CN1033795A - The method for preparing optically-active cotton phenol - Google Patents
The method for preparing optically-active cotton phenol Download PDFInfo
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- CN1033795A CN1033795A CN 87105990 CN87105990A CN1033795A CN 1033795 A CN1033795 A CN 1033795A CN 87105990 CN87105990 CN 87105990 CN 87105990 A CN87105990 A CN 87105990A CN 1033795 A CN1033795 A CN 1033795A
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Abstract
Preparation formula I
a/ I
bThe method of opticity gossypol.This method comprises: a) (i) is with the condenses hydrolysis of (+) or (-) gossypol and optically active amines, and (ii) purifying gained (+) or (-) gossypol when needed, or b) from inequality (+) and (-) gossypol mixture of enantiomers, removes lower a kind of of content, obtain another kind of enantiomorph.
Description
The present invention relates to the method for the optically-active cotton phenol of preparation formula I a/b.
Gossypol is Malvaceae plant upland cotton and sea island cotton (Gossypium) seed, root, the contained two naphthaldehyde compounds of a kind of polyphenol hydroxyl of stem.Racemization gossypol routine clinic trial surplus 8,800 confirms to have the male-contraception effect, and (male contraception medicine whole nation cooperative groups, Chinese Medical Journal, 58(1978), 455) are efficient to be 99.98%.Because on probation, some users have been taken place by hypokalemia illness, (patient shows weak, " feeling like jelly " even paralysis), this becomes the major obstacle of clinical application racemization gossypol.1979, Chinese Academy of Sciences's Shanghai medicine extracts (+) gossypol and is used for animal experiment from the natural phant populnea, show different with the racemization gossypol, there are not antifertility action (Wang Yue-e etc., Acta Pharmaceutica Sinica, 14(1979) 662), infer that thus (-) gossypol should be the antifertility optically active isomer.This discovery has caused the interest of researcher to (-) gossypol, the World Health Organization has also subsidized some laboratories are sought (-) gossypol and split the racemization gossypol from natural phant research, be intended to further promotion to the research of (-) gossypol antifertility action and other physiologically active, promotion is to the use of gossypol, carrying out of the synthetic and various theoretical investigationes of its derivative, especially the antifertility activity of optically-active cotton phenol and toxic side effect research has important and profound significance to the growth that utilizes safe pharmaceutical methods control population.
Optically-active cotton phenol can extract from natural phant or through the fractionation of racemization gossypol and obtain.But do not find directly to obtain through extraction method the natural plant resource of (-) gossypol in the past as yet up to 1987.People (Dechary, J.M.and Pradel such as Dechary in 1971, P, J.Am.Oil Chem, Soc.48(1971) 563) once attempted the racemization gossypol to be split with two kinds of approach: the one, according to the acidity of gossypol phenolic group, handle gossypol with optically active alkaloid such as morphine, quinine, cinchonine etc., hope can split by salifiable method.The 2nd, utilize aldehyde radical and optically active primary amine in the gossypol molecule, as (s)-1-Methylphenethylamine, the method for R-naphthyl ethamine and (s)-2-amino-1-propyl alcohol condensation, but all do not obtain expected results.The undeclared reason of author is not talked concrete experiment yet.Thereafter this respect research was also once carried out in some laboratories, but all not successes.The contriver is devoted to the research of this theme, successfully the racemization gossypol is split as (+), (-) optically-active cotton phenol (Si Yikang etc., Science Bulletin first, 28(1983), but, be unsuitable for providing in a large number optically-active cotton phenol 10:640), because method is numerous and diverse and preparation amount is little.After this Britain Matlin etc. once report split racemization gossypol (Matlin with the HPLC method, S.A etc., J.of High Resolution Chromato-graphy and Chromatography Com-munications 7(1984), 629), but because this method material costliness, condition should not be grasped, and generally should not adopt in industrial practice.
The objective of the invention is to develop a kind of easy and simple to handle, simple with material, the novel method of preparation optically-active cotton phenol with practical value.
The method for preparing optically-active cotton phenol of the present invention can be divided into three kinds of methods, is respectively: I. prepare the method for optically-active cotton phenol through the approach that splits from racemization gossypol or the mixture that contains inequality (+), (-) gossypol; II. through (+), (-) gossypol contract conversion, hydrolysis between the optically active amines diastereomer, prepare the method for any required optically-active cotton phenol to greatest extent; III. from (+) of containing inequality, (-) gossypol mixture, extract the method for the higher optically-active cotton phenol of content wherein to greatest extent with acid precipitation method.
Specifically, the present invention is an I, with racemization gossypol and a certain amount of optical activity R or the condensation of S amino-complex, (+) gossypol that separate to generate contract mixture of optically active amines diastereomer of optically active amines and (-) gossypol that contracts, each diastereomer of getting obtains (+) and (-) gossypol through hydrolysis respectively again, obtains the method for highly purified optically-active cotton phenol in case of necessity through further recrystallization; Contract the conversion repeatedly between optically active amines of optically active amines and (-) gossypol of contracting of II, process (+) gossypol, more effectively obtain the needed optically-active cotton phenol optically active amines intermediate that contracts, after hydrolysis, obtain the method for required optically-active cotton phenol more to greatest extent; III, through from the mixture of (+) gossypol of containing inequality and (-) gossypol enantiomorph, with removing the lower enantiomorph of content with coprecipitation mode, and obtain the method for the higher enantiomorph of high-optical-purity, content with the acid that the racemization gossypol forms 1: 1 mixture.It is easy and simple to handle that thereby the present invention provides, and can be used for the operational path of industrial production and economically valuable.
