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Method of preparing cyclopamine from jervine

A technology of cyclopamine and mephenamine, which is applied in the field of medicine and can solve problems such as low content, low yield, and harsh reaction conditions

Inactive Publication Date: 2007-08-15
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the content of cyclopamine in plants is very low, only 1 / 10,000, and the chemical total synthesis is extremely difficult
It has been reported that using mephenamine as a raw material adopts the Wolff-Kishner method reduction to obtain cyclopamine, but in this method, hydrazine with high risk of inflammability is used, the reaction conditions are harsh, and the productive rate is low, only about 20% (Masamune , T., et al., Bull.Chem.Soc.Jpn.38(8):1374-1378(1965))
Then someone adopts the improved Wolff-Kishner-Huang Minglong method to reduce and prepare cyclopamine, but there is still the problem of low product yield (about 50%), and there is the existence of isomer 3-epicyclopamine (Zhou Jianxia, ​​etc. .Chinese Journal of Medicinal Chemistry, 16(5):303-305(2006)
The source of cyclopamine has become a major obstacle to its development into drugs

Method used

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  • Method of preparing cyclopamine from jervine
  • Method of preparing cyclopamine from jervine
  • Method of preparing cyclopamine from jervine

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Get the coarse powder of 5kg veratrum rhizome, cold-soak twice with 95% ethanol, each consumption is the ethanol of 30L. Concentrate the cold extract into a fluid extract, add 0.5kg of diatomaceous earth, let it air to nearly dry, then pack it into a column, and elute with sulfuric acid with a mass concentration of 2%. The eluted acidic water was adjusted to pH=9 with concentrated ammonia water, and filtered after standing for 2 hours to obtain 40 g of total alkaloids. Stir it into 100g of 200-300 mesh silica gel, and pack it with 1kg of 200-300 mesh silica gel. Elute with petroleum ether: ethyl acetate system (5:1-2:1-1:1-0:1), collect fractions 11-16, each 180 mL. After the fractions were concentrated to 60 mL, they were left to stand overnight in the refrigerator, and light yellow needle-like mephenamine was precipitated, with a total weight of 325 mg. The content is up to 99.1% as detected by HPLC.

Embodiment 2

[0035] Get the coarse powder of 5kg veratrum rhizome, heat extract 3 times with 75% ethanol, each consumption is the ethanol of 15L. The extract was concentrated until there was no alcohol smell, and the residue was acidified to pH=1 with 2% sulfuric acid. Centrifuge, take the supernatant, adjust the pH to 9 with concentrated ammonia water, and extract with chloroform three times, 2 L each time. The chloroform layer was concentrated to 0.5 L, mixed into 200 g of 200-300 mesh silica gel, evaporated to dryness, and packed with 2 kg of 200-300 mesh silica gel. Elute with dichloromethane:methanol system (20:1-10:1-5:1-2:1), collect 8-12 fractions, 180 mL each, concentrate and apply to Sephadex-LH20, elute with methanol to remove a small amount of flavonoids and pigments. After the fraction was concentrated to 60 mL, it was left to stand overnight in the refrigerator, and light yellow needle-like mephenamine was precipitated, with a total weight of 289 mg. The content detected b...

Embodiment 3

[0037] Dissolve 50 mg of mephenamine in 30 mL of ethylene glycol, add 10 μL of hydrazine hydrate, 5% volume ratio of polyethylene glycol 400 and 0.2 g of potassium hydroxide, stir at 160 ° C, cool down to 120 ° C after 2 hours, Remove water, then raise the temperature to 190±5°C, and react for about 2.5 hours. The reaction solution was added to 50 mL of water, and extracted with 100 mL×2 ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Concentrate to 5 mL, put it in the refrigerator overnight, and precipitate 28 mg of colorless needle-like crystals. The mother liquor is applied to a silica gel column, and eluted with a gradient petroleum ether: ethyl acetate mixture to obtain 6 mg of white powder, a total of 34 mg, with a yield of 70.3%. . Spray KBiI4 for color development after TLC development, and there is only one spot. Melting point 125-128°C, 1 H-NMR, 13 The C-NMR data are shown in Table 1, which is basically c...

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Abstract

The invention discloses a making method of cyclopamine and application in the medical domain, which comprises the following steps: adopting jervine from Veratrum plant as raw material; reacting jervine and hydrazine hydrate to produce hydrazone in the high-boiling point solvent; denitrifying acted by potassium hydroxide and tert-butanol potassium to form jervine; using carbowax 400 and TEBA as phase transmitting catalyst; connecting tumour cell Hh and Smo protein; dying cancer cell due to non-gene toxicity without influencing normal cell.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of cyclopamine, in particular to a method for preparing cyclopamine from a plant of the genus Veratrum, and the cyclopamine is used in the treatment of Applications in tumors expressing the Hh signaling pathway, such as pancreatic cancer, medulloblastoma, and small cell lung cancer. Background technique [0002] The Hedgehog (Hh) signaling pathway was first discovered in Drosophila, and it is a signaling pathway that triggers the development of Drosophila larvae. Further studies have shown that the Hh signaling pathway includes Patched (Ptc) protein, Smoothened (Smo) protein, Ci (Gli) protein, Cos2 protein, Fused kinase, protein SuFu complex, and the target gene. Hh protein is a secreted protein, which obtains activity through its own modification; Patched protein is the receptor of Hh signal protein; Smo protein is the converter of Hh signal. ...

Claims

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Application Information

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IPC IPC(8): C07J69/00A61K31/58A61P35/00A61K36/896
Inventor 张卫东李慧梁汤建张川苏娟沈云亨柳润辉
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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