CN104892668B - Prodrug and preparation method thereof before combretastatin analog water solublity - Google Patents
Prodrug and preparation method thereof before combretastatin analog water solublity Download PDFInfo
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Abstract
The present invention relates to a kind of prodrug of combretastatin analog and preparation method thereof.The structural formula of the prodrug is：The prodrug improves which and phoresys performance, makes to have in vivo and well phoresys property, can effectively achieve the prodrug of target site.
Description
Technical field
The present invention relates to a kind of water miscible combretastatin analog（Combretastatin A-4 analogue）'s
Before-prodrug and preparation method thereof.
Background technology
Combretastatin analog is small molecule tumor vascular targeting blocking reagent（Vascular Disrupting
Agents, VDA）.For tumor vessel, it can show that selectively targeted and blocking destroys the tumor vessel for having generated, make to swell
Tumor cannot get oxygen and nutrition, until tumor " dying of hunger ".Therefore, for the tumor core that existing chemotherapy and radiation can not be killed easily
The cancerous cell of center portion position, combretastatin analog thoroughly can kill from inside to outside (British Journal of Cancer
110, 2170-2177 (29 April 2014))。
Combretastatin analog is the cis 1,2- stilbene aryl amine derivatives of a class.As its water solublity is very low, limit
Clinical practice is made.At present, the serine hydrochlorate of combretastatin analog（AVE8062）Water-soluble prodrug flies-peace by promise is matched
The research and development of Wan Te drugmakers are into II phase clinical researches.But it is poor to there are still hydrolytic stability, it is bad to phoresy property in vivo, toxicity
Larger the problems such as.（Lancet Oncol. 2015 Apr 8.）
Prodrug（prodrug）Design has become one of important effective means in drug design field.With regard to prodrug concept
Many patent applications are had with application and power is obtained.But, such prodrug is usually present some problems, such as according to specificity target position
Cracking mechanism（Such as enzymatic activity）The prodrug of design, often fails because not reaching target position tissue；Improve water solublity and design
Injection prodrug, can be unstable because of which, easily decompose in the solution and can not apply etc..Overcome the disadvantages mentioned above of prodrug, before improvement
The property of medicine, apparently more promising method is using series connection latentiation at present（Cascade Latentiation）Method, i.e.,
The double prodrugs of design（Double prodrug）Or front-prodrug（Pro-prodrug）（Bundgaard H. The double
prodrug concept and its applications. Adv Drug Delivery Rev 1999; 3: 39）.Example
Such as：The prodrug that will be cracked in specific site, further latentiation improve which and phoresy performance, make
Fortune property, can effectively reach the prodrug of the prodrug of target site.For another example：Using series connection latentiation, have prodrug more satisfactory
Property, i.e., simultaneously there is external sufficiently stable property and the high susceptibility of regeneration parent drug in vivo.General thinking is
Elder generation Jing digests into prodrug in vivo to make external sufficiently stable pair of prodrug, and then Jing enzymes or non-enzymatic decomposition discharges rapidly parent medicine
Thing, so as to play drug effect.Further research finds：Elder generation Jing enzymolysis generates prodrug in vivo for double prodrugs or front-prodrug, then
Can the chemical action of Jing enzymes or non-enzymatic discharge rapidly parent drug, play drug effect.Early-stage Study shows, compound 3-（2 '-hydroxyl
Base -4 ', 6 ' -3,5-dimethylphenyl）The amide form thereof of -3,3- neopentanoic acids has fast reaction under pH environment in human body
Activity, can meet the requirement of double prodrug designs.The research of Milstien and Cohen groups（J. Am. Chem. Soc.
1972, 94 (26), 9158-9165）And the research of Caswell and Schmir groups（J. Am. Chem. Soc.
1980, 102 (14), 4815-4821）All show that the methyl on 3,3 upper dimethyl and 6 ' positions constitutes a so-called " front three
Base is locked " effect so that its molecule has quick lactonization.Just because of this characteristic, it is can be very good for designing
The prodrug of aminated compoundss.
