CN101220054B - Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt - Google Patents
Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt Download PDFInfo
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Abstract
The invention provides a preparation method of Combretastatin A-4 disodium phosphate. The method carries out the synthesis according to the synthesizing route shown as follows; wherein X is chlorine or bromine; R1 and R2 are tert-butyl, triphenyl methyl, 2-cynaoethyl, benzyl, phenyl, 4-nitrophenyl, 4-nitrobenzyl and 2-nitrobenzyl and R1 and R2 can be identical or different substituting groups. The method adopts bis-alkoxyl phosphoryl halide as the phosphorylation reagent, which is inexpensive and easy to acquire. Catalyst DMAP is added in the reaction to milden the reaction condition and stabilize the reaction temperature. The reaction time is short and the operation is simple. The phosphorylation intermediate needs no purification. The invention also has the advantages of high yield, good quality of product and easy industrial production.
Description
Technical field
The present invention relates to the preparation method of Combretastatin Combretastatin A-4 organic phosphate disodium salt.
Background technology
A human and mammiferous major causes of death is a tumor disease.A notable feature of tumour is exactly improper propagation.No matter normal cell or tumour cell, its formation, metabolism machine differentiation and proliferation all be unable to do without capillary blood vessel, and studies show that tumour cell medium vessels endothelial cell proliferation speed much larger than normal cell, so the blood vessel supressor can suppress tumor vessel more specifically.At present, the tumor vessel inhibitor also is a hot fields of antitumor drug research.
Combretastatin A-4-4 (CA4) derives from African willow (Combretum caffrum, Cmbretaceae) extract (Pettit, G.R., et al. the earliest; Experientia, 1989,45,209).This compound can obviously suppress the polymerization of tubulin, thereby suppresses capillary blood vessel.Act on tumour cell and can suppress the tumour cell microcirculation, reach the purpose that suppresses tumor growth.But the water-soluble extreme difference of Combretastatin A-4-4 can not be directly as drug use.The back is found Combretastatin A-4-4 is made organic phosphate disodium salt after phosphorylation, and it is water-soluble better, and anti-tumor activity greatly improves.
Combretastatin A-4-4 organic phosphate disodium salt (CA4P), chemical name is: 3,4,5,4 '-tetramethoxy-cis-toluylene-3 '-O-Di-Sodium Phosphate, structural formula is as follows:
At present, by Combretastatin A-4-4 (CA4) preparation Combretastatin A-4-4 organic phosphate disodium salt (CA4P) bibliographical information following several method is arranged:
1. with dibenzyl phosphite and CA4 reaction, in the presence of trimethylchlorosilane and sodium iodide, slough benzyl subsequently.This method will use toxicity height and environmentally hazardous tetracol phenixin as solvent, will use more expensive silane reagent of price and sodium iodide when sloughing benzyl simultaneously, is unfavorable for industrialized production (GB2403949).
2. with two-(2,2,2-three chloroethyls) phosphoryl compound and CA4 reaction, again with zinc/acetic acid reduction.Use in this method two-(2,2,2-three chloroethyls) phosphoryl compound costs an arm and a leg, and severe reaction conditions, unsuitable industrialized production.
3. with Phosphorus Oxychloride or phosphorus oxybromide and CA4 reaction, basic hydrolysis obtains CA4P again.Though this method is simple to operate, Phosphorus Oxychloride or phosphorus oxybromide are active high, so byproduct of reaction is more, the lower and difficult quality control of product yield.
4. application number: 200510057001.0, denomination of invention: the preparation method of Combretastatin compound.Disclosed preparation method is: prepare the phosphinylidyne dihalo-earlier, obtain phosphodiester with the CA4 reaction again, obtain CA4P through hydrolysis, salify again.The used phosphorus esterification reagent of this method needs extra preparation; and need molecular distillation during preparation; complex operation inconvenience; the phosphorus acylation reaction time is longer; temperature will change in the reaction process, and because the phosphinylidyne dihalo-has two activity sites, causes the phosphorylated product purity bad; need further to make with extra care just can be used for the next step, cause whole technology cost higher.
