CN103288619A - Synthesis method of novel gossypol derivative - Google Patents
Synthesis method of novel gossypol derivative Download PDFInfo
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- CN103288619A CN103288619A CN201310039896XA CN201310039896A CN103288619A CN 103288619 A CN103288619 A CN 103288619A CN 201310039896X A CN201310039896X A CN 201310039896XA CN 201310039896 A CN201310039896 A CN 201310039896A CN 103288619 A CN103288619 A CN 103288619A
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Abstract
The invention discloses a synthesis method of a novel gossypol derivative. The method includes: firstly adding a concentrated strong alkali solution into gossypol acetate, letting them react at certain temperature, and removing the aldehyde group to obtain a product Apogossypol; adding a protective agent into the Apogossypol according to certain proportion, and letting them react under an appropriate temperature, thus obtaining the product Hexa-acetylapogossypol; under an appropriate temperature, subjecting the Hexa-acetylapogossypol to isopropyl removal reaction to obtain a product Hexa-acetyldesapogossypol; adding an oxidizing agent, and under an appropriate temperature, oxidizing the Hexa-acetyldesapogossypol to obtain the reaction product Tetra-acetyldesapogossypolone; adding a deprotection agent to conduct deprotection on the Tetra-acetyldesapogossypolone, thus obtaining the novel gossypol derivative Desapogossypolone with a molecular weight of 406 and a brownish red color. By means of five-step chemical reactions, the method provided in the invention changes the structure of the natural drug gossypol acetate. Compared with natural gossypol acetate, the obtained novel gossypol derivative Desapogossypolone has the characteristics of small molecular weight, good stability, and high anti-tumor activity, etc.
Description
Technical field
The present invention relates to the synthetic method of a kind of new cotton amphyl Desapogossypolone.
Background technology
Gossypol (gossypol) has another name called gossypol or cotton toxin, is a kind of yellow polyphenol dinaphthalene compound that forms in the Malvaceae plant cotton quirk, often is present in root, stem and the seed of cotton.Though about the research of gossypol before more than 100 years just because it usually can cause animal to poison, therefore, people are considered as waste treatment with it for a long time, and the applied research of gossypol is also stopped after getting a little knowledge of a subject or about sth..The sixties in 20th century, USSR (Union of Soviet Socialist Republics) scientist finds that gossypol has the effect that suppresses animal tumor cell, and it exists aldehyde formula, inner ether formula and three kinds of tautomers of ketenes formula.In addition, there are 2 aldehyde radicals that chemical property is very active in the gossypol structure, in case touch air, deterioration by oxidation take place easily, brought difficulty for transportation and storage.So, often be translated into the mixture of gossypols such as gossypol acetate, formic acid gossypol aborning, and do not change the biological activity of gossypol.
Gossypol acetate has antifertility, anti-malarial, various biological activity such as antiviral.Discovering in recent years, gossypol acetate can suppress the tumor cell line of vitro culture and zoografting growth of tumor, propagation, can can also strengthen tumour cell to the susceptibility of radiotherapy and alkylating agent to clinically the invalid recurrence of small part conventional chemotherapy or intractable metastatic breast cancer, neurospongioma, adrenal carcinoma patient being produced certain curative effect again.Therefore, preparation high purity and highly active gossypol acetate have become one of key issue of medicine industry development.
Two naphthalene nucleus link to each other with the C-C singly-bound in the gossypol molecule, can not rotate freely, and cause molecule to be asymmetry, produce left-handed and two kinds of optical isomers of dextrorotation.The research report is arranged: levorotation gossypol is the efficient micromolecular inhibitor of Bcl-2 and Bcl-XL, and kinds of tumor cells (as prostate cancer, bladder cancer, myelomatosis etc.) is all induced its effect of apoptosis.In addition, also there is synergy respectively and between multiple chemotherapeutics, radiotherapy, surgical operation and the antioxidant in levorotation gossypol.Experiment in vitro research further shows: levorotation gossypol has than racemization and the stronger anti-tumor activity of dextrorotation gossypol, and therefore, splitting the less and active higher levorotation gossypol of racemization gossypol acquisition toxicity has become the research focus.