The content of the invention
An object of the present invention be a kind of combretastatin analog is provided before-prodrug.
The second object of the present invention be this is provided before-preparation method of prodrug.
Utilization " sodium ascorbyl phosphate " water-soluble prodrug of the invention and " ' the trimethyl lock of hydroxy-amide class compound
Effect ', raising phoresy performance in vivo " theory, design synthesis combretastatin analog before-prodrug, construct first and have
The compound 2c of " trimethyl lock effect ".Flowed back in pyrovinic acid solution with 3,5- xylenols and senecioic acid methyl ester
Reaction, obtains 4,4,5,7- tetramethyl -3,4- dihydrocoumarin（2a）.Subsequently 2a makees reducing agent in lithium aluminium hydride reduction, anhydrous
Under conditions of tetrahydrofuran makees solvent, 3- is reduced into（2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl）- 3,3- dimethyl propanol
（2b）.Compound 2b is dissolved in dichloromethane, adds protection reagent tert-butyl chloro-silicane, in the effect of acid binding agent triethylamine
Under, room temperature reaction 24 hours, obtain 1-O- t-Butyldimethylsilyl -3- (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -
3,3- dimethyl propanol（2c）.Then implement Phosphation, form water-soluble phosphoruses acid disodium salt prodrug.Compound 2c is dissolved in nothing
Water tetrahydrofuran, under potassium tert-butoxide and the effect of four benzyl ester of pyrophosphoric acid, 60 DEG C are reacted 1 hour, obtain 1-O- fert-butyidimethylsilyls
Silicon substrate -3- [2 '-oxos（Dibenzyl phosphoric acid ester group）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- dimethyl propanol（2d）, change
Compound 2d dissolves in acetone, after adding potassium fluoride, instills brand-new Jones reagent, and 3- [2 '-oxos are obtained after reaction（Dibenzyl
Phosphate）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- neopentanoic acids（2e）.In tetrahydrofuran solvent, compound 2e exists
The lower thionyl chloride for dissolving, adding new steaming of stirring, was heated to reflux 4 as a child, the thionyl chloride of removal of solvent under reduced pressure and excess,
The remaining thing of anhydrous tetrahydro furan dissolving reaction is subsequently added again, adds cis-1,2-（3,4,4 ', 5- tetramethoxy -3 '
- amino）Stilbene（Combretastatin analog；Combretastatin A-4 analogue）, room temperature reaction overnight, post layer
After analysis is isolated and purified, combretastatin analog amidatioon prodrug is obtained（2f）.Combretastatin analog amidatioon prodrug（2f）It is molten
In acetonitrile is dried, under the conditions of ice-water bath, Deca bromotrimethylsilane uses thin plate chromatography（TCL）After tracking reaction completely, plus
Enter Feldalat NM/methanol solution, be stirred at room temperature down, when appearance is precipitated in a large number, add acetone, be stirred overnight to precipitation completely, must examine
Before cloth statin analog water solublity-prodrug 2g, the synthetic route of the method is：
For achieving the above object, the present invention is adopted the following technical scheme that：
Before a kind of water solublity of combretastatin analog-prodrug, it is characterised in that its structural formula is as follows：
。
Before a kind of water solublity for preparing above-mentioned combretastatin analog-method of prodrug, it is characterised in that the method
Concretely comprise the following steps：
A. 3,5- xylenols are pressed into 1 with senecioic acid methyl ester:1.1～1:1.5 mol ratio is dissolved in pyrovinic acid,
The lower back flow reaction of stirring terminates to TLC tracking reactions；By reactant liquor dilute with water, it is extracted with ethyl acetate, organic layer quality
Percent concentration is 5% NaHCO3Washing, then washed with saturation NaCl solution, anhydrous MgSO4It is dried, filters, filtrate rotation is steamed
Send out, then purified yellow solid, as 4,4,5,7- tetramethyl -3,4- dihydrocoumarin, its structural formula is：；
B., under inert atmosphere protection, by obtained by step a 4,4,5,7- tetramethyl -3,4- dihydrocoumarin is in lithium aluminium hydride reduction
