CN101798307B - Preparation method of cyclopamine - Google Patents
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- CN101798307B CN101798307B CN2010101331164A CN201010133116A CN101798307B CN 101798307 B CN101798307 B CN 101798307B CN 2010101331164 A CN2010101331164 A CN 2010101331164A CN 201010133116 A CN201010133116 A CN 201010133116A CN 101798307 B CN101798307 B CN 101798307B
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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
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of preparation method of cyclopamine, relating in particular to a kind of is the method for feedstock production cyclopamine with the peimisine.
Background technology
Cyclopamine (cyclopamine) is a kind of different steroid alkaloid, because of its teratogenesis came to light the sixties in last century.Current research shows that it is a kind of Shh Hedgehog pathway inhibitor, has good inhibition effect to kinds of tumors.Cyclopamine has at home and abroad caused and has paid close attention to widely and study as a kind of antineoplastic potential drug.
The discovery of cyclopamine comes from its teratogenesis, therefore, the sixties in last century to the eighties, only limit to teratogenesis for the research of cyclopamine.Up to the mid-90; Cyclopamine is found to be a kind of suppressor factor of hedgehog signal path; From having explained its teratogenesis in essence; Because the sudden change of hedgehog signal path is relevant with the morbidity of kinds of tumors, so cyclopamine has worldwide started research boom as a kind of potential anti-cancer agent.
Cyclopamine mainly exists in the liliaceous plant, has 4 kind of plant of report to be at present: mountain black false hellebore Veratrum califomicum (North America), Indian deer eat careless Comlily (North America), hair leaf black false hellebore Veratrum grandiflort～(China, Japan), Sinkiang Fritillary Bulb Fritillariapallidiflora Sehrenk (China).Keeler etc. have studied in the root, stem, leaf of mountain black false hellebore, the relation in cyclopamine content and environmental factors, picking season etc.; Separated and the evaluation of cyclopamine composition is all arranged in all the other 3 kind of plant, but its content does not appear in the newspapers all.
The source of cyclopamine mainly contains three kinds of approach.One of which, extraction separation from plant.The initial separation method reliably of cyclopamine is by Keeler report (Keeler, R.F., et al., Phytochemistry; 1968,7,303-306), after Otais etc. improve (Oatis; J.E., et al., Chen.Cent.J.2008; 2,12), cyclopamine is separated from the veratrum californicum dry substance and reach per mille.People such as Jayatilake have reported new process for extracting (WO2010002970) in patent; They find before with organic solvent extraction through the black false hellebore dry substance is carried out water treatment; The enzymatic conversion that glucone-11-deoxojervine (cycloposine) can be existed in the black false hellebore becomes cyclopamine, and then improves the separation content of cyclopamine.Though through the process for extracting cyclopamine can fast, economical obtain, yet plant origin is fewer, the world distributes also very limited, content also lower (Masamune, T, et al., Bull.Chem.Soc.Jpn.1965,38 (8), 1374-1378; Xu Dongming, etc.Botany Gazette 1990,32 (10) 789-793), thereby can not satisfy the needs of clinical study far away.Its two, the semi-synthetic cyclopamine that obtains.But the chemical structure more complicated of cyclopamine is through being that different steroidal carries out very difficulty of chemosynthesis with known steroidal feedstock conversion.Therefore, through the compound with loop-like crust amine structure being carried out chemical conversion or structure of modification becomes a kind of economy and practical approach.Jervine is because of its content in black false hellebore receives much concern than higher and aboundresources.Initial jervine be converted into cyclopamine by Masamune (Masamune, T, et al., Bull.Chem.Soc.Jpn.1965,38 (8), 1374-1378) report realize through adopting the reduction of Wolff-Kishner method, but productive rate only has about 20%.On the basis of Wolff-Kishner method of reducing, Nagata-Itazaki improved method (Nagata, W.and Itazaki, H., Chem.Ind. have appearred subsequently; 1964,1194) and the imperial improved method of yellow ring (Suginome, H., et al.; Bull.Chem.Soc.Jpn., 1980,53,210-213; The week swordsman, etc., Chinese pharmaceutical chemistry magazine, 2006,16,303-305), but productive rate still lower (about 50%).Patent (Chinese invention patent, 200710037751.0) report was arranged afterwards through improvement, added phase-transfer catalyst and high boiling solvent, and can make the productive rate of cyclopamine reach 60～80% the Wolff-Kishner-Huang reduction method.Yet more than several kinds of reduction methods all adopted the hydrazine of inflammable high-risk, and reaction needed high temperature (about 200C), conditional request is harsh, by product is many, is difficult to realize industrial production.Its three, complete synthesis cyclopamine.Document (Masamune, T., et al., J.Am.Chem.Soc., 1967,89:4521-4523; Mitsuhashi, H., et al., Tetrahedron Lett.1964,33:2281-2283) report utilizes steroidal raw material hecogenin to synthesize jervine, but building-up process is complicated and non-stereoselectivity, and productive rate is less than 1% also.Germanization scholar Giannis reported compound method (Giannis, A., et al., Angew.Chem.Int.Ed., 2009,48,7911-7914), but synthetic reached for 20 steps, reaction conditions is relatively harsher, productive rate also only has 1%.Therefore, cyclopamine comes source problem still to become it to be developed to the big obstacle into medicine.