More particularly, the invention provides
I. prepare the method for optically-active cotton phenol through the fractionation approach from racemization gossypol I a/b or the mixture that contains inequality (+), (-) gossypol, this method may further comprise the steps:
A) make above-mentioned racemization gossypol or contain the mixture of inequality (+), (-) gossypol and the primary amine of optically active monoamine type carries out condensation reaction;
B) gained racemization gossypol is contracted contract optically active amines diastereo-isomerism body and function chromatography or crystallization process of optically active amines diastereomer or inequality (+), (-) gossypol separates, and obtains (+) gossypol optically active amines and (-) gossypol optically active amines that contracts that contracts;
C) resulting (+) gossypol is contracted optically active amines and (-) gossypol contracts optically active amines respectively in solvent, and hydrolysis in the presence of contact substance obtains (+) gossypol or (-) gossypol; And
D), further improve the chemical purity and the optical purity of (+) gossypol or (-) gossypol with recrystallization method as needs.
II. through (+), (-) gossypol contract conversion, hydrolysis between the optically active amines diastereomer, prepare the method for any needed optically-active cotton phenol to greatest extent.This method may further comprise the steps:
A) ⅰ) a kind of isomer in above-mentioned two kinds of diastereomers is reached the catalytic condition lower section in solvent and change another kind of isomer into, obtain containing the mixture of above-mentioned two kinds of diastereomers;
Perhaps
ⅱ) will contain that the higher a kind of diastereomer of content partly changes another kind of diastereomer in the mixture of above-mentioned two kinds of diastereomers of inequality, the ratio that obtains contained two kinds of diastereomers more approaches the equilibrated non-enantiomer mixture;
B) handle the mixture of resulting diastereomer with chromatography or crystallization process, obtain needed the sort of diastereomer with separation.
C) with the hydrolysis and obtain (+) gossypol or (-) gossypol in the presence of contact substance in solvent of resulting diastereomer.
D), further improve the chemical purity and the optical purity of (+) gossypol or (-) gossypol with recrystallization method as needs.
III. from (+) of containing inequality, (-) gossypol mixture, extract the method for the higher optically-active cotton phenol of content wherein with acid precipitation method, this method may further comprise the steps:
A) can generate in the solution that the sedimentary acid of mixture in 1: 1 join (+) of containing inequality, (-) gossypol mixture with (+) gossypol of equivalent and (-) gossypol, the mixture of formation is removed, the residual higher the sort of optically active gossypol of content down with precipitation mode.
B) with organic solvent extraction and alkali neutralization method the optically-active cotton phenol in the mother liquor is separated with acid.
C) further improve (+) gossypol or (-) gossypol chemical purity and optical purity as needs with recrystallization method.
Above three kinds of methods provided by the present invention easily are that the quality of resulting optically-active cotton phenol also can be controlled with their specific rotatory power value easily general chemical industry, pharmacy personnel can be grasped except that necessary article, the working method that required equipment, reagent are general chemical, pharmacy field.
(+) that the inventive method provides or (-) optically-active cotton phenol can be used for studying the antifertility activity of gossypol, and poison is paid effect and mechanism of action.(-) gossypol adds the treatment that can be used for neoplastic diseases such as hysteromyoma, endometriosis, adenocarcinoma of endometrium, dysfunctional uterine hemorrhage and leukemia thereof behind pharmaceutically suitable excipient or the carrier.And can be used as derivative that feedstock production becomes them as antitumor, antiviral drug.
Below the present invention is described in more detail:
The invention provides the method I for preparing optically-active cotton phenol through the approach that splits from racemization gossypol or inequality (+), (-) gossypol mixture, split racemization gossypol or inequality (+), the used amine of (-) gossypol mixture in this method for having optically active left-handed or dextral single amine type primary amine, it is characterized by and have one or more chiral carbon, and be in usually on α carbon, β carbon or other the carbon of primary amine, wherein the available following general formula of part is represented:
R
1 。R wherein
1Comprise-H ,-CH
3,-C
2H
5Or other alkyl ,-CH
2-OH ,-COOCH
3,-COOC
2H
5And other ester group.R
2Comprise
Above listed optically active amines or its raceme can be buied by commercially available, or adopt currently known methods or the general chemical process similar to currently known methods to be synthesized into.Two kinds of optical isomers of R or S all can be used, and the salifiable method of then available d of raceme or l tartrate splits, or adopts preferred crystallization process to split.Be adoptable synthetic method below, wherein can contain on the aromatic ring or not contain other substituting group (for example-CH
3, OCH
3,-OH ,-Cl ,-Br ,-I ,-NHAc ,-NO
2,-SCH
3,-SO
2CH
3Or the like)
1.
R can comprise-CH
3,-C
2H
5,-C
3H
7Deng.
Referring to U.S.Pat, 2174242
J.Org.Chem.8 7（1943）
Referring to " national bulk drug technology compilation " P.60(1980)
In above-mentioned optically active amines, amine is for having the amine of polar group such as hydroxyl, nitro, halogen (fluorine, chlorine, bromine, iodine) preferably, for example optically active 1-(4-nitrophenyl)-2-amino-propanol-1,3,3-hydroxyl-amphetamine-2, Phenylalanine methyl esters, 1-hydroxyl-amphetamine-2 and 1-(4-chloro-phenyl-)-2-amino-propanol-1,3.
Those skilled in the art can understand, and the optical purity of used optically active amines is a principal element of the optical purity height of (+) or (-) gossypol of obtaining after decision splits when splitting (+), (-) gossypol.In order to obtain the higher optically-active cotton phenol of optical purity, also should correspondingly adopt optically active amines during fractionation with higher optical purity.The optical purity ee% of the optically active amines that uses among the present invention is generally more than 98%, but the professional also can select the optically active amines of different optical purity according to the concrete needs of oneself for use.The used solvent of condensation reaction can be a polar organic solvent, comprises alcohols, as methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol etc.; Ethers is as ether, tetrahydrofuran (THF), dioxane, glycol monomethyl first or single ether, glycol dimethyl ether, ethylene glycol diethyl ether etc.; Also can use non-polar solvent, as benzene, hexane, hexanaphthene etc.
