CN101885738B - Method for synthesizing CA4P - Google Patents

Method for synthesizing CA4P Download PDF

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Publication number
CN101885738B
CN101885738B CN200910051154.2A CN200910051154A CN101885738B CN 101885738 B CN101885738 B CN 101885738B CN 200910051154 A CN200910051154 A CN 200910051154A CN 101885738 B CN101885738 B CN 101885738B
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ca4p
ether
solvent
trityloxy
reaction
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CN101885738A (en
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吴范宏
肖繁花
周卫国
徐方明
熊杨
苏敏
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Nanjing Zhuotai Pharmaceutical Co ltd
Shanghai Huali Biomedical Co ltd
Zhejiang Wild Wind Pharmaceutical Co Ltd
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ZHEJIANG WILDWIND PHARMACEUTICAL CO Ltd
SHANGHAI HUALI BIOPHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/14—Styryl dyes
    • C09B23/148—Stilbene dyes containing the moiety -C6H5-CH=CH-C6H5

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of chemical synthesis and relates to a method for preparing CA4P, in particular to a method for synthesizing CA4P by the following steps that: isovanillin and trityl chloride, which serve as raw materials, are used to form 3- triphenylmethoxy-4-methoxybenzaldehyde which is an intermediate isovanillin protector; the 3- triphenylmethoxy-4-methoxybenzaldehyde and 3,4,5-trimethoxy-triphenyl benzylidene bromide phosphine salt undergo a Wittig reaction , and the protective group is removed by hydrolysis to obtain CA4; and the CA4 and phosphonic acid bis(phenylmethyl)ester react to form benzyl phosphate, and the benzyl group is removed to form a sodium salt to obtain the target compound, namely CA4P.

Description

A kind of method of synthesizing CA 4 P
Technical field
The present invention relates to a kind of preparation method of CA 4 P (CA4P), belong to chemical industry synthesis field.Particularly to relate to isovanillin and trityl chloride for raw material, obtain intermediate isovanillin protective 3-trityloxy-4-methoxybenzaldehyde; 3-trityloxy-4-methoxybenzaldehyde and 3,4,5-trimethoxy benzyl bromine triphenylphosphine salt obtain CA4 through Wittig reaction, hydrolysis Deprotection; Become benzyl phosphate ester through CA4 with dibenzyl phosphite, debenzylation becomes sodium salt to obtain the synthetic method of target compound CA 4 P.
Background technology
The new antitumoral prodrug that CA 4 P (CA4P) is developed by OXIGENE company of the U.S., its former medicine is CA4 (Combretastatin A4), is to be separated a kind of polyhydroxystilbene natural product obtained from the bark of African shrub Combretum Caffrum.CA4P is tubulin binding agent, the mitotic division process of tumor vascular endothelial cell can be disturbed, there is very strong anti-angiogenic effect, anticancer increases, suppress tubulin to be assembled and chemicotherapy sensitization, CA4P also has the good pharmacokinetic property of applicable clinical application because of its precursor design and presents targeting to knurl body, CA4P all shows activity in vivo to all cancer models, be described as blood-vessels target agent (Vascular Targeti-ng Agent, VTA) outstanding person in is the VTA that in global range, first enters clinical study.
The synthetic route of CA 4 P is divided into two to walk greatly.The first step is the former medicine CA4 of synthesis; Second step synthesizes prodrug CA4P by CA4 again.