At present, the gossypol that uses in the clinical and research all shows certain toxic side effect.This mainly is because the aldehyde radical in its structure easily is combined with the amino of protein or enzyme, forms stable Schiff ' s alkali, thus the biological function of blocking-up enzyme or protein.The anti-tumor in vivo activity research shows that when using gossypol separately, the clinical response rate reduces on the contrary, may be because patient's plasma proteins has suppressed the anti-tumor activity of gossypol.Therefore, synthesize a kind of new gossypol derivative, can keep the anti-tumor activity of gossypol, can reduce plasma proteins again to its inhibition, and not change the function of plasma proteins, this is a present important goal to the gossypol development research.In recent years, for the result for the treatment of that improves gossypol, alleviate its toxic side effect, Chinese scholars is modified the gossypol molecular structure, has synthesized a series of gossypol derivatives, as gossypol Schiff ' s alkali, monoaldehyde gossypol, levorotation gossypol Schiff ' s alkali etc., and show good effect.
At present, most of patent all relates to extraction and the application thereof about gossypol.As: Chinese invention patent " extracts the gossypol novel process " and (ZL89107264) discloses a kind of method that extracts gossypol acetate from absorbent cotton benevolence; Chinese invention patent " production method of gossypol acetate raw material " (ZL200410025855.6) discloses a kind of method of utilizing acetone thermal backflow-acetic acid recrystallization gossypol; Chinese patent literature " utilizes method and the isolated plant of gossypol in the microwave radiation extraction cottonseed " and (CN1789226A) discloses a kind of microwave radiation of utilizing extract method for the gossypol that kills mouse from cottonseed; It is that gossypol acetate is treated leukemic application that Chinese invention patent " application in preparation treatment leukemia medicament of gossypol and derivative thereof " (ZL200610072171.0) discloses a kind of gossypol derivative that utilizes.And also do not have similar report about the synthetic relevant patent of gossypol derivative.
Summary of the invention
The present invention aims to provide the synthetic method of a kind of new cotton amphyl Desapogossypolone, can prepare highly purified new cotton amphyl Deapogossypolone efficiently.
For reaching above purpose, the present invention takes following technical scheme to be achieved.
The synthetic method of a kind of new cotton amphyl Deapogossypolone comprises the steps:
A. take by weighing the gossypol acetate of certain mass, by mass volume ratio 1: 3-1: 10 to add concentration be the sodium hydroxide solution of 20%-45%, heated and stirred reaction 30-300 minute, temperature of reaction is 40 ℃-120 ℃, after reaction finishes, cooling also adds 75%-98% sulfuric acid 1-15ml, with extraction solvent extract and vacuum concentration to doing, obtain head product Apogossypol; Described extraction solvent is any one in ether, ethyl acetate, sherwood oil, ethanol, the methyl alcohol.
B. take by weighing a certain amount of head product Apogossypol, by mass volume ratio 1: 2-1: 10 add organic solvents dissolves fully, by mass volume ratio 1: 2-1: 10 add acetylation reagents reacts, temperature of reaction is 50 ℃-200 ℃, reaction times is 20-120 minute, after reaction finishes, is cooled to room temperature and places 30-120 minute, add that extraction solvent extracts and vacuum concentration to doing, and its recrystallization purifying is obtained the second step product Hexa-acetylapogossypol; Described organic solvent is any one of pyridine, dioxane, Glacial acetic acid; Described acetylation reagent is diacetyl oxide, glacial acetic acid, any one in the diisopropyl ethyl amine; Described extraction solvent is a kind of in ethyl acetate, ether, acetone, the trichloromethane.
C. take by weighing a certain amount of second product Hexa-acetylapogossypol, by mass ratio or mass volume ratio 1: 5-1: 10 add organic reagents carries out sec.-propyl and removes reaction, temperature of reaction is 10 ℃-80 ℃, reaction times is 10-120 minute, after reaction finishes, add extraction solvent extraction and vacuum concentration to doing, its recrystallization purifying is obtained third product Hexa-acetyldesapogossypol; Described organic solvent is the mixture of one or both solvents of the vitriol oil, perchloric acid, concentrated nitric acid; Described extraction solvent is any one in ether, ethanol, acetone, the methyl alcohol.