The Anhui bulb of fritillary (being called for short the Anhui shellfish) is the dry bulb of Liliaceae Fritillaria plant Fritillariaanhuiensis S.C.Chen and S.F.Yin, and Wan Xi Da Bie Mountain area, Anhui is born in the open country; In the period of the letter out thread; The loaded produce history of this medicine, and use as the bulb of fritillary widely among the people, Yin nourishing and lung moistening is arranged; Relieving cough and reducing sputum, the effect of mass dissipating and swelling eliminating.
The Anhui bulb of fritillary in the carrying out of eighties success wild commentaries on classics man plant test; And be a kind new medicine Chinese medicinal materials by ministry of Health of China approval February nineteen ninety; Ratify this new drug February nineteen ninety-five and formally produce, present Xuancheng, Anhui, there is bulb of fritillary planting base, large-area Anhui on ground such as Ningguo.
Anhui bulb of fritillary aboundresources, cheap.The contriver utilizes peimisine for the feedstock production cyclopamine, has optimized reaction conditions, can make things convenient for to prepare cyclopamine expeditiously, and required reaction conditions reaches easily, is suitable for industrial production.Prepare cyclopamine through peimisine and become a practicable approach.
Summary of the invention
What technical problem to be solved by this invention was that research and design a kind ofly reacts quick and convenient, productive rate is high is the method for feedstock production cyclopamine with the peimisine.
The present invention provides a kind of preparation method of cyclopamine.A kind of method that is prepared cyclopamine by peimisine specifically is provided.
The structural formula of peimisine is following:
The structural formula of cyclopamine is following:
The inventive method may further comprise the steps:
The reaction formula for preparing cyclopamine by peimisine:
Condensation reaction takes place in (1) peimisine, benzol sulfohydrazide in alcohol under strong acid catalysis; Reaction finishes the back concentrating under reduced pressure and makes midbody 1 tosylhydrazone; The mol ratio of peimisine and benzol sulfohydrazide is 1 in the reaction: 0.8-3.0, and optimum mole ratio is 1: 1.1-1.5, temperature of reaction is 0-100 ℃; Optimal reaction temperature is 5-30 ℃, and the reaction times is 2-4 hour.
Said strong acid catalyst is concentrated hydrochloric acid, tosic acid, trifluoroacetic acid, sulfuric acid,, acetate and formic acid etc., consumption and peimisine mol ratio are 1.0-3.0: 1.
Said alcohol is methyl alcohol, ethanol or Virahol, and consumption is that per 100 milligrams of peimisine add 15-30ml.
Said extraction solvent is an ETHYLE ACETATE, methylene dichloride, and one or more in the chloroform extract 3 times, and each consumption is that per 100 milligrams of peimisine add 20-30ml.
(2) midbody 1 tosylhydrazone bullion is treated or can directly be used for down step reaction.