Setting-up point of the present invention can be selected between the boiling point of solvent in room temperature.Temperature is between 40-85 ℃ preferably.
According to the present invention to contract a pair of diastereomer R on chromatogram of optically active amines of resulting (+), (-) gossypol
fDifference size (the △ R of value
fThe size of value), the investigation result of the different chemical of the difference of solubleness and condenses and optical stability in solvent, the present invention can adopt chromatography or crystallization process to separate non-enantiomer mixture respectively.
Chromatography described in the present invention comprises normal pressure post layer chromatography, middle compression leg layer chromatography, high performance column layer chromatography.Wherein used weighting agent is that silica gel, aluminum oxide, Mierocrystalline cellulose, polymeric amide octadecyl or ion-exchange bonding equate, preferred chromatography weighting agent is a silica gel.
Eluent can be according to condenses R on thin-layer chromatography
fThe difference of value is selected, and generally can adopt usual vehicle, comprises hydro carbons, as hexane, hexanaphthene, benzene etc.; Ethers is as ether, sherwood oil, dioxane etc.; Chloroparaffin is as methylene dichloride, trichloromethane, trichloroethane etc.; The ester class is as ethyl acetate etc.; Alcohols as methyl alcohol etc., can adopt the unitary system or the mixed system of above listed solvent, is preferably the employing mixed system.
Elutant is monitored with chromatography, can be tlc, high performance liquid chromatography, comparatively convenient feasible be tlc.Used condition is: various silica gel, aluminum oxide, the made thin layer of Mierocrystalline cellulose, and the solvent that can be used as developping agent has ethers, and as ether, sherwood oil, dioxane, tetrahydrofuran (THF) etc., hydro carbons is as hexane, hexanaphthene, benzene etc.; The ester class is as the mixture of single solvents such as ethyl acetate or above solvent.
When crystallization process separates non-enantiomer mixture, condensation reaction gained (+), (-) gossypol optically active amines non-enantiomer mixture that contracts is carried out crystallization in appropriate solvent.Solvent for use can comprise moisture or water-free alcohols, as moisture or water-free following alcohol: methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol etc.; Ethers is as ether, sherwood oil, tetrahydrofuran (THF), dioxane etc.; Hydro carbons is as hexane, hexanaphthene, benzene etc.; The alkyl chloride hydro carbons is as methylene dichloride, chloroform, ethylene dichloride etc.; The ester class is as the mixture of single solvents such as ethyl acetate or above solvent.Preferred solvent is an alcohols.
The method according to this invention, (+) gossypol or (-) gossypol contract the optically active amines diastereomer respectively in solvent in the presence of contact substance hydrolysis obtain optically active (+) or (-) gossypol.The available hydrolysising solvent comprises hydro carbons, as benzene, hexane, hexanaphthene etc.; Ethers is as ether, sherwood oil, tetrahydrofuran (THF), dioxane etc.; Ketone is as acetone, methylethylketone etc.; The alkyl chloride hydro carbons, as methylene dichloride, chloroform etc.; Alcohols is as methyl alcohol, ethanol etc.; And the mixture or the aqueous mixture of above-mentioned two kinds or multiple solvent.Be preferably the aqueous mixture of above solvent.
What can be used as contact substance has: acid comprises strong organic acid; As formic acid, acetate, tosic acid etc., mineral acid: as phosphoric acid, hydrochloric acid, sulfuric acid etc., and various Zeo-karb.Can adopt single acid, the mixture of also available above various acid.Acid preferably has hydrochloric acid, sulfuric acid, acetate, and hydrochloric acid and hydrochloric acid-acetate mixing acid is preferably arranged.
Hydrolysis temperature can be between room temperature and 80 ℃.
Hydrolysis reaction can adopt tlc to monitor.Monitoring thin-layer chromatography condition used when the selection of various conditions can separate with chromatography is identical.
Organic layer is successively used alkali after the hydrolysis, as salt of wormwood, sodium bicarbonate etc. be washed to neutrality, remove desolvate after directly crystallization or in appropriate solvent through the decolouring post crystallization.Adoptable recrystallisation solvent can comprise: hydro carbons, as hexane, hexanaphthene, benzene etc.; Ethers, as ether, sherwood oil, dioxane etc., moisture or water-free alcohols, for example moisture or water-free following alcohol, as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol etc.; And the mixed system of above-mentioned two kinds or multiple solvent.Preferred solvent has mixed solvents such as ether-sherwood oil, benzene-sherwood oil.Can obtain optical purity and chemical purity all greater than 90% required optically-active cotton phenol through primary crystallization generally speaking, but crystalline mother solution often decreases through its optical purity of crystallization of separating out again after concentrating, therefore the optically-active cotton phenol that obtains can be carried out further crystallization in case of necessity, choice of Solvent can be selected identical with the crystalline solvent, through optically-active cotton phenol is further separated with the racemization gossypol, its chemical purity of gained optically-active cotton phenol is identified through high performance liquid chromatography, all can reach more than 99%, optical purity is identified through specific optical rotation method and high performance liquid chromatography, also can be reached more than 97%.
For reclaiming resolution reagent, the water layer part of hydrolyzed solution makes the resolving agent optically active amines free with the highly basic alkalization, use then and filter, or the method for solvent extraction reclaims.Used suitable alkali comprises ammonium hydroxide, sodium hydroxide or potassium hydroxide solution.
The method according to this invention, the contract stability of optically active amines of (+) gossypol or (-) gossypol is tested with single-phase or two-phase tlc, the developping agent that is suitable for this testing method can be selected ordinary organic solvents for use, comprises the mixed solution of single solvents such as ether, sherwood oil, dioxane, hexane, hexanaphthene, benzene, ethyl acetate, methylene dichloride or above solvent.Suitable absorption carrier can be selected silica gel, aluminum oxide, Mierocrystalline cellulose, polymeric amide etc. for use, first dry mutually after, carry out second phase demodulation again.