D. take by weighing a certain amount of third product Hexa-acetyldesapogossypol, by mass volume ratio 1: 5-1: 10 add organic reagents dissolves fully, by mass ratio or mass volume ratio 1: 1-1: 40 add oxygenants reacts, temperature of reaction is 20 ℃-150 ℃, reaction times is 10-180 minute, add extraction solvent extraction and vacuum concentration to doing, its recrystallization purifying is obtained the 4th product Tetra-acetyldesapogossypolone; Described organic solvent is a kind of in glacial acetic acid, dioxane, the pyridine; Described oxygenant is a kind of in the vitriol oil, Periodic acid, the dichromic acid or both mixtures; Described extraction solvent is any one in methyl alcohol, ether, ethanol, the acetone.
E. take by weighing a certain amount of the 4th product Tetra-acetyldesapogossypolone, by mass volume ratio 1: 5-1: 20 add dioxane dissolves fully, by mass volume ratio 1: 5-1: 15 to add concentration be that the salt of wormwood of 20%-40% reacts, temperature of reaction is 50 ℃-150 ℃, reaction times is 30-200 minute, after reaction finishes, add dilute hydrochloric acid regulator solution pH value and be 3-5, add extraction solvent extraction and vacuum concentration to doing, recrystallization purifying obtains final product Desapogossypolone; Described extraction solvent is any one in acetone, ether, methyl alcohol, the ethanol.
2. the synthetic method of new cotton amphyl Desapogossypolone according to claim 1 is characterized in that, the described described organic reagent of sec.-propyl that goes is in the vitriol oil, concentrated nitric acid, the perchloric acid any one.
3. the synthetic method of a kind of new cotton amphyl of usefulness according to claim 1 Desapogossypolone is characterized in that, described oxygenant is any one in the vitriol oil, dichromic acid, the Periodic acid.
In the such scheme, the described sec.-propyl reagent that goes is in the vitriol oil, concentrated nitric acid, the perchloric acid any one.Described oxygenant is any one in the vitriol oil, dichromic acid, the Periodic acid.
The method of the synthetic Desapogossypolone of the present invention has following obvious effects: (1) Desapogossypolone that the present invention synthesized has important use to be worth aspect medicine, has good antitumor action.(2) synthetic method that arrives involved in the present invention is simple to operation, has especially selected the purification process of recrystallization for use, greatly reduces synthetic cost and generated time.(3) the present invention has not only improved combined coefficient and productive rate by selecting adequate protective agent, oxygenant for use and removing sec.-propyl reagent, and has saved the synthetic needed time greatly.
Description of drawings
The present invention is described in further detail below in conjunction with drawings and Examples.
Fig. 1 is the infrared spectrogram of example 2 of the present invention, example 15 gained Desapogossypolone.IR (cm in the spectrogram
-1): 3424vOH (stretching vibration of hydroxyl O-H key); 2960vCH
3-(antisymmetric stretching vibration of methyl c h bond); 2874vC-H (symmetrical stretching vibration of methyl c h bond); 1660 places and 1430 sharp-pointed absorption peaks are characteristic peaks of intramolecularly quinoid structure; 1611,1579vC-H (aromatic ring C=C skeletal vibration); 1440vCH
3COO
-(carboxylic acid ion CH
3COO
-Stretching vibration); 1379vO-H (formation vibration of phenolic hydroxyl group O-H); 1269vC-O (stretching vibration of phenol C-O); 966,912,841vC-H (aromatic ring C-H flexural vibration).
Fig. 2 is the nuclear magnetic resonance map of example 4 of the present invention, example 12 gained Desapogossypolone.7.26ppm is CHCl in the spectrogram
3The vibration peak of middle hydrogen atom is solvent peak.The corresponding peak value of main group is followed successively by: 1.94ppm place is hydrogen atom vibration peak in the direct-connected methyl on the naphthalene nucleus (the 3 high peak value).Originally this peak value should be at the 2.1ppm place, but because the influence of naphthalene nucleus conjugation makes peak value slightly be offset; 4.1ppm locating to split the crest of branch is the vibration peak of tertiary carbon atom hydrogen atom in the sec.-propyl; 6.15ppm the vibration peak of four hydroxyl institute hydrogen atoms in the corresponding molecule of the low and slow crest of the locating outside, the core substance intramolecularly does not contain aldehyde radical.