Synthesis about CA4 mainly contains following three kinds of methods: Perkin method, Suzuki reaction method, Wittig reaction method.Document WO0249994 reports Perkin method, and adopt 3,4,5-trimethoxy phenyl acetic acid and Isovanillin to be raw material preparation, this method Problems existing is, Penkin reacts the ratio that a step does not provide high cis-trans-isomer; Final step decarboxylic reaction temperature is higher, needs more than 230 DEG C, is not suitable for suitability for industrialized production; The side reactions such as the double bond in addition in CA4 is easy to be oxidized 200 DEG C of temperature, be polymerized, isomerization, so this route is not desirable route.ZL200410051498 reports the modification method of Perkin reaction, just raw material is changed into 3,4,5-Trimethoxybenzaldehyde and homoanisic acid, but can not solve root problem.Document J.Org.Chem., 2001,66:8135 report Suzuki reaction method, and desired raw material 3,4,5-trimethoxy phenylo boric acid is expensive.Document Synthesis, 1999:1656-1660 report the modification method of Suzuki, and 3,4,5-Trimethoxybenzaldehyde is obtained 3,4,5-trimethoxy phenylacetylene through two-step reaction, then reduce obtain CA4 with 4-iodo-2-anisole naphtholic coupler, borane reagent.This method overcomes the cis-trans isomerization of double bond in Wittig reaction, but needs the cold condition of-78 DEG C, and preparation process needs to use expensive organic palladium reagent Pd (PPh 3) 4, be unsuitable for suitability for industrialized production.
Wittig method is the isovanillin and 3 of hydroxyl protection; 4,5-trimethoxy benzyl bromine triphenylphosphine salt obtains CA4,3 by Wittig reaction, Deprotection; 4; 5-trimethoxy benzyl bromine triphenylphosphine salt with 3,4,5-trimethoxybenzyl alcohol for raw material; through bromo, become phosphonium salt synthesis; this method technological operation is simple, and most of raw material is easy to get, and the product configuration obtained is mainly Z (ratio of Z/E is 3.6: 1).Document Chinese Journal of Pharmaceuticals; 2001; 32:531-532 and document J.Med.Chem., 1995,38:1666-1672 report isovanillin TERT-BUTYL DIMETHYL CHLORO SILANE and protect; although this method total recovery is very high; but product configuration is mainly E, the ratio of Z/E is only 1: 1.5, is separated and needs silicagel column; and deprotecting regent is expensive, be not suitable for suitability for industrialized production.Document ZL200410042580 reports the polymer supported synthetic method of CA4, is protected by the 3-position of polymer supported synthesis isovanillin, and the immobilized resin price used by it is expensive, and domestic supply is very limited, limits the industrialization of the method.
CA4P is the organic phosphate disodium salt of CA4.Synthesize CA4P phosphoric acid ester double sodium salt by CA4, different synthetic routes, mainly adopts different phosphate reagent.CN1465580 reports phosphorus oxychloride method, and after phosphorus oxychloride direct reaction, because CA4P is very easily water-soluble, last CA4P and inorganic salt are difficult to be separated, and cause production quality control difficulty.WO0206279 reports chloro two-(2,2,2-trichloroethyl) phosphonate methods, with chloro two-(2,2,2-trichloroethyl) phosphonic acid ester and CA4 reaction, subsequently with zinc and acetic acid reduction, then obtain product with sodium bicarbonate or sodium hydroxide salify.Raw material is more expensive, and condition is harsh, needs could wait until CA4P sodium salt through twice resins exchange, in operation and industrialization, there is significant limitation.Separating-purifying operation is complicated, yield is low, is not suitable for scale operation, cannot meet the needs of clinical trial.Chinese Journal of Pharmaceuticals, 2001,32:531-532 gives N, the method for N-diethyl amido-di-t-butyl phosphonic acid ester, and method reagent price is higher, cost is too high.
Summary of the invention
The object of the invention is to overcome above-mentioned weak point, a kind of preparation method being suitable for preparation of industrialization CA 4 P is provided.
To relate to isovanillin and trityl chloride for raw material, obtain intermediate isovanillin protective 3-trityloxy-4-methoxybenzaldehyde; 3-trityloxy-4-methoxybenzaldehyde and 3,4,5-trimethoxy benzyl bromine triphenylphosphine salt (phosphonium salt) obtain CA4 through wittig reaction, hydrolysis deprotection; CA4 warp becomes benzyl phosphate ester with dibenzyl phosphite, debenzylation becomes sodium salt to obtain the synthetic method of target compound CA 4 P.