Further specify the method I that provides among the present invention with the flow process I below:
The present invention also provides through (+), (-) gossypol contract conversion, hydrolysis between the optically active amines diastereomer, the method II for preparing any required optically-active cotton phenol to greatest extent, mentionedly in this method be applicable to that the reaction solvent that contracts any optically-active cotton phenol optically active amines is converted into its diastereomer can be an ordinary organic solvents, comprise ethers, as ether, sherwood oil, dioxane, tetrahydrofuran (THF) etc.; Hydro carbons is as benzene, hexane, hexanaphthene etc.; Halogenated alkane is as methylene dichloride, chloroform, ethylene dichloride, trichloroethane etc.; Ketone is as acetone, methylethylketone etc.; Alcohols is as the mixture of single solvents such as methyl alcohol, ethanol, propyl alcohol, Virahol or above-mentioned solvent.
Suitable catalytic condition comprises the daylight of non-direct irradiation, UV-irradiation or add free radical and promote agent, as 2,2 '-the two 2-methyl propionitrile of azo.
Transforming required temperature can be from selecting arbitrarily between the room temperature to 70 ℃.
Ratio and conversion condition thereof between each isomer in used condenses mixture when transformation time depends on concrete optically active amines used when preparing condenses, conversion, to the factors such as specific requirement of transforming degree, generally can be that several minutes arrives some days.The optically active amines preferably that the present invention is used to transform has S-1-Methylphenethylamine, the vertical amine of (+) dehydrogenation and (+)-1-Racemicp-hydroxyamphetamine-2.
Identical through the condition selection in the method I among the recrystallization condition of separation, hydrolysis and the hydrolysate of the condenses non-enantiomer mixture after transforming and the present invention.
Further specify the method II that provides among the present invention with the flow process II below:
The flow process II is depicted as the conversion process of required (-) gossypol, and similar flow process can be used for the conversion situation of required (+) gossypol.
The present invention provides again with acid precipitation method from (+) of containing inequality, (-) gossypol mixture, extracts the method III of the higher optically-active cotton phenol of content wherein to greatest extent.What wherein be suitable for can comprise small molecular organic acids such as formic acid, acetate with (+) gossypol and (-) gossypol generation sedimentary acid of mixture in 1: 1 of equivalent.Its consumption can change in a big way, but the minimum amount that can not be lower than the mole number of the gossypol in the solution.
The solvent that is suitable for when generating the mixture precipitation can be common organic solvent, comprises ethers, as ether, sherwood oil, dioxane, tetrahydrofuran (THF) etc.; Hydro carbons, as hexane, hexanaphthene, benzene etc.; The haloalkane hydro carbons is as methylene dichloride chloroform, ethylene dichloride, trichloroethane etc.; Ketone is as acetone, methylethylketone etc.; The ester class is as ethyl acetate etc.; Alcohols, as methyl alcohol, ethanol, propyl alcohol, Virahol etc.; Preferred solvent is an ether, acetone, methylene dichloride.
Temperature of reaction with room temperature to 50 ℃ for well.
Further specify the method III that provides among the present invention with the flow process III below:
Following examples will further be illustrated the present invention, but the present invention is not limited.
Embodiment
Embodiment 1-4 prepares optically-active cotton phenol from the racemization gossypol through method for splitting
Example 1 is with (-)-1-(of Soviet Union p-nitrophenyl)-2-amino-propanol-1,3 is a resolving agent, and the racemization gossypol is split the preparation optically-active cotton phenol.
Racemization gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-preparation of 2-amino-propanol-1,3;
24 gram (0.046 mol) racemization gossypols and 22.5 gram (0.106 mol) (-)-(the p-nitrophenyl)-2-of Soviet Union amino-propylene glycol-1,3, reflux is 10～15 minutes in 50 milliliters of acetone, reaction solution is cooled to room temperature, remove and desolvate to such an extent that condenses 41.7 restrains, yield 100%, ultimate analysis: racemization gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-and 2-amino-propylene glycol-1,3(C
48H
50N
4O
14) 2H
2O molecular weight 942.9
Theoretical value % experimental value %
C 61.14 61.09 61.03
H 5.77 5.65 5.61
N 5.94 6.32 6.35
(α)
20 D°=-240 ± 20(acetone)
Normal pressure post layer chromatography separates racemization gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3:
Separating above crude product with silica gel column chromatography under normal pressure, is elutriant with the ether, can obtain 19 grams (45.6%) (calculating with theoretical amount) (-) gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3(A), (a)
20 D°=-930 ± 30(acetone).Reaching 17 gram (40.8%) (+) gossypols contracts (-)-the 1-(p-nitrophenyl)-2-amino-propylene glycol-1,3(B), (a)
20 D°=+ 400 ± 20, the rate of recovery 86.4%.
Crystallization process separates racemization gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3:
10 gram (0.0193 mol) racemization gossypols and 9.5 gram (0.0447 mol) (-)-1-(of Soviet Union p-nitrophenyls)-2-amino-propylene glycol-1,3, after stirring heating refluxed 10～15 minutes in 50 ml methanol, low temperature is placed and is separated out yellow solid, (-) gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3(A), (a)
20 D°=930 ± 30, weigh 6.3 grams, be 36% with racemization gossypol calculated yield, to contain 50%(-in the racemization gossypol) the gossypol calculated yield is 72%.
