CN104892668A - Combretastatin A-4 analogue water soluble pro-prodrug, and preparation method thereof - Google Patents
Combretastatin A-4 analogue water soluble pro-prodrug, and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a combretastatin A-4 analogue pro-prodrug, and a preparation method thereof. The structure formula of the combretastatin A-4 analogue pro-prodrug is represented by a formula in the invention; and the combretastatin A-4 analogue pro-prodrug with improved transporting performance can be used for preparing a prodrug which possesses excellent transporting performance in vivo and is capable of reaching action target positions effectively.
Description
Technical field
Before the present invention relates to a kind of water miscible combretastatin analogue (Combretastatin A-4 analogue)-prodrug and preparation method thereof.
Background technology
Combretastatin analogue is that small molecule tumor vascular targeting blocks reagent (Vascular Disrupting Agents, VDA).It can demonstrate selectively targeted for tumor vessel and block the tumor vessel destroying and generated, and makes tumour can not get oxygen and nutrition, until tumour " is died of hunger ".Therefore, for the cancer cells at the tumour core position that existing chemotherapy and radiation can not kill easily, combretastatin analogue can thoroughly kill from inside to outside (
british Journal of Cancer 110, 2170-2177 (29 April 2014)).
Combretastatin analogue is a class cis stilbene aryl amine derivatives.Because it is water-soluble very low, limit clinical application.At present, combretastatin analogue Serine hydrochloride (AVE8062) water-soluble prodrug by Sai Nuo fly-Aventis Pharmaceutical Company research and develop enter II phase clinical study.But still there is stability to hydrolysis difference, phoresy the problems such as character is bad, and toxicity is larger in body.（Lancet Oncol. 2015 Apr 8.）
Prodrug (prodrug) design has become one of effective means important in medicinal design field.Have many patent applications about prodrug concept and application and obtain power.But such prodrug usually exists some problems, as the prodrug designed according to specificity target position decomposing machine system (as enzymic activity), often lost efficacy because not reaching target position tissue; For improving water-soluble and injection prodrug that is that design, can be unstable because of it, easily decompose in the solution and can not apply.Overcome the above-mentioned shortcoming of prodrug; improve the character of prodrug; it seems that more promising method adopts series connection latentiation (Cascade Latentiation) method at present, i.e. the two prodrug (Double prodrug) of design or front-prodrug (Pro-prodrug) (Bundgaard H. The double prodrug concept and its applications. Adv Drug Delivery Rev 1999; 3:39).Such as: by the prodrug in specific site cracking, further latentiation, improves it and phoresys performance, makes to have in vivo and well phoresys character, effectively can arrive the prodrug of the prodrug of target site.For another example: adopt series connection latentiation, make prodrug have comparatively ideal character, namely there is external enough stability and the high susceptibility of internal regeneration parent drug simultaneously.General thinking makes external sufficiently stable pair of prodrug first become prodrug through enzymolysis in vivo, then decomposes through enzyme or non-enzymatic and discharge parent drug rapidly, thus play drug effect.Further study discovery: two prodrug or front-prodrug first generate prodrug through enzymolysis in vivo, then can discharge parent drug rapidly through the chemical action of enzyme or non-enzymatic, play drug effect.Early-stage Study shows, compound 3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl) amide form thereof of-3,3-neopentanoic acids has rapid reaction activity under pH value environment in human body, can meet the requirement of two prodrug design.Research (the J. Am. Chem. Soc. of Milstien and Cohen group
1972, 94 (26), 9158-9165) and research (the J. Am. Chem. Soc. of Caswell and Schmir group
1980, 102 (14), 4815-4821) all show 3,3 methyl gone up on dimethyl and 6 ' position form a what is called " trimethylammonium lock " effect, make its molecule have quick lactonization.Just because of this characteristic, it can well be used for designing the prodrug of aminated compounds.
Summary of the invention
Before an object of the present invention is to provide a kind of combretastatin analogue-prodrug.
Before two of object of the present invention is to provide this-preparation method of prodrug.