Under conditions of anhydrous tetrahydro furan makees solvent, 3- is reduced into（2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl）- 3,3- dimethyl propylenes
Alcohol, its structural formula is：；
C. under an inert atmosphere, by 3- obtained by step b（2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl）- 3,3- dimethyl propanol
1 is pressed with protection reagent tert-butyl chloro-silicane:1.1～1:1.5 mol ratio is dissolved in dichloromethane, in acid binding agent triethylamine
In the presence of, stirring reaction terminates to TLC tracking reactions；Reacting liquid filtering, after filtrate is spin-dried for, is dissolved with dichloromethane, washing
Wash, the anhydrous MgSO of organic faciess4It is dried, filters, filtrate rotary evaporation, separated purification obtains 1-O- tert-butyldimethyl silyls
Base -3- (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- dimethyl propanol, its structural formula is：；
D. by 1-O- t-Butyldimethylsilyls -3- obtained by step c (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- two
Methylpropanol and potassium tert-butoxide press 1:1.1～1:1.5 mol ratio is dissolved in tetrahydrofuran, is back to reactant liquor and is changed into from blueness
Yellow；Four benzyl ester of pyrophosphoric acid is added, is continued to be stirred at reflux to react to TLC tracking reactions and is terminated；Oil is added after being cooled to room temperature
Ether, filters, and filtrate removes solvent, and separated purification obtains 1-O- t-Butyldimethylsilyl -3- [2 '-oxos（Dibenzyl phosphoric acid
Ester group）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- dimethyl propanol, its structural formula is：；It is described
Four benzyl ester of pyrophosphoric acid and 1-O- t-Butyldimethylsilyl -3- (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- dimethyl
The mol ratio of propanol is：1:1.1～1:1.5；
E. in ice-water bath, by 1-O- t-Butyldimethylsilyls -3- obtained by step d (2 '-hydroxyl -4 ', 6 '-diformazan
Base phenyl) -3,3- dimethyl propanol and potassium fluoride press 1:4～1:7 mol ratio is dissolved in acetone, is being slowly added dropwise catalyst use
The Jones reagents of amount, continue stirring reaction and terminate to TLC tracking reactions；To in reactant liquor Deca isopropanol to reactant liquor by Huang
Green becomes native green, and it is in aeruginouss to continue stirring to reactant liquor；Remove solvent and obtain dark green solid, dissolved with ethyl acetate,
Washing, is extracted with ethyl acetate, and organic faciess saturation NaCl solution is washed, and is dried, and filters, and removes solvent, then whitely purified
Solid, as 3- [2 '-oxos（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- neopentanoic acids, its structure
Formula is：；
F. by 3- [2 '-oxos obtained by step e（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- diformazans
Base propanoic acid and thionyl chloride press 1:2～1:5 mol ratio is dissolved in tetrahydrofuran solvent, and back flow reaction 4 as a child, removes solvent
With excessive thionyl chloride, the remaining thing of anhydrous tetrahydro furan dissolving reaction is subsequently added again, cis-1,2- is added（3, 4,
4,5- -3 '-amino of tetramethoxy）Stilbene, room temperature reaction are complete to TLC tracking reactions, it is separated after purification, examined
Cloth statin analog amidatioon prodrug, its structural formula is：；Described
3- [2 '-oxos（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- neopentanoic acids and cis-1,2-（3,
4,4,5- -3 '-amino of tetramethoxy）The mol ratio of stilbene is：1:0.5～1:1；
G. combretastatin analog amidatioon prodrug obtained by step f is dissolved in acetonitrile, under the conditions of ice-water bath, Deca
Bromotrimethylsilane, continues stirring reaction and reacts complete to TLC tracking, add the methanol solution of Feldalat NM, be stirred at room temperature anti-
There should be white precipitate to generate；A large amount of acetone solns are added to be stirred overnight, sucking filtration obtains white powder solid, as combretastatin is similar to
Before the water solublity of thing-prodrug, its structural formula is：.