Mother liquor is poured into and is got yellow solid in the water, filters, and weighs 12 grams, is Soviet Union (-)-1-(p-nitrophenyl that contracts with (+) gossypol)-2-amino-propylene glycol-1, be main 3(B), contain the mixture of a small amount of (A).(a)
17 D°=120 ± 20(acetone) contain about B75% total recovery 98%.
Hydrolysis (-) gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3 is to (-) gossypol:
With 6 gram (0.006 mol (-) gossypol contract Soviet Union (-)-1-(p-nitrophenyl)-2-amino-propylene glycol-1,3 are suspended in 200 milliliters of ether of the no superoxide that contains 20 milliliters of Glacial acetic acid and 16 milliliters of concentrated hydrochloric acids, stirring heating refluxed 4 hours, reaction solution is chilled to room temperature, tell the sour water layer, (the sour water layer is through alkaline purification, recyclable light live amine).The ether layer is through washing, and potash water is washed till neutrality, and drying is removed partial solvent, adds an amount of sherwood oil, and room temperature is placed, and has crystallization to separate out.Go out filter, can get light yellow crystallization 1.65 grams of needle-like.Mother liquor can get same crystallization 1.28 grams, yield 85% after concentrating.Product behind recrystallization, 185～7 ℃ of fusing points, (a)
20 D°=-360 ± 10(chloroform), be () gossypol, MS:518(M), 500,482,467,454,439,226,205,150,149, chemical purity＞99%.(HPLC) optical purity ee%＞98.8%(HPLC).
Hydrolysis (+) gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3 is to (+) gossypol:
(+) gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3,17.5 gram (0.0186 mol) is with condition hydrolysis same as described above, get crude product 9.5 grams, after with the decolouring of silica gel column layer chromatogram, primary crystallization gets 4.27 grams, yield 44%, product behind recrystallization, 185～7 ℃ of fusing points, (a)
20 D°=360 ± 10(chloroform), chemical purity＞99%(HPLC), optical purity ee%＞97%(HPLC).
Example 2 is a resolving agent with L-3-hydroxyl-amphetamine-2, and the racemization gossypol is split the preparation optically-active cotton phenol
The contract preparation of L-3-hydroxyl-amphetamine-2 of racemization gossypol:
3 gram (0.0058 mol) racemization gossypols are dissolved in 150 milliliters of Virahols, stir 20 milliliters of L-3-hydroxyl-amphetamine-2 aqueous isopropanols that contain 2.6 grams (0.0174 mol) of adding down.Reflux 5～10 minutes, reaction solution is chilled to room temperature, removes and desolvates product crystallization in ether-sherwood oil mixed solvent.Get 2.72 gram crude products.
1HNMR(CDCl
3) 90Hz, δ: 1.52(d,
), 2.08(s, 6H,
), 3(m, 4H ,-CH
2OH), 3.52～3.96(m, 8H,
), 7.28(s, 10H,
), 7.68(s, 2H, C
4, C
4,-H) 9.60,9.68(s, 2H, C
11, C
11,-H), (a)
20 D°=-the 155.3(chloroform), 140～142 ℃ of fusing points.
Above condenses can adopt and example 1 identical operations, separates resulting isolate (-) the gossypol L-3-hydroxyl-amphetamine-2 that contracts, (a) under normal pressure through the silica gel column layer chromatography
20 D°=-the 849.2(chloroform).Can obtain (-) gossypol through hydrolysis; Another isolate hydrolysis of resulting separation can be obtained (+) gossypol.
Example 3 is a resolving agent with the S-a-methylbenzylamine, and the racemization gossypol is split the preparation optically-active cotton phenol.
The contract preparation of S-a-methylbenzylamine of racemization gossypol:
0.5 restraining (0.002 mol) racemization gossypols, in 50 milliliters of ether, mixes gram (0.004 mol) S-a-methylbenzylamine (98%) and 1.04, and reflux 10 minutes.Reaction solution is chilled to room temperature, removes and desolvates to such an extent that condenses 1.3 restrains yield 86.4%.Ultimate analysis:
C
46H
43N
2O
6, molecular weight 724.9,
Calculated value %:C 76.22 H 6.69 N 3.86
Experimental value %:C 76.19 H 6.92 N 3.80
76.94 6.66 3.79
(a)
20 D°=+ 53(CHCl
3), 245 °～9 ℃ of fusing points.
In the compression leg layer chromatography separate the racemization gossypol S-a-methylbenzylamine that contracts:
Condenses 0.4 gram carries out middle compression leg layer chromatography with silica gel H as weighting agent and separates, and pressure is in 2.5～3 kilograms per centimeter
2In the scope, be eluent with anhydrous diethyl ether-sherwood oil blend solvent, separable (+) gossypol S-a-methylbenzylamine 0.15 gram that contracts, (a) of obtaining
17 D°=+ 739(CHCl
3), (-) gossypol S-a-methylbenzylamine 0.13 gram that contracts, (a)
17 D°=-643(CHCl
3), yield is more than 70%.
Hydrolysis (+) gossypol contracts the S-a-methylbenzylamine to (+) gossypol
(+) gossypol S-a-methylbenzylamine 0.45 gram that contracts is suspended in 200 milliliters of ether-sherwood oil mixed solution, after adding an amount of methylene dichloride and making the solid dissolving, adds 3 milliliters of concentrated hydrochloric acids, room temperature placement 1～2 day.The reaction solution branch vibration layer, the ether layer is through being washed to neutrality, drying.Hydrolyzate is pressed the chromatography decolouring in the silica gel that peracid treatment is crossed, use benzene-sherwood oil mixed solvent crystallization again, gets the light yellow needle crystal of 0.18 gram, and fusing point 183-5 ℃, (a)
15 D°=+ 375.6(CHCl
3), yield 78.1%, optical purity ee%＞96.8%(HPLC measures).
Example 4 is a resolving agent with L-Phenylalanine methyl esters, and the racemization gossypol is split the preparation optically-active cotton phenol.