Fig. 3 is the mass-spectrogram of example 1 of the present invention, example 7 gained Desapogossypolone, and wherein X-coordinate represents molecular weight, ordinate zou represents percent concentration.The molecular weight of gained Desapogossypolone is 406 as can be seen from collection of illustrative plates.
Fig. 4 is respectively example 1-15 gained Desapogossypolone The pharmacological results of the present invention.X-coordinate represents drug level among the figure, ordinate zou represents cancer cells survival percentage ratio, IC
50Represent medium lethal dose.As can be seen from the figure, under same drug level, the medium lethal dose value (IC of Desapogossypolone in prostate cancer PC3 cell and LNCaP cell
50) be respectively 5.67 and 5.08; Medium lethal dose value (the IC of gossypol in prostate cancer PC3 cell and LNCaP cell
50) be respectively 11.53 and 10.35.
The building-up process of Fig. 5 example gained of the present invention Desapogossypolone (V).
Embodiment
In order to make purpose of the present invention, technical scheme and advantage clearer, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explaining the present invention, and be not used in restriction the present invention.
The 5 gram gossypol acetates that weigh with scale add 20% sodium hydroxide 15ml, and 40 ℃ of stirring reactions 300 minutes after reaction finishes, cool off and add 75% vitriol oil 15ml.Extract two to three times with ether, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 9.6ml dioxane dissolving head product I, and add diacetyl oxide 4.8ml, 50 ℃ of following stirring reactions 120 minutes, be cooled to room temperature after the end and use ethyl acetate extraction 2-3 time, be concentrated into dried under the vacuum, carry out recrystallization purifying with ethyl acetate and can obtain pure product 3.6 grams of product II, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent vitriol oil 18ml, 80 ℃ were reacted 120 minutes down, be cooled to room temperature after the end and use extracted with diethyl ether 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With dioxane 15ml lysate III, add oxygenant vitriol oil 120ml, 150 ℃ were reacted 180 minutes, be cooled to room temperature after the end and use extracted with diethyl ether 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.5 gram, color is orange.With dioxane lysate IV, add 20% salt of wormwood 7ml, 50 ℃ were reacted 300 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 3, and with ethyl acetate extraction 2-3 time, vacuum concentration carries out recrystallization purifying with methyl alcohol and can obtain pure product 1.2 grams of product V Desapogossypolone to doing, and color is red-brown.
The 5 gram gossypol acetates that weigh with scale add 30% sodium hydroxide 50ml, and 90 ℃ of stirring reactions 30 minutes after reaction finishes, cool off and add 98% vitriol oil 1ml.Extract two to three times with ethyl acetate, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 48ml dioxane dissolving head product I, and add glacial acetic acid 48ml, 200 ℃ of following stirring reactions 20 minutes, be cooled to room temperature after the end and use acetone extract 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with trichloromethane and can obtain the pure product of product II 3.6 grams, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent vitriol oil 36ml, 10 ℃ were reacted 10 minutes down, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With dioxane 30ml lysate III, add oxygenant dichromic acid 120ml, 20 ℃ were reacted 10 minutes, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.5 gram, color is orange.With dioxane lysate IV, add 40% salt of wormwood 30ml, 150 ℃ were reacted 30 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 5, and with ethyl acetate extraction 2-3 time, vacuum concentration carries out recrystallization purifying with methyl alcohol and can obtain pure product 1.2 grams of product V Desapogossypolone to doing, and color is red-brown.