Utilization " sodium phosphate salt " water-soluble prodrug of the invention and the theory of " ' the trimethylammonium lock effect ' of hydroxy-amide compounds; improve in body and phoresy performance ", before design and synthesis combretastatin analogue-and prodrug, first construct the compound with " trimethylammonium lock effect "
2c.the back flow reaction in methylsulphonic acid solution with MX and senecioic acid methyl esters, obtain 4,4,5,7-tetramethyl--3,4-melilotine (
2a).Subsequently
2amake reductive agent at lithium aluminum hydride, under anhydrous tetrahydro furan makes the condition of solvent, be reduced into 3-(2 ' – hydroxyl-4 ', 6 ' – 3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol (
2b).Compound
2bbe dissolved in methylene dichloride, add protection reagent TERT-BUTYL DIMETHYL CHLORO SILANE, under the effect of acid binding agent triethylamine; room temperature reaction 24 hours; obtain 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol (
2c).Then implement Phosphation, form water-soluble phosphorus acid disodium salt prodrug.Compound
2cbe dissolved in anhydrous tetrahydro furan, under potassium tert.-butoxide and the effect of tetra-sodium four benzyl ester, 60 DEG C reaction 1 hour, obtain 1-O-t-Butyldimethylsilyl-3-[2 '-oxo (dibenzyl phosphoric acid ester group)-4 ', 6 '-3,5-dimethylphenyl]-3,3-dimethyl propyl alcohol (
2d), compound
2ddissolve in acetone, after adding Potassium monofluoride, instillation brand-new Jones reagent, after reaction 3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3,3-neopentanoic acids (
2e).In tetrahydrofuran solvent, compound
2eunder agitation dissolve, add new thionyl chloride of steaming again, reflux 4 as a child, removal of solvent under reduced pressure and excessive thionyl chloride, again add the remaining thing of anhydrous tetrahydro furan solubilizing reaction subsequently, add cis-1,2-(3,4,4 ', 5-tetramethoxy-3 ’ – is amino) toluylene (combretastatin analogue; Combretastatin A-4 analogue), room temperature reaction spends the night, after column chromatographic isolation and purification, obtain combretastatin analogue amidation prodrug (
2f).Combretastatin analogue amidation prodrug (
2f) be dissolved in dry acetonitrile, under ice-water bath condition, drip bromotrimethylsilane, after reacting completely with thin plate chromatography (TCL) tracking, add sodium methylate/methanol solution, under stirring at room temperature, when occurring precipitating in a large number, add acetone, stir spend the night to precipitation completely, obtain combretastatin analogue water-soluble before-prodrug
2g,the synthetic route of the method is:
For achieving the above object, the present invention adopts following technical scheme:
Combretastatin analogue water-soluble before-prodrug, it is characterized in that its structural formula is as follows:
。
Prepare above-mentioned combretastatin analogue water-soluble before-method of prodrug, it is characterized in that the concrete steps of the method are:
A. MX and senecioic acid methyl esters are dissolved in methylsulphonic acid by the mol ratio of 1:1.1 ~ 1:1.5, stir lower back flow reaction and follow the tracks of reaction end to TLC; By reaction solution dilute with water, be extracted with ethyl acetate, organic layer mass percent concentration is the NaHCO of 5%
3washing, then wash by saturated NaCl solution, anhydrous MgSO
4drying, filter, filtrate rotary evaporation, then through yellow solid of purifying to obtain, be 4,4,5,7-tetramethyl--3,4-melilotine, its structural formula is:
;
B. under inert atmosphere protection, by step a gained 4,4,5; 7-tetramethyl--3,4-melilotine makes the condition of solvent at lithium aluminum hydride anhydrous tetrahydro furan under, be reduced into 3-(2 ’ – hydroxyl-4 '; 6 ' – 3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol, its structural formula is:
;
C. under an inert atmosphere, by step b gained 3-(2 ’ – hydroxyl-4 ', 6 ’ – 3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol and protection reagent TERT-BUTYL DIMETHYL CHLORO SILANE are dissolved in methylene dichloride by the mol ratio of 1:1.1 ~ 1:1.5, under the effect of acid binding agent triethylamine, stirring reaction is followed the tracks of reaction to TLC and is terminated; Reacting liquid filtering, after filtrate is spin-dried for, dissolves with methylene dichloride, water washing, the anhydrous MgSO of organic phase