Said strong acid catalyst is concentrated hydrochloric acid, tosic acid, trifluoroacetic acid, sulfuric acid or formic acid; Consumption and peimisine mol ratio are 1.0-3.0: 1; When strong acid catalyst was tosic acid, trifluoroacetic acid or formic acid, midbody 1 bullion that reaction obtains directly was used to next step reaction; When strong acid catalyst was concentrated hydrochloric acid, dilute sulphuric acid or acetate, midbody 1 bullion that reaction obtains needed washing, and ethyl acetate extraction is 3 times then, and anhydrous sodium sulfate drying is evaporated to dried midbody 1 bullion that obtains and just is used for next step reaction.
(3) midbody 1 of purifying, highly basic back flow reaction in organic solvent, reaction is cooled to 0-30 ℃ after finishing, filters, ETHYLE ACETATE or washed with dichloromethane, concentrating under reduced pressure gets the cyclopamine bullion, and recrystallization obtains the cyclopamine of purifying then.
The midbody 1 and the highly basic mass ratio of reaction are 1: 0.1-3.0, optimum quality ratio are 1: 0.5-1.5.Highly basic is sodium hydroxide, Pottasium Hydroxide, sodium hydride, lithium hydride, potassium hydride KH, butyllithium, sodium Metal 99.5 or potassium metal, and the mass ratio of consumption and midbody 1 is 0.1-3.0: 1; Solvent is toluene or YLENE, and consumption is that per 100 milligrams of midbodys 1 add 10-30ml.Temperature of reaction is 100 ℃-130 ℃, and the reaction times is 3-8 hour.
The used solvent of recrystallization purifying is an acetone, and ETHYLE ACETATE, sherwood oil, one or more in the methyl alcohol, consumption are that per 100 milligrams of thick products add 5-15ml.Temperature is by solvent boiling point to 30 ℃.
The fusing point and the nuclear magnetic data of the cyclopamine of the inventive method preparation are consistent with document.Fusing point: 237-238 ℃
The 1H-NMR of midbody 1 and 13C-NMR data:
1H?NMR(CD3OD，400MHz，)δ7.80(2H，d，J＝8.0Hz，ArH×2)，7.36(2H，d，J＝8.0Hz，ArH×2)，4.56(1H，s，br，-OH)，2.41(3H，s，ArCH
3)，1.56(3H，s，CH
3-18)，0.98(3H，s，CH
3-19)，0.48(3H，s，CH
3-27)，
13C?NMR(CD3OD，100MHz)δ160.2，142.9，141.2，135.4，128.3，127.3，126.6，85.2，74.1，69.9，65.1，53.8，50.5，45.3，44.3，38.8，37.8，36.6.35.8，30.6，30.3，30.0，29.4，27.6，23.3，19.6，17.2，11.3，9.9，9.0，8.5.
The 1H-NMR of cyclopamine and 13C-NMR data:
1H?NMR(CDCl3，400MHz，)δ5.36(1H，brs，H-6)，3.51(1H，m，W1/2＝22.2Hz，H-3)，3.21(1H，m，H-23)，3.04(1H，m，H-26a)，2.64(1H，m，H-22)，1.63(3H，s，H-18)，0.95(3H，s，H-18)，0.93(3H，d，J＝6.8Hz，H-27)，0.92(3H，d，J＝6.8Hz，H-21)；
13C?NMR(CDCl3，100MHz)δ141.3，141.8，126.7，122.1，85.8，75.3，72.0，66.3，54.6，52.3，49.5，42.0，41.7，39.7，39.2，38.4，36.8，32.1，31.6，31.4，31.3，29.2，24.7，19.1，18.9，13.3，11.1.
The present invention and existing method relatively have following advantage.A). productive rate is high, and by product is few, various conditions attempt reaching 85～95% (by Jie's amine sweet smell be converted into the cyclopamine productive rate be reported as 20～80% and by product many); B). purifying is simple, need not column chromatography purification, the finished product only need simple recrystallization to get final product; C). simple to operate, temperature of reaction is below 130 ℃, (is converted into by Jie's amine sweet smell that cyclopamine is temperature required to be commonly 180～240C) than reduce greatly in the past; D). agents useful for same is cheap, toxicity little (being converted into the hydrazine that cyclopamine is used inflammable high-risk by Jie's amine sweet smell); E). raw materials used peimisine is higher at Chinese medicinal materials bulb of fritillary content, and bulb of fritillary species resource is abundant and distribution is very extensive, cheap, extracts also more convenient.