5, PCT/US01/22403 discloses the preparation method of Combretastatin compound.CA4 is dissolved in the acetonitrile, and logical argon gas adds DMAP, and the reaction down of two-(2,2,2-three chloroethyls) chloro phosphoric acid ester normal temperature adds triethylamine behind the 20min, normal-temperature reaction, and 30 minutes TLC confirm to react completely.Add copper/zinc mixture, be heated to 40 ℃, after 30 minutes, add 2 in batches, the 4-diacetylmethane was cooled to room temperature after 1.5 hours.Reaction mixture filters, and acetonitrile washes twice, adds entry in the filtrate, on ice bath, cool off, separate out solid, add Dowex ion exchange resin, remove ice bath, mixture becomes orange homogeneous phase, removes by filter resin, the filtrate evaporate to dryness is removed most acetonitriles, resistates is dissolved in the ethanol, and Dropwise 5 0% sodium hydroxide solution stirred 30 minutes to pH12～14, filter solid 50ml washing with alcohol.With crude product CA4P, be dissolved in the methanol-water mixing solutions, filter, be heated to 35～40 ℃ and kept 1 hour, be cooled to 30 ℃, add acetone, be cooled to room temperature, stirred 2 hours, and added acetone again, stirred 12～16 hours, filter next day, filter cake acetone washed twice is washed with acetone again, and product is in 40 ℃ of vacuum-dryings.This method purge process is cumbersome.
What above-mentioned patent adopted is: CA4 is with two-(2,2,2-three chloroethyls) chloro phosphoric acid ester, its chemical property is active, causes reaction product wayward, and yield is very low, and is 12-14 with the CA4P crude product at pH value, and chemical property is extremely unstable, also can cause productive rate to reduce; Simultaneously also cause follow-up purification process numerous and diverse, adopt ion exchange resin to carry out separation and purification, cost is increased greatly, more be unfavorable for industrialized production.Above-mentioned patent application is also mentioned and is adopted carbon tetrabromide di(2-ethylhexyl)phosphate phenyl to react except adopting outside (2,2,2-three chloroethyls), and its purifying mode is loaded down with trivial details equally, is not easy to the industrialized production operation.
Summary of the invention
Technical scheme of the present invention has provided the preparation method of a kind of new CA4P.
The invention provides the preparation method of Combretastatin Combretastatin A-4 organic phosphate disodium salt, it is to synthesize by following synthetic route:
X is a chlorine or bromine; R
1With R
2Be the tertiary butyl, trityl group, 2-cyano ethyl, benzyl, phenyl, 4-nitrophenyl, 2-nitrophenyl, 4-nitrobenzyl, 2-nitrobenzyl, R
1With R
2Be identical or different substituting group.
Further preferably, described R
1With R
2Be the tertiary butyl.
Particularly, it comprises the steps:
(1) Combretastatin A-4 is dissolved in the aprotic solvent, in the presence of acid scavenger and DMAP, drip the solution of two-oxyl phosphoryl chlorides, dropping temperature is: 20-40 ℃, dropwise, after uniform temp reacted 0.5～2 hour, and added the water termination reaction, extract product, obtain the phosphoric acid ester III of Combretastatin A-4 behind the evaporate to dryness with non-polar organic solvent;
(2) phosphoric acid ester (III) with Combretastatin A-4 is dissolved in the organic solvent, removes R
1And R
2, again in methyl alcohol with the NaOH salify, add the acetone crystallization, obtain CA4P disodium salt (I) behind the filtration drying.
Wherein, alkyl comprises in the described two-oxyl phosphoryl chlorides of a step: aliphatic alkyl: the tertiary butyl, trityl group, 2-cyano ethyl, benzyl, 4-nitrobenzyl or 2-nitrobenzyl; Aromatic hydrocarbyl: phenyl, 4-nitrophenyl.Further preferably, described alkyl is the tertiary butyl or benzyl.
The described non-polar organic solvent of a step is a methylene dichloride, 1,1-ethylene dichloride, 1,2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether or isopropyl ether.Described non-polar organic solvent does not dissolve each other with water, but can lysate.
Wherein, the described aprotic solvent of a step is: acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, 1,1-ethylene dichloride, 1,2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether or isopropyl ether.
Wherein, the described acid scavenger of a step is heterocyclic amine, trialkylamine or mineral alkali.Described trialkylamine is a diisopropylethylamine.
Wherein, the described organic solvent of b step is: methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, diisopropyl ether, t-butyl methyl ether, ethyl acetate or butylacetate.
Described b step removes R
1And R
2The method of blocking group is:
(1) R
1With R
2During for the tertiary butyl, trityl group, remove with acid-hydrolysis method;
(2) R
1With R
2During for 2-cyano ethyl substituted alkyl, remove with alkali hydrolysis method;
(3) R
1With R
2During for phenyl, 4-nitrophenyl, 2-nitrophenyl, 4-nitrobenzyl or 2-nitrobenzyl, remove with metallic reducing or catalytic hydrogenation method.