4drying, filters, filtrate rotary evaporation, and obtain 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol through separating-purifying, its structural formula is:
;
D. by step c gained 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol and potassium tert.-butoxide are dissolved in tetrahydrofuran (THF) by the mol ratio of 1:1.1 ~ 1:1.5, are back to reaction solution and become yellow from blueness; Add tetra-sodium four benzyl ester again, continue stirring and refluxing reaction and follow the tracks of reaction end to TLC; Add sherwood oil after being chilled to room temperature, filter, filtrate removes solvent, and obtain 1-O-t-Butyldimethylsilyl-3-[2 '-oxo (dibenzyl phosphoric acid ester group)-4 ', 6 '-3,5-dimethylphenyl]-3,3-dimethyl propyl alcohol through separating-purifying, its structural formula is:
; The mol ratio of described tetra-sodium four benzyl ester and 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol is: 1:1.1 ~ 1:1.5;
E. in ice-water bath, by steps d gained 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol and Potassium monofluoride are dissolved in acetone by the mol ratio of 1:4 ~ 1:7, slowly dripping the Jones reagent of catalyst levels, continuing stirring reaction and terminate to TLC tracking reaction; In reaction solution, drip Virahol become soil green to reaction solution by yellow-green colour, continuing to be stirred to reaction solution is blue-greenish colour; Except desolventizing obtains dark green solid, with acetic acid ethyl dissolution, washing, be extracted with ethyl acetate, the saturated NaCl solution of organic phase is washed, dry, filters, remove solvent, again through white solid of purifying to obtain, be 3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3,3-neopentanoic acid, its structural formula is:
;
F. by step e gained 3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3, 3-neopentanoic acid and thionyl chloride are dissolved in tetrahydrofuran solvent by the mol ratio of 1:2 ~ 1:5, back flow reaction 4 as a child, except desolventizing and excessive thionyl chloride, again add the remaining thing of anhydrous tetrahydro furan solubilizing reaction subsequently, add cis-1 again, 2-(3, 4, 4, 5-tetramethoxy-3 ’ – is amino) toluylene, room temperature reaction is followed the tracks of to TLC and is reacted completely, after separation and purification, obtain combretastatin analogue amidation 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-tetramethoxy-3 ’ – is amino) mol ratio of toluylene is: 1:0.5 ~ 1:1,
G. step f gained combretastatin analogue amidation prodrug is dissolved in acetonitrile, under ice-water bath condition, drip bromotrimethylsilane, continue stirring reaction and react completely to TLC tracking, add the methanol solution of sodium methylate again, stirring at room temperature reaction adularescent precipitation generates; Add a large amount of acetone soln stir spend the night, suction filtration obtains white powder solid, be combretastatin analogue water-soluble before-prodrug, its structural formula is:.
Combretastatin analogue involved in the present invention water-soluble before-prodrug is a kind of control release type prodrug of novelty.Tested by acute toxinology experiment codes and standards by new drug Research on Safety Assessment center, national Shanghai.The acute toxicity test in mice data display of the analogue viagra of this tested material, when dosage reaches 1000 mg/kg, animal occurs dead.Therefore this Preliminary Experiment to draft dosage be 300,500,1000 mg/kg, and the 4th day after administration increases by 2000 mg/kg dosage groups, observes toxic reaction and the death condition of animal after single-dose.Its acute toxinology experiment display MTD is 2000mg/kg.
The present invention, by tetra-sodium four benzyl ester, makes phenolic hydroxyl group Phosphation, forms sodium phosphate salt water-soluble prodrug.With 3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-neopentanoic acids, construct " trimethylammonium lock " effect, before formation-prodrug, promptly esterification Targeting delivery parent drug in vivo.Before this-and prodrug improves it and phoresys performance, has in vivo well to phoresy character, effectively can reach target site, and its release parent drug process is shown below:
。
Embodiment
Below each embodiment be combretastatin analogue water-soluble before-preparation method of prodrug, they are only for illustration of the present invention, not limitation of the invention.