The 5 gram gossypol acetates that weigh with scale add 45% sodium hydroxide 50ml, 120 ℃ of stirring reactions 30 minutes, and reaction is positioned over reactor in the frozen water after finishing, and adds 98% vitriol oil 1ml.Extract two to three times with sherwood oil, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 48ml dioxane dissolving head product I, and add diacetyl oxide 24ml, 200 ℃ of following stirring reactions 20 minutes, be cooled to room temperature after the end and placed 120 minutes, with alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with ethyl acetate and can obtain the pure product of product II 3.6 grams, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent vitriol oil 36ml, 10 ℃ were reacted 10 minutes down, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With dioxane 30ml lysate III, add oxygenant Periodic acid 120ml, 20 ℃ were reacted 10 minutes, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.5 gram, color is orange.With dioxane 24ml lysate IV, add 30% salt of wormwood 28ml, 120 ℃ were reacted 30 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 4, and with extracted with diethyl ether 2-3 time, vacuum concentration carries out recrystallization purifying with ethyl acetate and can obtain pure product 1.2 grams of product V Desapogossypolone to doing, and color is red-brown.
Embodiment 4
The 5 gram gossypol acetates that weigh with scale add 20% sodium hydroxide 15ml, 60 ℃ of stirring reactions 300 minutes, and reaction is positioned over reactor in the frozen water after finishing, and adds 85% vitriol oil 15ml.Extract two to three times with ethanol, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 9.6ml dissolve with methanol head product I, and add diisopropyl ethyl amine 4.8ml, 50 ℃ of following stirring reactions 120 minutes, be cooled to room temperature after the end and placed 30 minutes, with acetone extract 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain the pure product of product II 3.6 grams, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent vitriol oil 36ml, 10 ℃ were reacted 10 minutes down, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With dioxane 30ml lysate III, add oxygenant Periodic acid 120ml, 20 ℃ were reacted 10 minutes, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.1 gram, color is orange.With dioxane 5.5ml lysate IV, add 40% salt of wormwood 5.5ml, 50 ℃ were reacted 300 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 3, and with methanol extraction 2-3 time, vacuum concentration carries out recrystallization purifying with ethyl acetate and can obtain pure product 1.2 grams of product V Desapogossypolone to doing, and color is red-brown.
Embodiment 5
The 5 gram gossypol acetates that weigh with scale add 35% sodium hydroxide 30ml, 90 ℃ of stirring reactions 165 minutes, and reaction is positioned over reactor in the frozen water after finishing, and adds 90% vitriol oil 7ml.Extract two to three times with methyl alcohol, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 30ml dissolve with methanol head product I, and add glacial acetic acid 15ml, 120 ℃ of following stirring reactions 90 minutes, be cooled to room temperature after the end and placed 75 minutes, with acetone extract 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with trichloromethane and can obtain the pure product of product II 3.6 grams, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent concentrated nitric acid 36ml, 10 ℃ were reacted 10 minutes down, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With pyridine 30ml lysate III, add oxygenant dichromic acid 120ml, 20 ℃ were reacted 10 minutes, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.5 gram, color is orange.With dioxane 24ml lysate IV, add 20% salt of wormwood 15ml, 90 ℃ were reacted 120 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 4, with ethyl acetate extraction 2 times, use n-hexane extraction again 1 time, vacuum concentration is to doing, carry out recrystallization purifying with ethyl acetate and can obtain pure product 1.2 grams of product V Desapogossypolone, color is red-brown.
Embodiment 6
The 5 gram gossypol acetates that weigh with scale add 50% sodium hydroxide 50ml, 120 ℃ of stirring reactions 30 minutes, and reaction is positioned over reactor in the frozen water after finishing, and adds 98% vitriol oil 1ml.Extract two to three times with methyl alcohol, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 48ml dissolve with methanol head product I, and add diisopropyl ethyl amine 24ml, 200 ℃ of following stirring reactions 20 minutes, be cooled to room temperature after the end and placed 120 minutes, use ethyl acetate extraction 2 times earlier, use n-hexane extraction again 1 time, be concentrated into dried under the vacuum, carry out recrystallization purifying with ether and can obtain pure product 3.6 grams of product II, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent perchloric acid 36ml, 10 ℃ were reacted 10 minutes down, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With glacial acetic acid 30ml lysate III, add oxygenant Periodic acid 120ml, 20 ℃ were reacted 10 minutes, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.1 gram, color is orange.With dioxane 48ml lysate IV, add 30% salt of wormwood 32ml, 120 ℃ were reacted 30 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 5, and with ethyl acetate extraction 2-3 time, vacuum concentration carries out recrystallization purifying with methyl alcohol and can obtain pure product 0.6 gram of product VDesapogossypolone to doing, and color is red-brown.