In the present invention, the preparation of 3-trityloxy-4-methoxybenzaldehyde, adopts the method that isovanillin and triphenylmethyl chloride react under acid binding agent effect.The alkali reacting used is organic amine, and comprising triethylamine, diisopropyl ethyl amine, pyridine etc., also can be mineral alkali, as salt of wormwood, sodium carbonate etc.Solvent used is ethers, as ether, tetrahydrofuran (THF), diisopropyl ether, methyl tertiary butyl ether etc., also can be chlorinated hydrocarbon solvent, as methylene dichloride, chloroform etc.
The preparation of intermediate 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene, adopt 3-trityloxy-4-methoxybenzaldehyde and phosphonium salt under cryogenic, the method for reacting in ether solvent.Temperature of reaction is-5 ~-30 DEG C, and ether solvent is ether, tetrahydrofuran (THF), diisopropyl ether, methyl tertiary butyl ether etc.
The preparation of CA4 adopts the method for 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene Deprotection.Under mineral acid example hydrochloric acid exists, in aromatic hydrocarbons or alcohol organic solvent, reaction is obtained.The concentration of hydrochloric acid is 20 ~ 36%.Organic solvent is benzene, toluene, methyl alcohol, ethanol, n-propyl alcohol, Virahol.
(Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate (benzyl phosphate ester) prepares the method adopting CA4 and dibenzyl phosphite to react, and temperature of reaction is-5 ~-20 DEG C.Benzyl phosphate ester crude product does not need column chromatography to purify, and adopts the method for the mixed solvent recrystallization of alcohols and hydro carbons.Wherein alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, and varsol is sherwood oil, Skellysolve A, normal hexane, hexanaphthene, normal heptane.The ratio of mixed solvent and crude product is 2: 1 ~ 5: 1 (w/v); In mixed solvent, the ratio of alcohols and hydro carbons is 1: 0.5 ~ 1: 5.
CA4P prepares the method adopting benzyl phosphate ester and bromotrimethylsilane to react debenzylation.Temperature of reaction is 20 ~-15 DEG C.The method that CA4P crude product adopts water and acetone mixed solvent to refine is purified.In mixed solvent, the ratio of water and acetone is 1: 3 ~ 1: 8.The consumption of mixed solvent is 10 ~ 60 times (v/w) of CA4P crude product.
The preparation method of CA4P provided by the invention, raw material is cheap and easy to get, reaction conditions is gentle, operation is simple and feasible, yield high cost is low, is suitable for suitability for industrialized production.
The CA4P that the present invention obtains, its physico-chemical property and quality all meet index request.
Synthesis technique is as follows:
Embodiment
Below in conjunction with embodiment, the invention will be further described, but and unrestricted range of application of the present invention.
Embodiment 1:
1.13-trityloxy-4-methoxybenzaldehyde
In 500mL flask, add isovanillin 50g, trityl chloride 104g, triethylamine 65mL, dry tetrahydrofuran 180mL.Be warming up to backflow, react 4 ~ 5 hours.TLC display reaction terminates.In reaction system, add 100mL water stopped reaction, be cooled to 20-25 DEG C.Add ethyl acetate/normal heptane (1: 1) 80mL, have particulate state light yellow solid to generate.Throw out is filtered.Filter cake purified water is washed.Vacuum-drying, obtains 3-trityloxy-4-methoxybenzaldehyde 100g, yield 77%.