embodiment one:preparation 4,4,5,7-tetramethyl--3,4-melilotine (
2a)
Take MX (5.002 g 41 mmol) to add in the 50 ml eggplant-shape bottles that 5 ml methylsulphonic acid solution are housed, add senecioic acid methyl esters (5.161 g 45.2 mmol) under stirring again, adding rear solution is sorrel.Eggplant-shape bottle installs spherical condensation tube, drying tube successively, and oil bath is heated to 80 DEG C of magnetic agitation, condensing reflux, and TLC follows the tracks of (sherwood oil: ethyl acetate=1 ﹕ 1), and reaction terminates (about 12 hours).Reaction solution is added 800 ml water dilutions, be extracted with ethyl acetate (200 ml × 2), merge organic layer, 5% NaHCO
3washing (200 ml × 3), then wash by the saturated NaCl solution of 100 ml, anhydrous MgSO
4drying, filter, filtrate rotary evaporation obtains yellow solid, uses ethyl acetate-light petrol recrystallization, filters to obtain white crystalline solid, vacuum-drying (40 DEG C), and weigh to obtain 7.344 g, productive rate: 87.8%; Mp 89-90 DEG C;
Compound
2a:
1h NMR (500 MHz, CDCl
3) 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 propyl alcohol (2b)
Take LAH(1 equiv 0.951 g) to be dissolved in 40 ml and newly to steam tetrahydrofuran solution in 100 ml there-necked flasks, under ice bath, stir gray suspension, then Weigh Compound
2a(5.109 g 25 mmol) is dissolved in 18 ml and newly steams tetrahydrofuran solution, slowly instills in the tetrahydrofuran solution of above-mentioned LAH, have gas to generate under argon shield.Drip and finish, be naturally warming up to room temperature, stirring reaction 1 hour, TLC follows the tracks of reaction and terminates (sherwood oil: ethyl acetate=2 ﹕ 1).Slowly saturated NH is dripped in above-mentioned reaction solution
4cl solution is quenched to no longer bubbling, and solution becomes white suspension liquid.Filter (adding one deck diatomite drainage, absorption), filtrate adds 100 ml water mixing, with extracted with diethyl ether (50 ml × 3), merges organic phase, anhydrous MgSO
4drying, filter, filtrate rotary evaporation desolventizes to obtain colorless viscous liquid, and with ethyl acetate-normal hexane recrystallization, filter to obtain white bright crystalline solid, vacuum-drying (40 DEG C), weigh to obtain 4.655 g, productive rate: 89.4%; Mp 112-114 DEG C;
Compound
2b:
1h NMR (500 MHz, CDCl
3) 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 propyl alcohol (
2c)
Weigh Compound 2b(1.165 g 6.5 mmol) in 100 ml there-necked flasks, then add TERT-BUTYL DIMETHYL CHLORO SILANE (0.932 g 7.15 mmol), be dissolved in 20 ml methylene dichloride under argon shield, ice bath, stir about 10 minutes.Drip dichloromethane solution 6 ml of triethylamine (3.4 ml) in there-necked flask by constant pressure funnel, drip fast 1d/(6 ~ 7) S.Dropwise rear removing ice bath, be naturally warming up to room temperature, reaction system is shallow dark brown.Stirring reaction 24 h, reaction solution becomes clarification, and TLC follows the tracks of reaction and terminates (Shi You Mi ﹕ ethyl acetate=1 ﹕ 1), and reaction stops.Reacting liquid filtering, after filtrate is spin-dried for, then adds 25 ml methylene dichloride dissolvings, washes with water (10 ml × 4), merge organic phase, anhydrous MgSO
4drying, filter, filtrate rotary evaporation obtains white solid, with ethyl acetate-normal hexane recrystallization, filters to obtain colorless crystalline solid, vacuum-drying (40 DEG C), and weigh to obtain 2.064 g, productive rate: 98.6%;
Compound
2c:
1h NMR (500 MHz, CDCl
3) 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).
embodiment four:preparation 1-O-t-Butyldimethylsilyl-3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3,3-dimethyl propyl alcohol (
2d)
Weigh Compound
2c(0.252 g 0.78 mmol) is dissolved in 20 ml and newly steams THF solution in 100 ml there-necked flasks, adds potassium tert.-butoxide (0.1 g 0.86 mmol) again under stirring in bottle, and solution is in blue.Oil bath is heated to 60 DEG C, and the solution after about 5 minutes that refluxes becomes yellow from blueness.Add tetra-sodium four benzyl ester (0.463 g 0.86 mmol) while hot, continue to stir, have milky white precipitate to generate.Continue reaction 1 hour under reflux, TLC follows the tracks of reaction and terminates (Shi You Mi ﹕ ethyl acetate=3 ﹕ 2), and reaction stops heating, add 30 ml sherwood oils after being chilled to room temperature, filter, removing insolubles, filtrate is light yellow clear liquid, and decompression desolventizes, and obtains a yellow oil.Column chromatography for separation is purified (eluent: Yi Suan Yi Zhi ﹕ sherwood oil=1 ﹕ 3), and revolve steaming and desolventize, obtain light yellow look oily matter, vacuum-drying (40 DEG C), weigh to obtain 0.394g, productive rate: 87.2%.
