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Preparation method of cyclopamine

A technology for cyclopamine and the next step, which is applied in the field of preparation of cyclopamine using filimonium as a raw material, can solve the problems of non-stereoselectivity, complex synthesis process, and yield less than 1%, etc. Achieve the effect of simple operation, simple purification and cheap reagents

Active Publication Date: 2010-08-11
BASILEA PHARM CHINA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Literature (Masamune, T., et al., J.Am.Chem.Soc., 1967, 89: 4521-4523; Mitsuhashi, H., et al., Tetrahedron Lett. 1964, 33: 2281-2283) report using Synthesis of mephenamine from the steroidal raw material, pansaponin, but the synthesis process is complex and non-stereoselective, and the yield is less than 1%.
Therefore, the source of cyclopamine remains a major obstacle to its development as a drug

Method used

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  • Preparation method of cyclopamine
  • Preparation method of cyclopamine
  • Preparation method of cyclopamine

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Dissolve 500 mg of fritillary octane (obtained by the method in Example 3) and 315 mg of p-toluenesulfonyl hydrazide in 50 ml of methanol, add 0.1 ml of concentrated hydrochloric acid, stir at room temperature for 1 h, add 0.1 ml of concentrated hydrochloric acid, continue stirring for 2 h, and monitor by TLC. The response is complete. Concentrate under reduced pressure at 20-30°C to dryness, add 30ml of water, extract 50ml*3 with ethyl acetate, and concentrate under reduced pressure at 20-30°C to dryness to obtain crude white solid intermediate 1 tosylhydrazone. The crude intermediate 1 was dissolved in 70ml of toluene, 700mg of lithium hydride was added, heated and stirred at reflux (120°C) for 5 hours, and the reaction was complete as monitored by TLC. Cool to 20-30°C, filter and wash with ethyl acetate (30ml). The filtrate was concentrated to dryness under reduced pressure at 20-30°C to obtain the crude cyclopamine product, which was dissolved in 20ml of boiling ac...

Embodiment 2

[0042] Dissolve 100 mg of fritillary octane (obtained by the method in Example 3) and 63 mg of p-toluenesulfonyl hydrazide in 15 ml of methanol, add 70 mg of p-toluenesulfonic acid, stir at 40° C. for 5 h, and monitor the completion of the reaction by TLC. Concentrate under reduced pressure at 20-30°C to dryness to obtain crude intermediate 1 tosylhydrazone as a white solid. The crude product 1 was dissolved in 20ml of toluene, 220mg of sodium hydride was added, heated and stirred at reflux (120°C) for 5 hours, and the reaction was complete as monitored by TLC. Cool to 20-30°C, filter and wash with ethyl acetate (10ml). The filtrate was concentrated under reduced pressure at 20-30°C to obtain the crude cyclopamine product, which was dissolved in 5ml of boiling acetone, and 6ml of petroleum ether was slowly added until turbidity appeared, then left to cool to room temperature (15°C) , a large amount of white solid was separated out, and 84 mg of white solid cyclopamine was obt...

Embodiment 3

[0046] The Chinese herbal medicine fritillary fritillaria was crushed through a 80-100 mesh sieve, weighed 20kg, extracted 3 times (100Lx3) with 300L of 95% industrial ethanol at 20-30°C, combined the extracts, concentrated under reduced pressure with a vacuum pump, and the temperature of the water bath was 40°C, after removing the solvent, 1 kg of ethanol extract was obtained (extract density M:M=1:20). The ethanol extract was extracted 3 times with chloroform (10Lx3), the combined extracts were vacuum filtered, and concentrated under reduced pressure with a vacuum pump (water bath temperature was 30°C) to obtain 513g of chloroform extract (extract density M:M=1:40). The chloroform extract is separated with a normal phase silica gel column (300-400 mesh, Qingdao Marine) mobile phase as petroleum ether-acetone (2:1-1:1) (0.5% triethylamine) and 100ml of acetone at 20-25°C Recrystallization obtained fritillaria 1.5g.

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Abstract

The invention discloses a preparation method of cyclopamine, which comprises the steps of: taking peimisine as raw material; leading the peimisine and benzene sulfonyl hydrazide to have condensation reaction in alcohol under the catalysis of strong acid, and preparing intermediate 1 toluene sulfonamide; and leading the intermediate 1 toluene sulfonamide and strong base to have backflow reaction in organic solvent, and obtaining the cyclopamine. The peimisine is extracted from traditional Chinese medicine fritillary, and the invention also provides a method for extracting the peimisine. As the fritillary has rich source and low price, by adopting the peimisine as raw material to prepare the cyclopamine, the method optimizes the reaction condition, reduces the cost, is simple and convenient for operation, prepares the cyclopamine with high efficiency, and is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to a method for preparing cyclopamine, in particular to a method for preparing cyclopamine by using fritillaria as a raw material. Background technique [0002] Cyclopamine is an isosteroid alkaloid, which was discovered in the 1960s because of its teratogenic effect. The latest research shows that it is a hedgehog protein Hedgehog pathway inhibitor, which has a good inhibitory effect on a variety of tumors. As a potential antitumor drug, cyclopamine has attracted extensive attention and research at home and abroad. [0003] The discovery of cyclopamine stems from its teratogenic effect. Therefore, from the 1960s to the 1980s, the research on cyclopamine was limited to its teratogenic effect. Until the mid-1990s, cyclopamine was found to be an inhibitor of the hedgehog signaling pathway, which essentially explained its teratogenic effects, because mutations in the hedgehog signaling ...

Claims

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Application Information

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IPC IPC(8): C07D491/048
Inventor 沈征武郑书岩
Owner BASILEA PHARM CHINA LTD
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