Before the water solublity of combretastatin analog involved in the present invention-prodrug is a kind of novel control release type prodrug.By
National Shanghai new drug Research on Safety Assessment center is tested by acute toxinology experiment codes and standards.The analog ten thousand of the tested material
Chinese mugwort can acute toxicity test in mice data shows, when dosage reaches 1000 mg/kg, animal occur death.Therefore this test
It is 300,500,1000 mg/kg tentatively to draft dosage, and the 4th day after administration increases by 2000 mg/kg dosage groups, and observation is single
The toxic reaction and death condition of animal after secondary administration.Its acute toxinology experiment shows that MTD is 2000mg/kg.
The present invention passes through four benzyl ester of pyrophosphoric acid so that phenolic hydroxyl group Phosphation, forms sodium ascorbyl phosphate water-soluble prodrug.Use 3-
（2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl）- 3,3- neopentanoic acid, constructs " trimethyl lock " effect, before formation-prodrug,
Targeting delivery parent drug is esterified in vivo promptly.Before this-prodrug improves which and phoresys performance, in vivo with well phoresying property
Matter, target site can be effectively achieved, its release parent drug process is shown below：
。
Specific embodiment
Before each embodiment is the water solublity of combretastatin analog below-preparation method of prodrug, they are served only for
The present invention is illustrated, not limitation of the invention.
Embodiment one：Prepare 4,4,5,7- tetramethyl -3,4- dihydrocoumarin（2a）
Weigh 3,5- xylenols（5.002 g 41 mmol）Add the 50 ml eggplants equipped with 5 ml pyrovinic acid solution
In shape bottle, senecioic acid methyl ester under stirring, is added（5.161 g 45.2 mmol）, after addition, solution is in bronzing.In eggplant shape
Install spherical condensation tube, drying tube, oil bath heating to 80 DEG C of magnetic agitation, condensing reflux, TLC tracking on bottle successively（Petroleum ether：
Ethyl acetate=1 ﹕ 1）, reaction terminates（About 12 hours）.Reactant liquor plus 800 ml water are diluted, is extracted with ethyl acetate（200 ml
×2）, merge organic layer, 5% NaHCO3Washing（200 ml×3）, then washed with 100 ml saturation NaCl solutions, anhydrous MgSO4
It is dried, filters, filtrate rotary evaporation obtains yellow solid, uses ethyl acetate-light petrol recrystallization, filters to obtain white crystalline solid,
Vacuum drying（40℃）, weigh to obtain 7.344 g, yield：87.8%；mp 89-90℃；
Compound 2a：1H NMR (500 MHz, CDCl3) δ 6.741 (1H, d, J = 0.5 Hz)；6.711
(1H, d, J = 0.5Hz);2.589 (2H, s)；2.457 (3H, s)；2.270 (3H,s)；1.434 (6H, s).