Compound
2d:
1h NMR (500 MHz, CDCl
3) 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: preparation 3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3,3-neopentanoic acids (2e)
Weigh Compound 2d(0.394 g 0.68 mmol) be dissolved in 5 ml acetone in 25 ml there-necked flasks, ice bath, then add Potassium monofluoride (0.040 g 2.72 mmol) in bottle, stir 5 minutes.Dropping funnel slowly drips 0.6 ml brand-new Jones reagent in reaction flask, and solution is that brown generates with precipitation, continues stirring reaction 2 hours, and TLC follows the tracks of reaction and terminates (Shi You Mi ﹕ ethyl acetate=3 ﹕ 2).In reaction flask, drip Virahol 2.7 ml, it is green that solution becomes soil by yellow-green colour, and continue stirring 20 minutes, solution is blue-greenish colour.Reaction solution is transferred to 50 ml single port bottles, rotary evaporation removes desolventizing and obtains dark green solid.By dark green solid 12 ml acetic acid ethyl dissolutions, 15 ml H
2o washes, and is separated organic phase.Aqueous phase is extracted with ethyl acetate (10 ml × 3), merges organic phase.Saturated NaCl solution is washed (10 ml × 2), anhydrous MgSO
4drying, filter, filtrate rotary evaporation desolventizes to obtain yellow-green colour oily matter, with ether-normal hexane recrystallization, filters to obtain white solid, vacuum-drying (40 DEG C), and weigh to obtain 0.247 g, productive rate: 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 combretastatin analogue and
2eamidated products (
2f)
Weigh Compound
2e(0.531 g 1.1 mmol), in 50 ml eggplant type bottles, adds 40 ml and newly steams THF, stirring and dissolving, then add SOCl
2(0.17 ml; 2.3 mmol), install the spherical condensation tube with drying tube, heating reflux reaction 4 hours.Reaction terminates rear stopping heating, removes solvent and unnecessary SOCl after slightly cold under reduced pressure
2, obtain a light yellow oil.Oily matter is dissolved in 40 ml and newly steams THF, add combretastatin analogue (0.182 g 0.55 mmol) under stirring, stirring at room temperature reaction is spent the night, and TLC follows the tracks of and reacts completely.Decompression desolventizes, and oily matter column chromatography for separation is collected product point, revolves steaming and desolventize to obtain dark brown oily matter 0.402 g, productive rate 90%.
Compound
2f:
1h NMR (500 MHz, CDCl
3) 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:prepare combretastatin analogue water-soluble before-prodrug (2g)
Weigh Compound
2f(1.427g 1.8mmol), in 50ml round-bottomed flask, adds dry acetonitrile 9ml, stirring and dissolving under ice bath.Constant pressure funnel drips bromotrimethylsilane (0.6ml 4.5mmol), solution becomes purple from colourless, continue to stir, solution colour shoals gradually, TLC follows the tracks of reaction, add sodium methylate (195mg 3.6mmol) and methanol solution 18ml after reacting completely, stirring at room temperature, adularescent precipitation generates.Add the stirring of a large amount of acetone soln to spend the night, suction filtration obtains white powder solid, vacuum-drying (40 DEG C), and weigh to obtain 0.8972 g, productive rate: 75.8%;
Compound
2g:
1h NMR (500 MHz, D
2o) 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 (2)
1. combretastatin analogue water-soluble before-prodrug, it is characterized in that its structural formula is as follows:
。
2. prepare combretastatin analogue according to claim 1 water-soluble before-method of prodrug, it is characterized in that the concrete steps of the method are:
A. MX and senecioic acid methyl esters are dissolved in methylsulphonic acid by the mol ratio of 1:1.1 ~ 1:1.5, stir lower back flow reaction and follow the tracks of reaction end to TLC; By reaction solution dilute with water, be extracted with ethyl acetate, organic layer mass percent concentration is the NaHCO of 5%
3washing, then wash by saturated NaCl solution, anhydrous MgSO
4drying, filter, filtrate rotary evaporation, then through yellow solid of purifying to obtain, be 4,4,5,7-tetramethyl--3,4-melilotine, its structural formula is:
;
B. under inert atmosphere protection, by step a gained 4,4,5; 7-tetramethyl--3,4-melilotine makes the condition of solvent at lithium aluminum hydride anhydrous tetrahydro furan under, be reduced into 3-(2 ’ – hydroxyl-4 '; 6 ' – 3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol, its structural formula is:
;