Embodiment 7
The 5 gram gossypol acetates that weigh with scale add 20% sodium hydroxide 15ml, 60 ℃ of stirring reactions 300 minutes, and reaction is positioned over reactor in the frozen water after finishing, and adds 85% vitriol oil 15ml.Extract two to three times with ether, vacuum concentration obtains about 4.8 grams of head product I to doing, and color is greyish-green.With 9.6ml pyridine dissolving head product I, and add diacetyl oxide 4.8ml, 50 ℃ of following stirring reactions 120 minutes, be cooled to room temperature after the end and placed 30 minutes, with ethyl acetate extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with ethyl acetate and can obtain the pure product of product II 3.6 grams, color is pale yellow.Take by weighing product II3.6g, add and remove sec.-propyl reagent perchloric acid 36ml, 10 ℃ were reacted 10 minutes down, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product III3 gram, color is pale asphyxia.With glacial acetic acid 30ml lysate III, add oxygenant Periodic acid 120ml, 20 ℃ were reacted 10 minutes, be cooled to room temperature after the end and use alcohol extraction 2-3 time, be concentrated into driedly under the vacuum, carry out recrystallization purifying with methyl alcohol and can obtain purified product IV1.1 gram, color is orange.With dioxane 6.5ml lysate IV, add 30% salt of wormwood 6.5ml, 50 ℃ were reacted 300 minutes down, being cooled to room temperature after the end, to add dilute hydrochloric acid regulator solution pH value be 3, and with ethyl acetate extraction 2-3 time, vacuum concentration carries out recrystallization purifying with methyl alcohol and can obtain pure product 0.57 gram of product VDesapogossypolone to doing, and color is red-brown.
Above example has all carried out pharmacological evaluation, experimentation: in the CO2gas incubator under 37 ℃, cultivate prostate cancer cell (nutrient solution: 10%fetal bovine serum and 2mmol/L L-glutamine) with the culture plate in 96 holes respectively, Desapogossypolone (DMSO dissolving) solution with different concns adds simultaneously, cultivate after 4 days, WST-1 is joined in the culture plate, continue under 37 ℃ of oxygen free conditions to cultivate 1.5 hours.After the end, the Analysis of Plate instrument is surveyed its light absorption value under the 450nm.Experimental result shows: under the same concentration, and the IC of Desapogossypolone in prostate cancer PC3 cell and LNCaP cell
50Value is respectively 5.67 and 5.08; The IC50 value of gossypol in prostate cancer PC3 cell and LNCaP cell is respectively 11.53 and 10.35, can obviously find out from experimental result, and the effect of Desapogossypolone inhibition tumour cell is 2 times of gossypol.Also further illustrate the Desapogossypolone purity height that is synthesized, active strong.
