound II (60.0g, 196.0mmoL) in 500.0mL of N,N-dimethylformamide in a 1000mL three-neck flask, cool down to -5°C-0°C, add imidazole (53.3g, 783.9mmoL), Add tert-butyldimethylsilyl chloride (88.2g, 588.0mmoL) in batches, heat up to room temperature and stir for 15 hours, add water, extract with ethyl acetate, dry and concentrate to obtain the crude product, which is washed with ethyl acetate and n-heptyl Through alkane column chromatography, compound III (85.0 g) was obtai...

Embodiment 3

[0059] (1) Preparation of Compound II

[0060] Dissolve compound I (100.0g, 288.9mmoL) in 500.0mL methanol and 50.0mL water in a 1000mL three-necked flask, add hydrochloric acid (216.7g, 433.3mmoL) at room temperature, stir at room temperature for 15 hours, and concentrate the reaction solution to dryness to obtain The crude product was subjected to column chromatography with ethyl acetate and n-heptane to obtain compound II (60.2 g) with a yield of 67.9%.

[0061] (2) Preparation of Compound III

[0062] Dissolve compound II (60.0g, 196.0mmoL) in 500.0mL of N,N-dimethylformamide in a 1000mL three-neck flask, cool down to -5°C-0°C, add imidazole (53.3g, 783.9mmoL), Add tert-butyldimethylsilyl chloride (88.2g, 588.0mmoL) in batches, heat up to room temperature and stir for 15 hours, add water, extract with ethyl acetate, dry and concentrate to obtain the crude product, which is washed with ethyl acetate and n-heptyl Through alkane column chromatography, compound III (85.0 g) ...

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Abstract

The invention discloses a preparation method of an eldecalcitol A ring intermediate, and belongs to the technical field of organic chemistry, and the preparation method comprises the following steps:(1) dissolving a compound I in an organic solvent, and removing a propylidene protecting group under an acidic condition to obtain a compound II; (2) dissolving the compound II in an organic solvent,adding imidazole as an acid-binding agent, and adding tert-butyl dimethyl chlorosilane to react with the compound II to obtain a compound III; and (3) dissolving the compound III in an organic solvent, and carrying out etherification reaction on the compound III and a compound IV under the action of alkali to obtain a compound V; the preparation method is simple and convenient, the preparation route is greatly simplified, the raw materials are cheap and easy to obtain, the reaction conditions are mild, and the product is easy to purify.

Description

technical field [0001] The invention discloses a method for preparing an idecalcitol A ring intermediate, which belongs to the technical field of organic chemistry, and in particular relates to the preparation of a pharmaceutical intermediate. Background technique [0002] Idecalcidol is a drug jointly developed by Chugai Pharmaceutical and Chia Tai Pharmaceutical for the treatment of osteoporosis. Its curative effect is better than that of alfacalcidol, and its safety is similar to that of alfacalcidol. It is the latest drug for the treatment of osteoporosis, which was launched in Japan in 2011. Idecalcitol is a vitamin D analog that can more effectively increase bone density and reduce the risk of fractures. The market capacity is large, and the aging phenomenon in China has led to a large number of people with osteoporosis. [0003] According to the synthetic routes reported so far, its synthetic methods mainly include the following types. One is to use cholesteroloids ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1804C07F7/1892Y02P20/55
Inventor 魏鹏飞薛吉军常德山李毅冯伟伟吴瑞
Owner 甘肃皓天医药科技有限责任公司
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