The raw materials used peimisine of the present invention can extract acquisition from multiple bulb of fritillary plant, concrete extraction step is following:
With the pulverizing of the Chinese medicinal materials bulb of fritillary (crossing 80～100 mesh sieves), 20-25 ℃ of extraction down, combining extraction liquid, vacuum pump concentrating under reduced pressure (bath temperature is 40 ℃) get ethanol extract after removing and desolvating with 95% industrial alcohol.Ethanol extract is used chloroform extraction, the combining extraction liquid vacuum filtration, vacuum pump concentrating under reduced pressure (bath temperature is 30 ℃) gets chloroform medicinal extract.Chloroform medicinal extract separates with normal phase silicagel column (300-400 order, Qingdao Haiyang) and recrystallization obtains peimisine.
The said Chinese medicinal materials bulb of fritillary is extracted 3 times with 95% industrial alcohol, and each industrial alcohol consumption is the 4-8 times of W/W (mass ratio) of medicinal material weight; Ethanol extract is the 3-5 times of W/W (mass ratio) of ethanol extract weight with chloroform extraction 3 times at every turn.The used moving phase of column chromatography is sherwood oil-acetone (2: 1-1: 1) (0.5% triethylamine).With acetone recrystallization under room temperature (20-25 ℃).
Because bulb of fritillary aboundresources, cheap, the present invention utilizes peimisine for the feedstock production cyclopamine, has optimized reaction conditions, reduces cost, and is easy and simple to handle, prepares cyclopamine expeditiously, is suitable for the scale industrial production.
Embodiment
Embodiment 1.
500mg peimisine (method of embodiment 3 obtains) and 315mg p-toluene sulfonyl hydrazide are dissolved in the 50ml methyl alcohol, add the 0.1ml concentrated hydrochloric acid, behind the stirring at room 1h, add the 0.1ml concentrated hydrochloric acid, continue to stir 2h, the TLC monitoring reacts completely.20-30 ℃ is evaporated to the dried water 30ml that adds, ethyl acetate extraction 50ml*3, and 20-30 ℃ is evaporated to dried white solid midbody 1 tosylhydrazone bullion.Bullion midbody 1 is dissolved in the 70ml toluene, adds the 700mg lithium hydride, heated and stirred backflow (120 ℃) 5 hours, the TLC monitoring reacts completely.Be cooled to 20-30 ℃, filter, ETHYLE ACETATE (30ml) washing.Filtrating 20-30 ℃ is evaporated to dried; Obtain the thick product of cyclopamine, the thick product of cyclopamine is dissolved in the 20ml ebullient acetone (60 ℃), slowly adds sherwood oil 20ml to there being muddy sign to occur; Place then and be cooled to room temperature (15 ℃); A large amount of white solids are separated out, and filter and obtain 448mg white solid cyclopamine, productive rate 93%. midbodys 1 tosylhydrazone: LC-MS (+ESI): 596.3 ([M+H]+100%); Cyclopamine: LC-MS (+ESI): 412.3 ([M+H]+100%)
The 1H-NMR of midbody 1 tosylhydrazone and 13C-NMR data:
1H?NMR(CD3OD，400MHz，)δ7.80(2H，d，J＝8.0Hz，ArH×2)，7.36(2H，d，J＝8.0Hz，ArH×2)，4.56(1H，s，br，-OH)，2.41(3H，s，ArCH
3)，1.56(3H，s，CH
3-18)，0.98(3H，s，CH
3-19)，0.48(3H，s，CH
3-27)，
13C?NMR(CD3OD，100MHz)δ160.2，142.9，141.2，135.4，128.3，127.3，126.6，85.2，74.1，69.9，65.1，53.8，50.5，45.3，44.3，38.8，37.8，36.6.35.8，30.6，30.3，30.0，29.4，27.6，23.3，19.6，17.2，11.3，9.9，9.0，8.5.