1.2 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene
In 500mL four-hole bottle, under argon shield, add bromination trimethoxyphenyl methylene triphenyl phosphorus 65g, anhydrous tetrahydro furan 112mL.Be cooled to-25 DEG C, drip hexane solution (2.4M) 70mL of n-Butyl Lithium to system, drip between process control temp-25 ~-20 DEG C.Drip off rear stirring 1h, drip tetrahydrofuran (THF) (100mL) solution of 3-trityloxy-4-methoxybenzaldehyde (48.8g), drip off rear intensification naturally.After TLC tracking reaction raw materials has reacted.Add saturated aqueous common salt 300mL, branch vibration layer, organic layer saturated common salt water washing, anhydrous magnesium sulfate drying, distillation is except desolventizing.The ethyl acetate that raffinate adds 150mL stirs, and suction filtration obtains white solid, and vacuum-drying obtains 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene 56g, HPLC content 99% (Z/E=87/12), yield 80%.
1.3 3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene
In the there-necked flask of 200mL, added in ethanol 160mL by 55g 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene, add 37% concentrated hydrochloric acid 22mL, 25 DEG C are reacted 3 hours.Filter, filter cake pure water 60mL, sherwood oil 70mL wash, and vacuum-drying obtains product 32.3g.
1.4 (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate
In 500mL four-hole boiling flask, pass into argon gas, add 3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene 20g, dry acetonitrile 150mL, stirring and dissolving.Be cooled to-25 DEG C, add tetracol phenixin 12.7g, diisopropyl ethyl amine 12.3g, 4-dimethylaminopyridine 0.8g successively.Slow dropping dibenzyl phosphite 18.2g, control temperature is below-10 DEG C.Drip and disappear to raw material point with TLC tracking reaction.Add 0.5M potassium primary phosphate 52.5mL stopped reaction.Water layer dichloromethane extraction.The organic layer pure water, the brine It that merge, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure, obtains crude oil 50g.
50g crude oil ethyl acetate/petroleum ether (2: 1) recrystallization.Vacuum-drying obtains product (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate 25g.HPLC content 98.2%, yield 69%.
1.5 (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl Di-Sodium Phosphate (CA4P)
In 1000mL reaction flask, add (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate 90g, anhydrous acetonitrile 450mL, be cooled to 10 DEG C.Instillation bromotrimethylsilane 30mL.Dropwise, it is complete that TLC tracks to display reaction.Add methyl alcohol/sodium methoxide solution 80g (29.8%) at 10 DEG C, suction filtration, vacuum-drying obtain CA4P crude product 96g.
1.6 CA4P's is refining
Primary purification: CA4P crude product 96g is dissolved in 300mL purified water at 25 DEG C, adjusts about pH to 5 with 2% dilute hydrochloric acid.Filter after adding activated carbon decolorizing half an hour, water layer adds acetone 1500mL, filters, vacuum-drying obtains CA4P primary purification product 62g.
Secondary refining: be dissolved in 200mL purified water by CA4P primary purification product 62g, adjusts about pH to 5 with 2% dilute hydrochloric acid, filters.Filtrate adds acetone 920mL, and filtration, vacuum-drying obtain qualified CA4P product 54g.Yield 78.5%.
1H NMR(D 2O)，δ3.72(s，6H)，3.79(s，3H)，3.86(s，6H)，6.72(d，1H)，6.69(d，3H)，6.91(dd，2H)，7.41(s，1H)。
13C NMR(D 2O)，δ58.67，58.74，63.67，109.29，115.25，124.10，125.27，131.37，132.89，133.08，136.59，138.52，145.90，151.90，154.87
31P NMR(D 2O)，δ3.25
IR：980、995、1120、1234、1260、1430、1514、1580、3338cm -1
PH=7.8, moisture 1.8%, HPLC (AUC) 99.54%, content (titration) 99.7%.
Embodiment 2:
2.1 3-trityloxy-4-methoxybenzaldehydes
In 500mL flask, add isovanillin 50g, trityl chloride 104g, triethylamine 65mL, dry methylene chloride 180mL.Be warming up to backflow, TLC follows the tracks of reaction and terminates.In reaction system, add 100mL water stopped reaction, cool to normal temperature 20-25 DEG C.Add ethyl acetate/normal heptane (1: 1) 80mL, have particulate state light yellow solid to generate.Filtered by throw out, filter cake purified water is washed.Vacuum-drying, obtains 3-trityloxy-4-methoxybenzaldehyde 95g, yield 74%.