Wherein, described a, b step are operated in nitrogen or rare gas element.
This method is a phosphorus esterification reagent with the dialkoxy phosphoryl halogen; used phosphorus esterification reagent is cheap and easy to get; in reaction, add catalyzer DMAP simultaneously; make the reaction conditions gentleness, temperature of reaction is invariable, and the reaction times is short; simple to operate; the phosphorylated intermediate does not need purifying, and product yield height, quality are good, are easy to suitability for industrialized production.The mild condition of reaction, temperature of reaction is invariable, and the reaction times is short, and simple to operate, the phosphorylated intermediate does not need purifying, and product yield height, quality are good, are easy to suitability for industrialized production.
The invention will be further described by the following examples, it should be noted that reaction conditions and raw material purpose that following examples are related are the present invention is done better explanation, rather than limitation of the present invention.
Embodiment
Embodiment 1 temperature and the investigation in reaction times:
According to bibliographical information, conventional CA4P building-up reactions all is to carry out at low temperatures, and reaction time consumption is long, is unfavorable for effectively controlling reaction process, and this experiment is that the time and the temperature of reaction have been carried out comprehensive textual criticism, and is as follows:
Under the nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml methylene dichloride, drip the solution of two-(tert.-butoxy)-phosphoryl chloride 2.51g (0.011mol) and 10ml methylene dichloride under the differing temps.After dropwising, keep this temperature stirring reaction, monitor reaction process, disappear to raw material point with thin-layer chromatography, in reaction solution impouring 50ml frozen water, tell organic layer, water layer is used the 20ml dichloromethane extraction once again, merges organic layer, washing, drying, evaporate to dryness obtain CA4-two-(tert.-butoxy)-phosphoric acid ester, and reaction times and reaction yield under the differing temps see the following form:
Can determine that by above data 20～40 ℃ is optimal reaction temperature, the reaction times is no more than 1 hour.
The preparation of embodiment 2 Combretastatin Combretastatin A-4 organic phosphate disodium salts
Under nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml methylene dichloride; in 20 ℃, drip the solution of two-(tert.-butoxy)-phosphoryl chloride 2.51g (0.011mol) and 10ml methylene dichloride.After dropwising, keep this temperature stirring reaction, monitor reaction process, disappear to raw material point with thin-layer chromatography, reaction times is 0.5 hour, in reaction solution impouring 50ml frozen water, tell organic layer, water layer is used the 20ml dichloromethane extraction once again, merge organic layer, washing, drying, it is 94% oily matter CA4-two-(tert.-butoxy)-phosphoric acid ester 4.77g that evaporate to dryness obtains yield, and it is dropped into the logical in advance dry hydrogen chloride of 50ml to saturated methyl alcohol, stirring at room reaction 24 hours, the evaporated under reduced pressure solvent is dissolved in resistates in the 50ml methylene dichloride, be washed to neutrality, anhydrous sodium sulfate drying, evaporate to dryness, resistates are dissolved in the 25ml methyl alcohol, stir down and drip the NaOH-methanol solution to PH8--10, stirred 1 hour, and slowly dripped acetone 200ml, filter, the washing with acetone solid, drying under reduced pressure gets white powder product 3.64g, yield 82.7%.
The inventor is by comprehensively studying two a large amount of-oxyl phosphoryl chloride reagent, be surprised to find that, in the preparation process of preparation CA4P salts substances, CA4 and two-(tert.-butoxy)-phosphoryl chloride can react at 20-40 ℃, be difficult for producing side reaction and reaction conditions and simply be easy to control, the crude product yield reaches more than 80% simultaneously; In exquisite process, also do not need to adopt complicated methods such as ion exchange method, but just can obtain pure product, and yield is generally all more than 70%, even can reach more than 90% by dry hydrogen chloride to saturated methyl alcohol to the extraction of crude product.
The preparation of embodiment 3 Combretastatin Combretastatin A-4 organic phosphate disodium salts
Under nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml methylene dichloride; in 30 ℃, drip the solution of two-(2-cyano group oxyethyl group)-phosphoryl chloride 2.45g (0.011mol) and 10ml methylene dichloride.After dropwising, keep this temperature stirring reaction, monitor reaction process with thin-layer chromatography, disappear to raw material point, reaction times is 0.8 hour, in reaction solution impouring 50ml frozen water, tells organic layer, water layer is used the 20ml dichloromethane extraction once again, merge organic layer, washing, drying, it is 93% oily matter CA4-two-(2-chloroethoxy)-phosphoric acid ester 5.14g that evaporate to dryness obtains yield, it is dropped in the 25ml methyl alcohol, stir down and drip the NaOH-methanol solution, stirred 1 hour to PH8--10, slowly drip acetone 200ml, filter washing with acetone solid, drying under reduced pressure, get white powder product 3.43g, yield 78%.