The contract preparation of L-Phenylalanine methyl esters of racemization gossypol:
Virahol-the aqueous solution of 1.52 gram (0.0071 mol) L-Phenylalanine methyl ester hydrochlorides is joined in the solution that contains 2 gram (0.0039 mol) racemization gossypols, stir the Virahol-aqueous solution that adds 0.6 gram (0.0043 mol) salt of wormwood down, reflux 5～10 minutes, reaction is chilled to room temperature.Remove most of reaction solvent, obtain the part solid product, weigh 2.22 grams, yield 68.5%, (a)
20°=-327(CHCl
3), fusing point 144-146 ℃,
1H-NMR(CDCl
3), 90HZ: δ 1.54(d, 12H, CH
3CH
3), 2.1(s, 6H,
), 3.34(d, 4H,
), 3.82(s, 6H ,-OCH
3), 4.18～4.50(m, 2H,
), 7.26(s, 10H,
), 7.64(s, 2H, C
4, C
4,-H), 9.34,9.46(s, 2H, C
11, C
11,-H).
Above condenses can adopt and example 3 identical operations, through silicagel column look chromatography in depress separation, resulting isolate (-) the gossypol L-Phenylalanine methyl esters that contracts, (a)
20 D°=-679.2(CHCl
3), can obtain (-) gossypol through hydrolysis.Another isolate hydrolysis of resulting separation can be obtained (+) gossypol.
Embodiment 5～7 is through racemization gossypol contract conversion, hydrolysis between the diastereomer of optically active amines, preparation optically-active cotton phenol.
Example 5 is a resolving agent with the S-1-Methylphenethylamine, through contract the conversion between the diastereomer of optically active amines of racemization gossypol, and hydrolysis, the preparation optically-active cotton phenol,
The contract preparation of S-1-Methylphenethylamine of racemization gossypol:
9 gram (0.066 mol) S-1-Methylphenethylamines under agitation are added dropwise in 500 milliliters of aqueous isopropanols that contain 11.6 gram (0.02 mol) gossypols, are heated to and boil 5～10 minutes, reaction solution is chilled to room temperature, concentrate post crystallization, can obtain product 14 grams, productive rate 99%, (a)
24 D°=+ 222.9(CHCl
3), fusing point 197-200 ℃, ultimate analysis:
C
48H
52N
2O
6, calculated value %:C 76.57 H 6.96 N 3.73
Experimental value %:C 76.66 7.00 N 3.59
76.62 7.00 3.58
Above condenses can adopt with example 3 identical operations through in the compression leg layer chromatography separate (+) gossypol S-1-Methylphenethylamine (a) that contracts wherein
18 D°=+ 931(CHCl
3), (-) gossypol S-1-Methylphenethylamine (a) that contracts
30 D°=-400(CHCl
3).
(+) gossypol S-1-methyl ethyl-amine that contracts is converted into (+) gossypol S-1-Methylphenethylamine and (-) gossypol mixture of 1: 1 of S-1-Methylphenethylamine that contracts that contracts:
(+) gossypol S-1-Methylphenethylamine that contracts, (a)
18 D°=+ 931(CHCl
3), be dissolved in ether-sherwood oil mixed solvent, at room temperature lucifuge ground is not placed and was avoided the daylight direct irradiation in 1～2 day), can obtain (a)
30 D°=+ 242(CHCl
3) (+) gossypol S-1-Methylphenethylamine and (-) gossypol S-1-Methylphenethylamine that contracts that contracts that contains be bordering on 1: 1 mixture.
With same method, the S-1-Methylphenethylamine that (-) gossypol can be contracted, (a)
18 D°=-400(CHCl
3) be converted into (a)
30 D°=+ 203.2(CHCl
3) the mixture of condenses diastereomer.
The separation of compression leg layer chromatography in more than repeating through the mixture after changing can obtain preferably any diastereomer in the condenses once more, and through with the hydrolysis of example 3 the same terms, can obtain corresponding optically-active cotton phenol.
Example 6 is a resolving agent through contract the conversion between the diastereomer of optically active amines of racemization gossypol with the vertical amine of (+) dehydrogenation, and hydrolysis prepares optically-active cotton phenol
The contract preparation of the vertical amine of (+) dehydrogenation of racemization gossypol:
Restrain (0.0006 mol) racemization gossypol with 0.3 and be dissolved in 30 milliliters of Virahols, add the vertical amine of 0.378 gram (0.0013 mol) (+) dehydrogenation, reflux is 10 minutes under stirring, reaction solution is put to room temperature, after concentrating, places crystallization, get product 0.355 gram, yield 60%.(a)
20 D°=-13.9(CHCl
3), fusing point 211-213 ℃.
1HNMR（CDCl
3）90HZ;δ：1.0（s，6H，-CH
3），1.20（d，12H，
）1.52（d，12H，
），3.38（s，4H
），3.74（m，2H
），6.92-δ7.20（m，6H
），7.66（s，2H，C
4，C
4，-H），9.62 （s，2H，C
11，C
11，-H）。
Above condenses adopts to separate with the middle compression leg layer chromatography of example 3 the same terms and can obtain preferably (-) gossypol vertical amine of (+) dehydrogenation that contracts, (a)
19 D°=-560.4(CHCl
3), be hydrolyzed through adopting the hydrolysising condition identical with example 3, can obtain () gossypol.Undivided (-) gossypol vertical amine of (+) dehydrogenation and (+) gossypol (+) dehydrogenation that contracts that contracts is indulged amine mixt and can be adopted the conversion condition identical with example 5, convert it into (-) gossypol vertical amine of (+) dehydrogenation and (+) gossypol vertical amine of (+) dehydrogenation that contracts that contracts and be bordering on 1: 1 mixture, and again through in the compression leg layer chromatography separate to obtain more (-) gossypol vertical amine of (+) dehydrogenation that contracts, obtain more () gossypol after the hydrolysis.
Example 7 is a resolving agent through contract the conversion between the optically active amines diastereomer of racemization gossypol, hydrolysis, preparation optically active amines with (+)-1-Racemicp-hydroxyamphetamine-2-.