2.2 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene
In 500mL four-hole bottle, under argon shield, add bromination trimethoxyphenyl methylene triphenyl phosphorus 65g, anhydrous tetrahydro furan 112mL.Be cooled to-15 DEG C, drip hexane solution (2.4M) 70mL of n-Butyl Lithium to system, drip between process control temp-15 ~-10 DEG C.Drip off rear stirring 1 hour, drip tetrahydrofuran (THF) (100mL) solution of 3-trityloxy-4-methoxybenzaldehyde (48.8g), drip off rear intensification naturally.After TLC tracking raw material reaction is complete, add saturated aqueous common salt 150mL, branch vibration layer.Organic layer saturated common salt water washing, anhydrous magnesium sulfate drying, distillation is except desolventizing.The ethyl acetate that raffinate adds 150mL stirs, and suction filtration obtains white solid, and vacuum-drying obtains 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene 50g.HPLC content 99% (Z/E=78/21), yield 71%.
2.3 3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene
In the there-necked flask of 200mL, added in toluene 160mL by 55g 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene, add 37% concentrated hydrochloric acid 22mL, 25 DEG C are reacted 3 hours.Filter, filter cake pure water 60mL, sherwood oil 70mL wash, and vacuum-drying obtains product 22.2g.
2.4 (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate
In 500mL four-hole boiling flask, pass into argon gas, add 3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene 20g, dry acetonitrile 150mL, stirring and dissolving.Be cooled to-15 DEG C, add tetracol phenixin 12.7g, diisopropyl ethyl amine 12.3g, 4-dimethylaminopyridine 0.8g successively.Slow dropping dibenzyl phosphite 18.2g, control temperature is below-10 DEG C.Drip after following the tracks of reaction to raw material point disappearance with TLC, add 0.5M potassium primary phosphate 52.5mL stopped reaction.Water layer dichloromethane extraction.The organic layer pure water, the brine It that merge, anhydrous magnesium sulfate drying, suction filtration, vacuum distillation recovered solvent, evaporate to dryness, obtains crude oil 45g.
Crude oil 45g ethyl acetate/petroleum ether (2: 1) recrystallization.Vacuum-drying obtains product (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate 22g.HPLC content 98%, yield 60.7%.
2.5 (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl Di-Sodium Phosphate (CA4P)
In 1000mL reaction flask, add (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate 90g, anhydrous acetonitrile 450mL.Bromotrimethylsilane 30mL is instilled at 20 DEG C.Dropwise, it is complete that TLC tracks to display reaction.Drip methyl alcohol/sodium methoxide solution 80g (29.8%) at 20 DEG C, suction filtration, vacuum-drying obtain CA4P crude product 75g.
2.6 CA4P's is refining
Primary purification: CA4P crude product 75g is dissolved in 220mL purified water at 25 DEG C, adjusts about pH to 7.8 with 2% dilute hydrochloric acid.Filter after adding activated carbon decolorizing half an hour.Water layer adds acetone 900mL, and filtration, vacuum-drying obtain about CA4P primary purification product 48g.
Secondary refining: be dissolved in 150mL purified water by CA4P primary purification product 48g, adjusts about pH to 7.8 with 2% dilute hydrochloric acid, filters.Filtrate adds acetone 600mL, and filtration, vacuum-drying obtain qualified CA4P product 42g.Yield 61%.
PH 8.1, moisture 2.1%, HPLC (AUC) 99.56%, content (titration) 99.6%.