The preparation of embodiment 4 Combretastatin Combretastatin A-4 organic phosphate disodium salts
Under nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml methylene dichloride; in 20 ℃, drip the solution of two-(benzyloxy)-phosphoryl chloride 2.92g (0.011mol) and 10ml methylene dichloride.Keep this temperature stirring reaction, monitor reaction process with thin-layer chromatography, to the disappearance of raw material point, the reaction times is 1 hour, in reaction solution impouring 50ml frozen water, tell organic layer, water layer is used the 20ml dichloromethane extraction once again, merges organic layer, washing, dry, it is 96% oily matter CA4-two-(benzyloxy)-phosphoric acid ester 5.20g that evaporate to dryness obtains yield, and it is dropped in the 25ml methyl alcohol, adds 10%Pd/C 0.04g, logical hydrogen normal pressure stirring reaction is 24 hours under the room temperature, remove by filter catalyzer, stir down and drip the NaOH-methanol solution, stirred 1 hour to PH8--10, slowly drip acetone 200ml, filter washing with acetone solid, drying under reduced pressure, get white powder product 3.54g, yield 80.5%.
The preparation of embodiment 5 Combretastatin Combretastatin A-4 organic phosphate disodium salts
Under nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml trimethyl phosphite 99; in 25 ℃, drip the solution of two-(phenoxy group)-phosphoryl chloride 3.11g (0.011mol) and 10ml trimethyl phosphite 99.Keep this temperature stirring reaction, monitor reaction process with thin-layer chromatography, to the disappearance of raw material point, the reaction times is 0.8 hour, in reaction solution impouring 50ml frozen water, tell organic layer, water layer with the extraction of 20ml trimethyl phosphite 99 once, merges organic layer again, washing, dry, it is 90% oily matter CA4-two-(phenoxy group)-phosphoric acid ester 5.56g that evaporate to dryness obtains yield, and it is dropped in the 25ml ethanol, adds 10%Pd/C 0.04g, logical hydrogen normal pressure stirring reaction is 24 hours under the room temperature, remove by filter catalyzer, stir down and drip the NaOH-methanol solution, stirred 1 hour to PH8--10, slowly drip acetone 200ml, filter washing with acetone solid, drying under reduced pressure, get white powder product 3.18g, yield 72.3%.
The preparation of embodiment 6 Combretastatin Combretastatin A-4 organic phosphate disodium salts
Under nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml trichloromethane; in 20 ℃, drip the solution of two-(triphenyl methoxyl group)-phosphoryl chloride 6.61g (0.011mol) and 10ml trichloromethane.After dropwising, keep this temperature stirring reaction, monitor reaction process, disappear to raw material point with thin-layer chromatography, reaction times is 0.5 hour, in reaction solution impouring 50ml frozen water, tell organic layer, water layer is used the 20ml chloroform extraction once again, merge organic layer, washing, drying, it is 89% oily matter CA4-two-(triphenyl methoxyl group)-phosphoric acid ester 8.62g that evaporate to dryness obtains yield, and it is dropped into the logical in advance dry hydrogen chloride of 50ml to saturated methyl alcohol, stirring at room reaction 24 hours, the evaporated under reduced pressure solvent is dissolved in resistates in the 50ml methylene dichloride, be washed to neutrality, anhydrous sodium sulfate drying, evaporate to dryness, resistates are dissolved in the 25ml methyl alcohol, stir down and drip the NaOH-methanol solution to PH8--10, stirred 1 hour, and slowly dripped acetone 200ml, filter, the washing with acetone solid, drying under reduced pressure gets white powder product 3.06g, yield 69.5%.