C. under an inert atmosphere, by step b gained 3-(2 ’ – hydroxyl-4 ', 6 ’ – 3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol and protection reagent TERT-BUTYL DIMETHYL CHLORO SILANE are dissolved in methylene dichloride by the mol ratio of 1:1.1 ~ 1:1.5, under the effect of acid binding agent triethylamine, stirring reaction is followed the tracks of reaction to TLC and is terminated; Reacting liquid filtering, after filtrate is spin-dried for, dissolves with methylene dichloride, water washing, the anhydrous MgSO of organic phase
4drying, filters, filtrate rotary evaporation, and obtain 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol through separating-purifying, its structural formula is:
;
D. by step c gained 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol and potassium tert.-butoxide are dissolved in tetrahydrofuran (THF) by the mol ratio of 1:1.1 ~ 1:1.5, are back to reaction solution and become yellow from blueness; Add tetra-sodium four benzyl ester again, continue stirring and refluxing reaction and follow the tracks of reaction end to TLC; Add sherwood oil after being chilled to room temperature, filter, filtrate removes solvent, and obtain 1-O-t-Butyldimethylsilyl-3-[2 '-oxo (dibenzyl phosphoric acid ester group)-4 ', 6 '-3,5-dimethylphenyl]-3,3-dimethyl propyl alcohol through separating-purifying, its structural formula is:
; The mol ratio of described tetra-sodium four benzyl ester and 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol is: 1:1.1 ~ 1:1.5;
E. in ice-water bath, by steps d gained 1-O-t-Butyldimethylsilyl-3-(2 '-hydroxyl-4 ', 6 '-3,5-dimethylphenyl)-3,3-dimethyl propyl alcohol and Potassium monofluoride are dissolved in acetone by the mol ratio of 1:4 ~ 1:7, slowly dripping the Jones reagent of catalyst levels, continuing stirring reaction and terminate to TLC tracking reaction; In reaction solution, drip Virahol become soil green to reaction solution by yellow-green colour, continuing to be stirred to reaction solution is blue-greenish colour; Except desolventizing obtains dark green solid, with acetic acid ethyl dissolution, washing, be extracted with ethyl acetate, the saturated NaCl solution of organic phase is washed, dry, filters, remove solvent, again through white solid of purifying to obtain, be 3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3,3-neopentanoic acid, its structural formula is:
;
F. by step e gained 3-[2 '-oxo (dibenzyl phosphoric acid base)-4 ', 6 '-3,5-dimethylphenyl]-3, 3-neopentanoic acid and thionyl chloride are dissolved in tetrahydrofuran solvent by the mol ratio of 1:2 ~ 1:5, back flow reaction 4 as a child, except desolventizing and excessive thionyl chloride, again add the remaining thing of anhydrous tetrahydro furan solubilizing reaction subsequently, add cis-1 again, 2-(3, 4, 4, 5-tetramethoxy-3 ’ – is amino) toluylene, room temperature reaction is followed the tracks of to TLC and is reacted completely, after separation and purification, obtain combretastatin analogue amidation 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-tetramethoxy-3 ’ – is amino) mol ratio of toluylene is: 1:0.5 ~ 1:1,
G. step f gained combretastatin analogue amidation prodrug is dissolved in acetonitrile, under ice-water bath condition, drip bromotrimethylsilane, continue stirring reaction and react completely to TLC tracking, add the methanol solution of sodium methylate again, stirring at room temperature reaction adularescent precipitation generates; Add a large amount of acetone soln stir spend the night, suction filtration obtains white powder solid, be combretastatin analogue water-soluble before-prodrug, its structural formula is:
.
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| CN108607605A (en) * | 2018-06-11 | 2018-10-02 | 徐州得铸生物科技有限公司 | A kind of catalyst for synthesizing senecioic acid methyl esters |
| CN112898128A (en) * | 2021-02-08 | 2021-06-04 | 苏州华道生物药业股份有限公司 | Method for synthesizing 3-ethyl-4-methylpentanol as pheromone component of limonum aureum |
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| CN108607605A (en) * | 2018-06-11 | 2018-10-02 | 徐州得铸生物科技有限公司 | A kind of catalyst for synthesizing senecioic acid methyl esters |
| CN112898128A (en) * | 2021-02-08 | 2021-06-04 | 苏州华道生物药业股份有限公司 | Method for synthesizing 3-ethyl-4-methylpentanol as pheromone component of limonum aureum |
| CN112898128B (en) * | 2021-02-08 | 2023-07-07 | 苏州华道生物药业股份有限公司 | Synthesis method of russula rupestris ant pheromone component 3-ethyl-4-methylpentanol |
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