Claims (15)

1. prepare a method for CA 4 P, it is characterized in that, comprise the following steps:
(A) isovanillin and trityl chloride react under acid binding agent and specific solvent, obtain 3-trityloxy-4-methoxybenzaldehyde; Described acid binding agent is salt of wormwood or sodium carbonate, and described specific solvent is hydrochloric ether;
(B) 3-trityloxy-4-methoxybenzaldehyde and bromination trimethoxyphenyl methylene triphenyl phosphine are under cryogenic, be obtained by reacting intermediate 3 '-trityloxy-3,4,4 ', 5-tetramethoxy toluylene in ether solvent;
(C) 3 '-trityloxy-3,4, in the presence of a mineral acid, in alcohol organic solvent, CA4 is prepared in reaction to 4 ', 5-tetramethoxy toluylene; Described alcohol organic solvent is methyl alcohol, ethanol, n-propyl alcohol or Virahol;
(D) CA4 and dibenzyl phosphite react at a certain temperature, and the mixed solvent recrystallization through alcohols and hydro carbons obtains (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate;
(E) (Z)-5-(3,4,5-trimethoxy styryl)-2-p-methoxy-phenyl dibenzyl phosphate and bromotrimethylsilane react at a certain temperature, prepare CA4P;
(F) CA4P crude product is through the mixed solvent recrystallization of water and acetone, refiningly obtains CA4P sterling; Time refining, adjust ph is 7 ~ 7.8.
2. method according to claim 1, is characterized in that, described ether solvent is ether, tetrahydrofuran (THF), diisopropyl ether, methyl tertiary butyl ether; Described hydrochloric ether is methylene dichloride, chloroform.
3. method according to claim 1, is characterized in that, the cold condition described in step (B) is-5 ~-30 DEG C.
4. method according to claim 1, is characterized in that, the ether solvent described in step (B) is ether, tetrahydrofuran (THF), diisopropyl ether, methyl tertiary butyl ether.
5. the method according to right 1, is characterized in that, the mineral acid described in step (C) is hydrochloric acid.
6. method according to claim 5, is characterized in that, described in step (C), the concentration of hydrochloric acid is 20 ~ 36%.
7. method according to claim 1, is characterized in that, the temperature of reaction described in step (D) is-5 ~-20 DEG C.
8. method according to claim 1, is characterized in that, the alcoholic solvent described in step (D) is methyl alcohol, ethanol, n-propyl alcohol, Virahol.
9. method according to claim 1, is characterized in that, the varsol described in step (D) is sherwood oil, Skellysolve A, normal hexane, hexanaphthene, normal heptane.
10. method according to claim 1, is characterized in that the mixed solvent ratio of alcohols and hydro carbons in step (D) is 1: 0.5 ~ 1: 5.
11. methods according to claim 1, is characterized in that, in step (D), the ratio of mixed solvent and crude product is 2: 1 ~ 5: 1.
12. methods according to claim 1, is characterized in that, in step (E), temperature of reaction is 20 ~-15 DEG C.
13. methods according to claim 1, is characterized in that, in step (F), the ratio of mixed solvent water and acetone is 1: 3 ~ 1: 8.
14. methods according to claim 1, is characterized in that, in step (F), the ratio of water and acetone is 1: 3 ~ 1: 8.
15. methods according to claim 1, is characterized in that, in step (F), the consumption of mixed solvent is 10 ~ 60 times (v/w) of CA4P crude product.
CN200910051154.2A 2009-05-14 2009-05-14 Method for synthesizing CA4P Active CN101885738B (en)

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CN106137946A (en) * 2015-04-23 2016-11-23 上海华理生物医药有限公司 The preparation of a kind of self assembly drug-loading system containing health cloth STING and application thereof
CN107382796B (en) * 2017-08-11 2020-10-09 浙江华理生物制药有限公司 CA-4 antineoplastic medicine, synthetic method and application thereof
CN107311846B (en) * 2017-07-25 2022-05-13 上海华理生物医药股份有限公司 Gem difluoroethyl substituted stilbene and diphenylethane derivatives, and preparation method and application thereof
WO2019020016A1 (en) * 2017-07-25 2019-01-31 上海华理生物医药股份有限公司 Ca-4 antitumour drug, synthesis method and use thereof
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