Embodiment two：Preparation 3- (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- dimethyl propanol（2b）
Weigh LAH（1 equiv 0.951 g）It is dissolved in 40 ml and newly steams tetrahydrofuran solution in 100 ml there-necked flasks, ice
The lower stirring gray suspension of bath, then Weigh Compound 2a（5.109 g 25 mmol）Being dissolved in 18 ml, newly to steam tetrahydrofuran molten
Liquid, is slowly dropped in the tetrahydrofuran solution of above-mentioned LAH under argon protection, has gas to generate.Drop finishes, and warms naturally to room temperature,
Stirring reaction 1 hour, TLC tracking reactions terminate（Petroleum ether：Ethyl acetate=2 ﹕ 1）.Saturation is slowly added dropwise in above-mentioned reactant liquor
NH4Cl solution is quenched to no longer bubbling, and solution is into white suspension.Filter（Plus one layer of kieselguhr drainage, absorption）, filtrate adds
100 ml water mix, and are extracted with ether（50 ml×3）, merge organic faciess, anhydrous MgSO4It is dried, filters, filtrate rotary evaporation
Except solvent obtains colorless viscous liquid, with ethyl acetate-n-hexane recrystallization, white bright crystalline solid is filtered to obtain, be vacuum dried（40
℃）, weigh to obtain 4.655 g, yield：89.4%；mp 112-114℃；
Compound 2b：1H NMR (500 MHz, CDCl3) δ 6.487 (1H, d, J=0.5Hz), 6.334 (1H,
D, J=0.5Hz), 5.867 (1H, br), 3.624 (2H, t, J=7.0 Hz), 2.471 (3H, s), 2.233
(2H, t, J=7.0 Hz), 2.166 (3H, s), 1.548 (6H, s).
Embodiment three：Preparation 1-O- t-Butyldimethylsilyl -3- (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3-
Dimethyl propanol（2c）
Weigh Compound 2b（1.165 g 6.5 mmol）In 100 ml there-necked flasks, tert-butyldimethylsilyl chloride silicon is added
Alkane（0.932 g 7.15 mmol）, it is dissolved in 20 ml dichloromethane under argon protection, ice bath, stir about 10 minutes.By perseverance
Pressure Dropping funnel Deca triethylamine（3.4 ml）6 ml of dichloromethane solution in there-necked flask, drip speed 1d/（6~7）S.Drip
Ice bath is removed after finishing, room temperature is warmed naturally to, reaction system is in shallow dark brown.24 h of stirring reaction, reactant liquor become clarification, TLC with
Track reaction terminates（Shi You Mi ﹕ ethyl acetate=1 ﹕ 1）, reaction stopping.Reacting liquid filtering, after filtrate is spin-dried for, adds 25 ml bis-
Chloromethanes dissolve, and wash with water（10 ml×4）, merge organic faciess, anhydrous MgSO4It is dried, filters, filtrate rotary evaporation obtains white
Color solid, with ethyl acetate-n-hexane recrystallization, filters to obtain colorless crystalline solid, vacuum drying（40℃）, weigh 2.064
G, yield：98.6%;
Compound 2c：1H NMR (500 MHz, CDCl3) δ 6.487 (1H, d, J=0.5Hz), 6.409
(1H, d, J=0.5Hz), 5.622 (1H, br), 3.590 (2H, t, J=7.0 Hz), 2.449 (3H, s),
2.183 (3H, s), 2.108 (2H, t, J=7.0 Hz), 1.545 (6H, s), 0.868 (9H, s), 0.013
(6H, s)。
Example IV：Prepare 1-O- t-Butyldimethylsilyl -3- [2 '-oxos（Dibenzyl phosphoric acid base）- 4 ', 6 '-two
Aminomethyl phenyl] -3,3- dimethyl propanol（2d）
Weigh Compound 2c（0.252 g 0.78 mmol）Be dissolved in 20 ml THF solution is newly steamed in 100 ml there-necked flasks
In, potassium tert-butoxide is added under stirring（0.1 g 0.86 mmol）In bottle, solution is in blueness.Oil bath heating flows back to 60 DEG C
After about 5 minutes, solution is changed into yellow from blueness.Four benzyl ester of pyrophosphoric acid is added while hot（0.463 g 0.86 mmol）, continue stirring,
There is milky white precipitate to generate.Continue reaction 1 hour under reflux, TLC tracking reactions terminate（Shi You Mi ﹕ ethyl acetate=3 ﹕ 2）,
Reaction stopping heating, adds 30 ml petroleum ether, filters after being cooled to room temperature, remove insoluble matter, and filtrate is light yellow clear liquid, is reduced pressure
Except solvent, a yellow oil is obtained.Column chromatography for separation is purified（Eluant：Yi Suan Yi Zhi ﹕ petroleum ether=1 ﹕ 3）, rotate except solvent,
Obtain light yellow color grease, vacuum drying（40℃）, weigh to obtain 0.394g, yield：87.2%.