Embodiment 2.
100mg peimisine (method of embodiment 3 obtains) and 63mg p-toluene sulfonyl hydrazide are dissolved in the 15ml methyl alcohol, add the 70mg tosic acid, 40 ℃ are stirred 5h down, and the TLC monitoring reacts completely.20-30 ℃ is evaporated to dried white solid midbody 1 tosylhydrazone bullion.Thick product 1 is dissolved in the 20ml toluene, adds the 220mg sodium hydride, heated and stirred backflow (120 ℃) 5 hours, the TLC monitoring reacts completely.Be cooled to 20-30 ℃, filter, ETHYLE ACETATE (10ml) washing.The 20-30 ℃ of concentrating under reduced pressure of filtrating; Obtain the thick product of cyclopamine, the thick product of cyclopamine is dissolved in the 5ml ebullient acetone, slowly adds sherwood oil 6ml to there being muddy sign to occur; Place then and be cooled to room temperature (15 ℃); A large amount of white solids are separated out, and filter and obtain 84mg white solid cyclopamine, productive rate 87%. midbodys 1 tosylhydrazone: LC-MS (+ESI): 596.3 ([M+H]+100%); Cyclopamine: LC-MS (+ESI): 412.3 ([M+H]+100%
Cyclopamine 1H-NMR that makes and 13C-NMR data:
1H?NMR(CDCl3，400MHz，)δ5.36(1H，brs，H-6)，3.51(1H，m，W1/2＝22.2Hz，H-3)，3.21(1H，m，H-23)，3.04(1H，m，H-26a)，2.64(1H，m，H-22)，1.63(3H，s，H-18)，0.95(3H，s，H-18)，0.93(3H，d，J＝6.8Hz，H-27)，0.92(3H，d，J＝6.8Hz，H-21)；
13C?NMR(CDCl3，100MHz)δ141.3，141.8，126.7，122.1，85.8，75.3，72.0，66.3，54.6，52.3，49.5，42.0，41.7，39.7，39.2，38.4，36.8，32.1，31.6，31.4，31.3，29.2，24.7，19.1，18.9，13.3，11.1.
Embodiment 3
The Chinese medicinal materials Anhui Bulbus Fritillariae Uninbracteatae was pulverized 80～100 mesh sieves, took by weighing 20kg, with 95% industrial alcohol 300L; Extract 3 times (100Lx3), combining extraction liquid, vacuum pump concentrating under reduced pressure down at 20-30 ℃; Bath temperature is 40 ℃, except that getting ethanol extract 1kg (medicinal extract density M: M=1: 20) after desolvating.With ethanol extract with chloroform extraction 3 times (10Lx3), the combining extraction liquid vacuum filtration, vacuum pump concentrating under reduced pressure (bath temperature is 30 ℃) chloroform medicinal extract 513g (medicinal extract density M: M=1: 40).Chloroform medicinal extract is that (2: 1-1: 1) (0.5% triethylamine) separates and obtain peimisine 1.5g with acetone 100ml at 20-25 ℃ of recrystallization sherwood oil-acetone with normal phase silicagel column (300-400 order, Qingdao Haiyang) moving phase.
Claims (9)
1. the preparation method of a cyclopamine is characterized in that this method may further comprise the steps: reaction formula:
Condensation reaction takes place in (1) peimisine, benzol sulfohydrazide in alcohol under strong acid catalysis, reaction finishes the back concentrating under reduced pressure and makes midbody 1 tosylhydrazone bullion;
(2) midbody 1 tosylhydrazone bullion is treated or directly be used for next step reaction;
(3) midbody 1 tosylhydrazone, highly basic back flow reaction in organic solvent, reaction is cooled to 0-30 ℃ of filtration after finishing, and organic solvent washing, concentrating under reduced pressure get the cyclopamine bullion, and recrystallization obtains the cyclopamine of purifying then.
2. according to the preparation method of the said cyclopamine of claim 1, it is characterized in that the mol ratio of peimisine and benzol sulfohydrazide is 1 in said step (1) reaction: 0.8-3.0, temperature of reaction is 0-100 ℃, the reaction times is 2-6 hour.