The preparation of embodiment 7 Combretastatin Combretastatin A-4 organic phosphate disodium salts
Under nitrogen protection; with CA4 3.16g (0.01mol), 4-N; N-lutidine 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml trimethyl phosphite 99; in 25 ℃, drip the solution of two-(2-nitro-phenoxy)-phosphoryl chloride 3.94g (0.011mol) and 10ml trimethyl phosphite 99.Keep this temperature stirring reaction, monitor reaction process with thin-layer chromatography, to the disappearance of raw material point, the reaction times is 1 hour, in reaction solution impouring 50ml frozen water, tell organic layer, water layer with the extraction of 20ml trimethyl phosphite 99 once, merges organic layer again, washing, dry, it is 90% oily matter CA4-two-(phenoxy group)-phosphoric acid ester 6.32g that evaporate to dryness obtains yield, and it is dropped in the 25ml ethanol, adds 10%Pd/C0.04g, logical hydrogen normal pressure stirring reaction is 24 hours under the room temperature, remove by filter catalyzer, stir down and drip the NaOH-methanol solution, stirred 1 hour to PH8--10, slowly drip acetone 200ml, filter washing with acetone solid, drying under reduced pressure, get white powder product 3.26g, yield 74.1%.
Claims (8)
1. the preparation method of Combretastatin Combretastatin A-4 organic phosphate disodium salt, it is to synthesize by following synthetic route:
It is characterized in that: described X is a chlorine; R
1With R
2Be the tertiary butyl, trityl group, phenyl or benzyl, R
1With R
2Be identical or different substituting group;
It comprises the steps:
A, Combretastatin A-4 is dissolved in the aprotic solvent, in the presence of diisopropylethylamine and DMAP, drip the solution of two-oxyl phosphoryl chlorides, dropping temperature is: 20-40 ℃, dropwise, in uniform temp reaction 0.5～1 hour,, obtain the phosphoric acid ester III of Combretastatin A-4 behind the evaporate to dryness with extracting product with non-polar organic solvent after the frozen water termination reaction;
B, the phosphoric acid ester III of Combretastatin A-4 is dissolved in the organic solvent, removes R
1And R
2, again in methyl alcohol with the NaOH salify, add the acetone crystallization, obtain CA4P disodium salt I behind the filtration drying.
2. method according to claim 1 is characterized in that: alkyl is in the described two-oxyl phosphoryl chlorides of a step: the tertiary butyl, trityl group, benzyl or phenyl.
3. method according to claim 2 is characterized in that: alkyl is in the described two-oxyl phosphoryl chlorides of a step: the tertiary butyl or benzyl.
4. method according to claim 1, it is characterized in that: the described aprotic solvent of a step is: acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, 1,1-ethylene dichloride, 1,2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether or isopropyl ether.
5. method according to claim 1 is characterized in that: the described non-polar organic solvent of a step is normal hexane or hexanaphthene.
6. method according to claim 1 is characterized in that: the described organic solvent of b step is: methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, diisopropyl ether, t-butyl methyl ether, ethyl acetate or butylacetate.
7. method according to claim 1 is characterized in that: described b step removes R
1And R
2The method of blocking group is:
(1) R
1With R
2During for the tertiary butyl, trityl group, remove with acid-hydrolysis method;
(2) R
1With R
2During for phenyl or benzyl, remove with metallic reducing or catalytic hydrogenation method.
8. method according to claim 1 is characterized in that: described a, b step are operated in nitrogen or rare gas element.
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| CN101514213B (en) * | 2009-03-20 | 2011-12-28 | 南京臣功制药有限公司 | Method for preparing Combretastatin A-1 phosphate ester tetrasodium salt |
| CN103408591B (en) * | 2013-07-17 | 2016-04-20 | 张家港威胜生物医药有限公司 | A kind of synthetic method of Pterostilene organic phosphate disodium salt |
| CN104892668B (en) * | 2015-05-12 | 2017-03-29 | 上海大学 | Prodrug and preparation method thereof before combretastatin analog water solublity |
| CN112225673B (en) * | 2020-11-13 | 2022-08-02 | 义乌市华耀医药科技有限公司 | Amino combretastatin derivative and application thereof |
| CN113549106B (en) * | 2021-07-14 | 2023-05-26 | 淮阴工学院 | Combretastatin derivative and preparation method and application thereof |
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|---|---|---|---|---|
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| CN1465580A (en) * | 2002-06-07 | 2004-01-07 | 深圳市北大高科技股份有限公司 | Simple method for synthesizing pro-drug of compete A-4 |
| CN1737004A (en) * | 2005-04-06 | 2006-02-22 | 西南合成制药股份有限公司 | Combretastatin compound preparation method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| CN1465580A (en) * | 2002-06-07 | 2004-01-07 | 深圳市北大高科技股份有限公司 | Simple method for synthesizing pro-drug of compete A-4 |
| CN1737004A (en) * | 2005-04-06 | 2006-02-22 | 西南合成制药股份有限公司 | Combretastatin compound preparation method |
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