The racemization gossypol contracts (+)-preparation of 1-Racemicp-hydroxyamphetamine-2:
With 1.59 grams (8.49 * 10
-3Mol) (+)-1-Racemicp-hydroxyamphetamine-2 hydrochloride and 0.59 gram (4.3 * 10
-3Mol) salt of wormwood mixes, and adds that a spot of water makes it dissolving and with the ether extraction unhindered amina.Extraction liquid joins and contains 2 grams (3.86 * 10
-3Mol) in the aqueous isopropanol of racemization gossypol, heated and stirred makes it to reflux 5～10 minutes, and reaction solution is chilled to room temperature, and solvent is removed crystallization in ethanol one water, and once obtaining the crystalline amount is 1.4 grams, yield 47%.
1HNMR90HZ（CDCl
3），δ：1.30（d，6H，-CH
3），1.56（d，12H
Above condenses adopts and separates with the middle compression leg layer chromatography of example 3 the same terms, can obtain preferably that (+) gossypol contracts (+)-1-Racemicp-hydroxyamphetamine-2, contracts with (-) gossypol-1-Racemicp-hydroxyamphetamine-2.Containing (-) gossypol in the mixing composition of not separating fully contracts (+)-and 1-Racemicp-hydroxyamphetamine-2 is more, accounts for 74%, (a)
20 D°=-529.4(CHCl
3).Through this part composition being used the method for transformation identical transform, can obtain (a) with example 5
20 D°=-26.9(CHCl
3) contain the mixture that two kinds of diastereomers are about 1: 1, this mixture again through in the compression leg layer separate and can obtain (+) gossypol condenses and (-) gossypol condenses again.Separating obtained product process and the hydrolysis of example 3 the same terms can obtain (+) gossypol and (-) gossypol respectively.
Embodiment 8-9 by (+) of containing inequality, (-) gossypol mixture, prepares the method for any required optically-active cotton phenol with acid precipitation method to greatest extent
Example 8, from the hydrolysate that contains (+) gossypol condenses of 75%, extract optical purity (+) gossypol with the acetate precipitator method:
Contain about 75% (+) gossypol Soviet Union (-)-1-(p-nitrophenyl that contracts)-2-amino-propylene glycol-1,3(B) (its preparation method, the visible example 1 of separation method) 12 grams (0.0132 mol), (a)
20 D°=+ 120 ± 20(acetone), with the method hydrolysis of example 1, the ether layer adds 5 milliliters of Glacial acetic acid through being washed till neutral after drying and concentrating, and low temperature is placed mixture 2.65 grams of separating out acetate and the formation of racemization gossypol.Mother liquor is after soda solution is washed and is washed to neutrality, and dry and process silica gel column layer chromatogram decolouring can obtain needle crystal 1.9 grams, (a)
15 D°=+ 353(CHCl
3), 185 °～7 ℃ of fusing points are (+) gossypol.The yield that obtains primary crystallization is that 43%(calculates to contain (+) gossypol).Crystalline mother solution also can obtain (+) gossypol through concentrating.
Example 9. is with acetate precipitator method preparation optically pure (+) gossypol in the gossypol sample of being purchased by (+) gossypol that contains inequality and (-) gossypol.
3 gram gossypol crude products add a small amount of ether dissolution, filter the back and add 10 milliliters of ice acid acid, place until separating out solid.The mixture that acetate that filtration is separated out and racemization gossypol form, filtrate is through being washed to neutrality with sodium bicarbonate and after extracted with diethyl ether, drying, decolouring through the post layer chromatography, and crystallization in benzene-sherwood oil mixed solvent obtains 70 milligrams of needle crystals, (a)
17 D°=+ 369.8(CHCl
3), 185 °～7 ℃ of fusing points.
Claims (15)
1, the method for the optically-active cotton phenol of preparation formula I a or I b,
This method comprises the steps:
a)
(ⅰ) with the condenses of (+) gossypol or (-) gossypol and optically active amines, i.e. (+) gossypol optically active amines or (-) gossypol optically active amines hydrolysis of contracting of contracting obtains (+) gossypol or (-) gossypol accordingly, this optically active amines is left-handed or dextral single amine type primary amine, have one or more chiral carbon, chiral carbon is on α carbon, β carbon or other carbon of primary amine usually
And,
(ⅱ) purifying resulting (+) gossypol or (-) gossypol when needed,
Perhaps,
B) from the mixture of (+) gossypol of containing inequality and (-) gossypol enantiomorph, remove the lower a kind of enantiomorph of content, obtain another kind of enantiomorph.
2, according to the method for the step a) of claim 1, wherein said optically active amines can be represented by the formula:
3, according to the method for claim 2, wherein said optically active amines is the optically active amines that contains hydroxyl, nitro, halogen isopolarity group.
4, according to the method for claim 3, wherein said optically active amines is selected from has optically active following amine: the 1-(4-nitrophenyl)-and 2-amino-propanol-1,3,3-hydroxyl-amphetamine-2-, Phenylalanine methyl esters, 1-hydroxyl-amphetamine-2 and 1-(4-chloro-phenyl-)-2-amino-propanol-1,3.
5, according to the method for step a) in the claim 1, wherein the contract hydrolysis of optically active amines of (+) or (-) gossypol is in the presence of contact substance, carries out in solvent.
6, according to the method for claim 5, wherein contact substance is to be selected from least a in the following material: hydrochloric acid, hydrochloric acid-acetate, sulfuric acid, tosic acid and the Zeo-karb of dense or dilution.
7, according to step a) or claim 2,3,4 in the claim 1,5 or 6 method, wherein said (+) gossypol optically active amines or (-) gossypol optically active amines that contracts that contracts obtains with following method, and this method comprises:
A) make the mixture that contains arbitrary proportion (+) gossypol and (-) gossypol in solvent, carry out condensation reaction with said optically active amines, contained (+) gossypol contract non-enantiomer mixture of optically active amines of optically active amines and (-) gossypol that contracts, handle this mixture with chromatography or crystallization process then, thereby with above-mentioned two diastereomers separately.