The above only is preferred embodiment of the present invention, not in order to limiting the present invention, all any modifications of doing within the spirit and principles in the present invention, is equal to and replaces and improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. the synthetic method of a new cotton amphyl Desapogossypolone is characterized in that, this synthetic method comprises the steps:
The first step. take by weighing the gossypol acetate of certain mass, by mass volume ratio 1: 3-1: 10 to add concentration be the sodium hydroxide solution of 20%-45%, heated and stirred reaction 30-300 minute, temperature of reaction is 40 ℃-120 ℃, after reaction finishes, cooling also adds 75%-98% sulfuric acid 1-15ml, with extraction solvent extract and vacuum concentration to doing, obtain head product Apogossypol;
Second step. take by weighing a certain amount of head product Apogossypol, by mass volume ratio 1: 2-1: 10 add organic solvents dissolves fully, by mass volume ratio 1: 2-1: 10 add acetylation reagents reacts, temperature of reaction is 50 ℃-200 ℃, reaction times is 20-120 minute, after reaction finishes, is cooled to room temperature and places 30-120 minute, add that extraction solvent extracts and vacuum concentration to doing, and its recrystallization purifying is obtained the second step product Hexa-acetylapogossypol;
The 3rd step. take by weighing a certain amount of second product Hexa-acetylapogossypol, by mass ratio or mass volume ratio 1: 5-1: 10 add organic reagents carries out sec.-propyl and removes reaction, temperature of reaction is 10 ℃-80 ℃, reaction times is 10-120 minute, after reaction finishes, add extraction solvent extraction and vacuum concentration to doing, its recrystallization purifying is obtained third product Hexa-acetyldesapogossypol;
The 4th step. take by weighing a certain amount of third product Hexa-acetyldesapogossypol, by mass volume ratio 1: 5-1: 10 add organic reagents dissolves fully, by mass ratio or mass volume ratio 1: 1-1: 40 add oxygenants reacts, temperature of reaction is 20 ℃-150 ℃, reaction times is 10-180 minute, add extraction solvent extraction and vacuum concentration to doing, its recrystallization purifying is obtained the 4th product Tetra-acetyldesapogossypolone;
The 5th step. take by weighing a certain amount of the 4th product Tetra-acetyldesapogossypolone, by mass volume ratio 1: 5-1: 20 add dioxane dissolves fully, by mass volume ratio 1: 5-1: 15 to add concentration be that the salt of wormwood of 20%-40% reacts, temperature of reaction is 50 ℃-150 ℃, reaction times is 30-200 minute, after reaction finishes, add dilute hydrochloric acid regulator solution pH value and be 3-5, add extraction solvent extraction and vacuum concentration to doing, recrystallization purifying obtains final product Desapogossypolone.
2. the synthetic method of new cotton amphyl Desapogossypolone according to claim 1 is characterized in that, the extraction solvent described in the first step is any one in ether, ethyl acetate, sherwood oil, ethanol, the methyl alcohol.
3. the synthetic method of new cotton amphyl Desapogossypolone according to claim 1 is characterized in that, the organic solvent described in second step is any one of pyridine, dioxane, glacial acetic acid; Described acetylation reagent is diacetyl oxide, glacial acetic acid, any one in the diisopropyl ethyl amine; Described extraction solvent is any one in ethyl acetate, ether, acetone, the trichloromethane.
4. the synthetic method of new cotton amphyl Desapogossypolone according to claim 1 is characterized in that, the organic solvent described in the 3rd step is a kind of of the vitriol oil, perchloric acid, concentrated nitric acid; Described extraction solvent is any one in ether, ethanol, acetone, the methyl alcohol.
5. the synthetic method of new cotton amphyl Desapogossypolone according to claim 1 is characterized in that, the organic solvent described in the 4th step is any one in glacial acetic acid, dioxane, the pyridine; Described oxygenant is a kind of in the vitriol oil, Periodic acid, the dichromic acid; Described extraction solvent is any one in methyl alcohol, ether, ethanol, the acetone.
6. the synthetic method of new cotton amphyl Desapogossypolone according to claim 1 is characterized in that, the extraction solvent described in the 5th step is any one in acetone, ether, methyl alcohol, the ethanol.
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| CN104817472A (en) * | 2015-03-25 | 2015-08-05 | 武汉大学 | Novel gossypol derivatives, and preparation method and antineoplastic application thereof |
| CN110143857A (en) * | 2018-02-12 | 2019-08-20 | 华南理工大学 | A kind of synthetic method of hemigossypol, gossypol and their analog |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817472A (en) * | 2015-03-25 | 2015-08-05 | 武汉大学 | Novel gossypol derivatives, and preparation method and antineoplastic application thereof |
| CN110143857A (en) * | 2018-02-12 | 2019-08-20 | 华南理工大学 | A kind of synthetic method of hemigossypol, gossypol and their analog |
| CN110143857B (en) * | 2018-02-12 | 2021-11-30 | 华南理工大学 | Synthetic method of semi-gossypol, gossypol and analogs thereof |
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