Compound 2d:1H NMR (500 MHz, CDCl3) δ 7.135 (10H, m), 6.838 (1H, d, J=
0.5Hz), 6.654 (1H, d, J=0.5Hz), 5.171 (4H, d, J=8.0 Hz), 3.562 (2H, t, J=
7.0 Hz), 2.462 (3H, s), 2.149 (3H, s), 2.096 (2H, t, J=7.0 Hz), 1.598 (6H,
S), 0.921 (9H, s), 0.021 (6H, s).
Embodiment five：Prepare 3- [2 '-oxos（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- diformazans
Base propanoic acid（2e）
Weigh Compound 2d（0.394 g 0.68 mmol）5 ml acetone are dissolved in 25 ml there-necked flasks, ice bath, then
Add potassium fluoride（0.040 g 2.72 mmol）In bottle, stir 5 minutes.Dropping funnel is slowly added dropwise 0.6 ml brand-news Jones
In reaction bulb, solution is brown to be generated reagent with precipitation, continues stirring reaction 2 hours, and TLC tracking reactions terminate（Oil
Mi ﹕ ethyl acetate=3 ﹕ 2）.2.7 ml of Deca isopropanol in reaction bulb, solution become native green by yellow green, continue stirring 20
Minute, solution is in aeruginouss.Reactant liquor is transferred to into 50 ml single port bottles, rotary evaporation removes solvent and obtains dark green solid.Will be deep
Green solid is dissolved with 12 ml ethyl acetate, 15 ml H2O is washed, and separates organic faciess.Water is mutually extracted with ethyl acetate（10 ml×
3）, merge organic faciess.Saturation NaCl solution is washed（10 ml×2）, anhydrous MgSO4It is dried, filters, filtrate rotary evaporation removes solvent
Yellow green grease is obtained, with ether-n-hexane recrystallization, white solid is filtered to obtain, is vacuum dried（40℃）, weigh 0.247
G, yield：75.4%；
Compound 2e:1H NMR (500 MHz, DMSO-d6) δ 11.804 (1H, br), 7.367 (10H,
M), 6.929 (1H, d, J=0.5Hz), 6.735 (1H, d, J=0.5Hz), 5.141 (4H, d, J=8.0
Hz), 2.795 (2H, s), 2.475 (3H, s), 2.103 (3H, s), 1.512 (6H, s).
Embodiment six：Prepare the amidated products of combretastatin analog and 2e（2f）
Weigh Compound 2e（0.531 g 1.1 mmol）In 50 ml eggplant type bottles, add 40 ml newly to steam THF, stir
Dissolving, adds SOCl2（0.17 ml；2.3 mmol）, the spherical condensation tube with drying tube is installed, heating reflux reaction 4 is little
When.Reaction stops heating after terminating, it is slightly cold after remove solvent and unnecessary SOCl under reduced pressure2, obtain a light yellow oil.By oily
Thing is dissolved in 40 ml and newly steams THF, and stirring is lower to add combretastatin analog（0.182 g 0.55 mmol）, reaction is stirred at room temperature
Overnight, TLC tracking reaction is complete.Grease column chromatography for separation is collected product point except solvent by decompression, is rotated except solvent obtains dark brown
0.402 g of grease, yield 90%.