Perhaps,
B) (ⅰ) with a kind of another kind that partly is transformed in above-mentioned two kinds of diastereomers, obtain containing the mixture of above-mentioned two kinds of diastereomers, adopt in the claim 7 the described separation method of step a) separately again these two kinds of diastereomers,
Perhaps,
(ⅱ) will contain that the higher a kind of enantiomorph of content partly changes another kind in the mixture of above-mentioned two kinds of diastereomers of inequality, obtain two kinds of ratios between diastereomer and more level off to the equilibrated mixture, adopt in the claim 7 the described separation method of step a) separately again these two kinds of diastereomers.
8, according to (ⅰ) step by step or method (ⅱ) in claim 7 step b), the wherein said process that a kind of diastereo-isomerism body portion is converted into another kind of diastereomer is carried out under catalytic condition.
9, method according to Claim 8, wherein said catalytic condition are photoactivations or promote agent catalysis with free radical.
10, according to the method for claim 9, wherein with 2,2 '-azo is two-and 2-methyl propionitrile is used as free radical and promotes agent.
11, according to the method for claim 7, wherein said chromatography is selected from common pressure liquid chromatography medium pressure liquid chromatography method and high pressure lipuid chromatography (HPLC).
12, according to the method for (ⅱ) step by step in claim 1 step a), wherein (+) gossypol that obtains of purifying or the method for (-) gossypol are recrystallization method or chromatogram-crystallization process.
13, according to the method for removing the less a kind of enantiomorph of content from contain inequality (+) and (-) gossypol mixture of enantiomers of step b) in the claim 1, this method comprises the steps:
A) can join in the solution of above-mentioned mixture of enantiomers with the sedimentary material of (-) gossypol generation mixture with (+) gossypol of equivalent a kind of, generate the mixture precipitation of (+) gossypol and (-) gossypol and this material, and,
B) from system, remove above-mentioned precipitation and solvent, obtain the single kind of enantiomorph that content is higher.
C) in case of necessity to carry out purifying with the same procedure described in the right 12.
14, according to the method for step a) in the claim 13, said can be formic acid, acetate with equivalent (+) gossypol and the sedimentary material of (-) gossypol generation mixture.
15, according to step a method in the claim 13, wherein the solution of mixture of enantiomers is meant enantiomorph is dissolved at least a in the following solvent: ether, acetone, chloroform, methylene dichloride and benzene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 87105990 CN1017705B (en) | 1987-12-26 | 1987-12-26 | Preparation method of optically-active cotton phenol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 87105990 CN1017705B (en) | 1987-12-26 | 1987-12-26 | Preparation method of optically-active cotton phenol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1033795A true CN1033795A (en) | 1989-07-12 |
| CN1017705B CN1017705B (en) | 1992-08-05 |
Family
ID=4815533
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 87105990 Expired CN1017705B (en) | 1987-12-26 | 1987-12-26 | Preparation method of optically-active cotton phenol |
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| Country | Link |
|---|---|
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7342046B2 (en) | 2004-03-25 | 2008-03-11 | The Regents Of The University Of Michigan | Gossypol co-crystals and the use thereof |
| US7354928B2 (en) | 2001-11-01 | 2008-04-08 | The Regents Of The University Of Michigan | Small molecule inhibitors targeted at Bcl-2 |
| US7432304B2 (en) | 2001-05-30 | 2008-10-07 | The Regents Of The University Of Michigan | Small molecule antagonists of Bcl-2 family proteins |
| US7557251B2 (en) | 2006-03-30 | 2009-07-07 | The Regents Of The University Of Michigan | Production of gossypol co-crystals |
| US7696372B2 (en) | 2007-10-01 | 2010-04-13 | Ascenta Therapeutics, Inc. | Process for preparing R-gossypol L-phenylalaninol dienamine |
| CN103524314A (en) * | 2013-10-28 | 2014-01-22 | 杨雪飞 | Preparation method for L-gossypol through high-speed countercurrent chromatography |
-
1987
- 1987-12-26 CN CN 87105990 patent/CN1017705B/en not_active Expired
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7432304B2 (en) | 2001-05-30 | 2008-10-07 | The Regents Of The University Of Michigan | Small molecule antagonists of Bcl-2 family proteins |
| US8163805B2 (en) | 2001-05-30 | 2012-04-24 | The Regents Of The University Of Michigan | Small molecule antagonists of Bcl-2 family proteins |
| US7354928B2 (en) | 2001-11-01 | 2008-04-08 | The Regents Of The University Of Michigan | Small molecule inhibitors targeted at Bcl-2 |
| US7342046B2 (en) | 2004-03-25 | 2008-03-11 | The Regents Of The University Of Michigan | Gossypol co-crystals and the use thereof |
| US7432300B2 (en) | 2004-03-25 | 2008-10-07 | The Regents Of The University Of Michigan | Gossypol co-crystals and the use thereof |
| US7557251B2 (en) | 2006-03-30 | 2009-07-07 | The Regents Of The University Of Michigan | Production of gossypol co-crystals |
| US7696372B2 (en) | 2007-10-01 | 2010-04-13 | Ascenta Therapeutics, Inc. | Process for preparing R-gossypol L-phenylalaninol dienamine |
| CN103524314A (en) * | 2013-10-28 | 2014-01-22 | 杨雪飞 | Preparation method for L-gossypol through high-speed countercurrent chromatography |
| CN103524314B (en) * | 2013-10-28 | 2015-08-19 | 杨雪飞 | A kind of high-speed countercurrent chromatography that adopts is separated the method preparing levorotation gossypol |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1017705B (en) | 1992-08-05 |
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