3. according to the preparation method of the said cyclopamine of claim 1, it is characterized in that the mol ratio of peimisine and benzol sulfohydrazide is 1 in said step (1) reaction: 1.1-1.5, temperature of reaction is 5-30 ℃.
4. according to the preparation method of the said cyclopamine of claim 1, it is characterized in that strong acid catalyst is concentrated hydrochloric acid, tosic acid, trifluoroacetic acid, sulfuric acid or formic acid in said step (1) reaction; Consumption and peimisine mol ratio are 1.0-3.0: 1; When strong acid catalyst was tosic acid, trifluoroacetic acid or formic acid, midbody 1 bullion that reaction obtains directly was used to next step reaction; When strong acid catalyst was concentrated hydrochloric acid or sulfuric acid, midbody 1 bullion that reaction obtains was through washing, and ethyl acetate extraction is 3 times then, and anhydrous sodium sulfate drying is evaporated to dried midbody 1 bullion that obtains and is used for next step reaction.
5. according to the preparation method of the said cyclopamine of claim 1, it is characterized in that the alcohol in said step (1) reaction is methyl alcohol, ethanol or Virahol, consumption is that per 100 milligrams of peimisine add 15-30ml alcohol; Extraction solvent is one or more in ETHYLE ACETATE, methylene dichloride or the chloroform, extracts 3 times, and each consumption is that per 100 milligrams of peimisine add 20-30ml.
6. according to the preparation method of the said cyclopamine of claim 1, it is characterized in that midbody 1 tosylhydrazone and the highly basic mass ratio in said step (3) reaction is 1: 0.1-3.0; Highly basic is sodium hydroxide, Pottasium Hydroxide, sodium hydride, lithium hydride, potassium hydride KH or butyllithium, and the mass ratio of consumption and midbody 1 is 0.1-3.0: 1; Solvent is toluene or YLENE, and consumption is that per 100 milligrams of midbodys 1 add 10-30ml, and temperature of reaction is 100 ℃-130 ℃, and the reaction times is 3-8 hour.
7. according to the preparation method of the said cyclopamine of claim 1; It is characterized in that the used solvent of said step (3) recrystallization purifying is one or more in acetone, ETHYLE ACETATE, sherwood oil or the methyl alcohol; Consumption is that per 100 milligrams of thick products add 5-15ml, and temperature is by solvent boiling point to 30 ℃.
8. according to the preparation method of the said cyclopamine of claim 1; It is characterized in that said raw material peimisine is to extract from the Chinese medicinal materials bulb of fritillary to obtain, said extraction comprises the following steps: the Chinese medicinal materials bulb of fritillary was pulverized 80～100 mesh sieves, extracts down at 20-25 ℃ with 95% industrial alcohol; Combining extraction liquid; Vacuum pump concentrating under reduced pressure, bath temperature are 40 ℃, except that getting ethanol extract after desolvating; Ethanol extract is used chloroform extraction, and combining extraction liquid vacuum filtration, vacuum pump concentrating under reduced pressure, bath temperature are 30 ℃ and get chloroform medicinal extract that chloroform medicinal extract separates with normal phase silicagel column 300-400 order and recrystallization obtains peimisine.
9. preparation method according to claim 9 is characterized in that the said Chinese medicinal materials bulb of fritillary extracts 3 times with 95% industrial alcohol, and each industrial alcohol consumption is 4-8 times of W/W of Chinese medicinal materials bulb of fritillary weight; Ethanol extract is 3-5 times of W/W of ethanol extract weight with chloroform extraction 3 times at every turn; The used moving phase of column chromatography is sherwood oil-acetone 2: 1-1: 1,0.5% triethylamine; Behind the column chromatography with acetone at 20-25 ℃ of recrystallization.
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| CN104861034B (en) * | 2014-02-24 | 2017-04-19 | 中国人民解放军第二军医大学 | Cyclopamine analogue three-membered cyclic cyclopamine and derivatives thereof, and preparation and application of three-membered ring cyclopamine and derivatives thereof |
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