Compound 2f：1H NMR (500 MHz, CDCl3) δ 8.238 (1H, br), 7.670 (1H, s),
7.291 (10H, m), 7.114 (1H, s), 6.931 (1H, d, J=0.5Hz), 6.920 (1H, q, J=
8.5Hz), 6.722 (1H, d, J=0.5Hz), 6.708 (1H, s), 6.582 (1H, d, J=8.5Hz),
6.465 (1H, d, J=12.5Hz), 6.386 (1H, d, J=12.5Hz), 5.108 (4H, d, J=8Hz),
3.825 (3H, s), 3.772 (3H, s), 3.645 (6H, s), 2.879 (2H, s), 2.467 (3H, s),
2.158 (3H, s), 1.647 (6H, s).
Embodiment seven：Before preparing combretastatin analog water solublity-prodrug（2g）
Weigh Compound 2f（1.427g 1.8mmol）In 50ml round-bottomed flasks, dry acetonitrile 9ml, ice bath are added
Lower stirring and dissolving.Constant pressure funnel Deca bromotrimethylsilane（0.6ml 4.5mmol）, solution is changed into purple from colourless, after
Continuous stirring, solution colour gradually become shallower as, TLC tracking reactions, and Feldalat NM is added after reaction completely（195mg 3.6mmol）And methanol
Solution 18ml, is stirred at room temperature, and has white precipitate to generate.A large amount of acetone solns are added to be stirred overnight, sucking filtration obtains white powder solid,
Vacuum drying（40℃）, weigh to obtain 0.8972 g, yield：75.8%；
Compound 2g：1H NMR (500 MHz, D2O) δ 8.226 (1H, br), 7.645 (1H, s), 7.117
(1H, s), 6.923 (1H, d, J=0.5Hz), 6.878 (1H, q, J=8.5Hz), 6.767 (1H, d, J=
0.5Hz), 6.718 (1H, s), 6.585 (1H, d, J=8.5Hz), 6.457 (1H, d, J=12Hz),
6.382 (1H, d, J=12.5Hz), 3.834 (3H, s), 3.766 (3H, s), 3.638 (6H, s), 2.855
(2H, s), 2.439 (3H, s), 2.143 (3H, s), 1.623 (6H, s).
Claims (1)
1. a kind of method of before water solublity for preparing combretastatin analog-prodrug, it is characterised in that the concrete steps of the method
For：
A. 3,5- xylenols are pressed into 1 with senecioic acid methyl ester:1.1～1:1.5 mol ratio is dissolved in pyrovinic acid, under stirring
Back flow reaction terminates to TLC tracking reactions；By reactant liquor dilute with water, it is extracted with ethyl acetate, organic layer mass percent
Concentration is 5% NaHCO3Washing, then washed with saturation NaCl solution, anhydrous MgSO4It is dried, filters, filtrate rotary evaporation, then Jing
Purify to obtain yellow solid, as 4,4,5,7- tetramethyl -3,4- dihydrocoumarin, its structural formula is：；
B., under inert atmosphere protection, by obtained by step a 4,4,5,7- tetramethyl -3,4- dihydrocoumarin is anhydrous in lithium aluminium hydride reduction
Under conditions of tetrahydrofuran makees solvent, 3- is reduced into（2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl）- 3,3- dimethyl propanol,
Its structural formula is：；
C. under an inert atmosphere, by 3- obtained by step b（2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl）- 3,3- dimethyl propanol and guarantor
Shield reagent tert-butyl chloro-silicane presses 1:1.1～1:1.5 mol ratio is dissolved in dichloromethane, in the work of acid binding agent triethylamine
With under, stirring reaction terminates to TLC tracking reactions；Reacting liquid filtering, after filtrate is spin-dried for, is dissolved with dichloromethane, and water washing has
Machine mutually uses anhydrous MgSO4It is dried, filters, filtrate rotary evaporation, separated purification obtains 1-O- t-Butyldimethylsilyl -3-
(2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- dimethyl propanol, its structural formula is：；
D. by 1-O- t-Butyldimethylsilyls -3- obtained by step c (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- dimethyl
Propanol and potassium tert-butoxide press 1:1.1～1:1.5 mol ratio is dissolved in tetrahydrofuran, is back to reactant liquor and is changed into yellow from blueness
Color；Four benzyl ester of pyrophosphoric acid is added, is continued to be stirred at reflux to react to TLC tracking reactions and is terminated；Petroleum ether is added after being cooled to room temperature,
Filter, filtrate removes solvent, separated purification obtains 1-O- t-Butyldimethylsilyl -3- [2 '-oxos（Dibenzyl phosphate
Base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- dimethyl propanol, its structural formula is：；It is described
Four benzyl ester of pyrophosphoric acid and 1-O- t-Butyldimethylsilyl -3- (2 '-hydroxyl -4 ', 6 ' -3,5-dimethylphenyl) -3,3- dimethyl
The mol ratio of propanol is：1:1.1～1:1.5；
E. in ice-water bath, by 1-O- t-Butyldimethylsilyls -3- obtained by step d (2 '-hydroxyl -4 ', 6 '-dimethyl benzene
Base) -3,3- dimethyl propanol and potassium fluoride press 1:4～1:7 mol ratio is dissolved in acetone, is being slowly added dropwise catalyst amount
Jones reagents, continue stirring reaction and terminate to TLC tracking reactions；To in reactant liquor Deca isopropanol to reactant liquor by yellow green
Become native green, it is in aeruginouss to continue stirring to reactant liquor；Remove solvent and obtain dark green solid, dissolved with ethyl acetate, washing,
It is extracted with ethyl acetate, organic faciess saturation NaCl solution is washed, is dried, filter, removes solvent, then purified white solid,
As 3- [2 '-oxos（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- neopentanoic acids, its structural formula is：；
F. by 3- [2 '-oxos obtained by step e（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- dimethyl propylenes
Acid and thionyl chloride press 1:2～1:5 mol ratio is dissolved in tetrahydrofuran solvent, and back flow reaction 4 as a child, removes solvent and mistake
The thionyl chloride of amount, subsequently adds the remaining thing of anhydrous tetrahydro furan dissolving reaction again, adds cis-1,2-（3, 4, 4,
5- -3 '-amino of tetramethoxy）Stilbene, room temperature reaction are complete to TLC tracking reactions, it is separated after purification, obtain Kao Buta
Spit of fland analog amidatioon prodrug, its structural formula is：；Described 3-
[2 '-oxo（Dibenzyl phosphoric acid base）- 4 ', 6 ' -3,5-dimethylphenyl] -3,3- neopentanoic acids and cis-1,2-（3, 4,
4,5- -3 '-amino of tetramethoxy）The mol ratio of stilbene is：1:0.5～1:1；
G. combretastatin analog amidatioon prodrug obtained by step f is dissolved in acetonitrile, under the conditions of ice-water bath, Deca front three
Bromide silane, continues stirring reaction and reacts complete to TLC tracking, add the methanol solution of Feldalat NM, and reaction is stirred at room temperature to be had
White precipitate is generated；A large amount of acetone solns are added to be stirred overnight, sucking filtration obtains white powder solid, as combretastatin analog
Before water solublity-prodrug, its structural formula is：。
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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 |
| WO2002006279A1 (en) * | 2000-07-17 | 2002-01-24 | Oxigene Inc | Efficient method of synthesizing combretastatin a-4 prodrugs |
| CN101220054A (en) * | 2008-01-29 | 2008-07-16 | 成都恒基医药科技有限公司 | Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt |
| CN102015620A (en) * | 2008-02-28 | 2011-04-13 | 赛诺菲-安万特 | Method for preparing combretastatin |
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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 |
| WO2002006279A1 (en) * | 2000-07-17 | 2002-01-24 | Oxigene Inc | Efficient method of synthesizing combretastatin a-4 prodrugs |
| CN101220054A (en) * | 2008-01-29 | 2008-07-16 | 成都恒基医药科技有限公司 | Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt |
| CN102015620A (en) * | 2008-02-28 | 2011-04-13 | 赛诺菲-安万特 | Method for preparing combretastatin |
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