CN106800542A - A kind of hydrophily paclitaxel analog compound and preparation method thereof - Google Patents
A kind of hydrophily paclitaxel analog compound and preparation method thereof Download PDFInfo
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- CN106800542A CN106800542A CN201611264228.7A CN201611264228A CN106800542A CN 106800542 A CN106800542 A CN 106800542A CN 201611264228 A CN201611264228 A CN 201611264228A CN 106800542 A CN106800542 A CN 106800542A
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- hydrophily
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- taxol
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- -1 paclitaxel analog compound Chemical class 0.000 title claims abstract description 45
- 230000010148 water-pollination Effects 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 53
- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 43
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000002243 precursor Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000012467 final product Substances 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 7
- 239000001630 malic acid Substances 0.000 claims description 7
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 5
- 235000011090 malic acid Nutrition 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 3
- 244000050510 Cunninghamia lanceolata Species 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000001369 metatartaric acid Substances 0.000 claims description 2
- 235000011042 metatartaric acid Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 150000004579 taxol derivatives Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 238000005815 base catalysis Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 8
- 229940005605 valeric acid Drugs 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 5
- 229960003668 docetaxel Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 229910004373 HOAc Inorganic materials 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- HWXBTNAVRSUOJR-UHFFFAOYSA-N 2-hydroxyglutaric acid Chemical class OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 241001116500 Taxus Species 0.000 description 1
- 241001149649 Taxus wallichiana var. chinensis Species 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- BCZFSDNVXODRAJ-JTTNIQEDSA-N lycopodine Chemical compound C1CCN2CCC[C@@H]3[C@H]4C[C@@H](C)C[C@]32[C@H]1C(=O)C4 BCZFSDNVXODRAJ-JTTNIQEDSA-N 0.000 description 1
- BCZFSDNVXODRAJ-ZHMBSYLPSA-N lycopodine Natural products C1CCN2CCC[C@@H]3[C@H]4C[C@H](C)C[C@]32[C@H]1C(=O)C4 BCZFSDNVXODRAJ-ZHMBSYLPSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of hydrophily paclitaxel analog compound and preparation method thereof.The preparation method step of the hydrophily paclitaxel analog compound is specific as follows：By taxol and hydrophilic small molecules compound, reaction obtains hydrophily taxol compound precursor under base catalyst catalysis, then sloughs protectiveness group and obtains final product hydrophily taxol compound.Compared with prior art, hydrophily paclitaxel analog compound preparation method of the present invention has the advantages that easy, quick, high income；After taxol is through the method structural modification, stable chemical nature, water solubility improves a lot.
Description
Technical field
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of hydrophily paclitaxel analog compound and
Its preparation method.
Background technology
Taxol is a kind of diterpene-kind compound with efficient active anticancer extracted from Chinese yew genus plants.1977
The drug candidate that year is confirmed as anticancer starts clinical trial, and be subsequently found taxol has very strong work to various human tumors
Property.U.S. FDA official approval taxol is used for the treatment of oophoroma within 1992, and hereafter taxol is applied to various common evils quickly
Property tumour is such as：Breast cancer, lung cancer, colorectal cancer, melanoma, incidence cancer etc., and achieve significant curative effect.Taxol is fat
Soluble drug, the solubility in water only has 0.25ug/mL, causes to the limitation in terms of the medicine formulation application, can only be by
Injection is made in cosolvent to use.Clinically the injection of tradition application uses non-ionic surfactant polyoxyethylene castor oil
(Cremophor EL) is used as solvent, but its toxicity is big, and allergic reaction incidence is high, easily causes low blood pressure, fash and breathing tired
The adverse reactions such as difficulty.Therefore, the water solubility problems of taxol, the focus as taxol new drug research in recent years are solved.
The existing method for solving taxol soluble problem includes changing formulation and the broad aspect of modifying for chemical structure two.Its
In, changing the method for formulation includes preparing Paclitaxel liposome, yew alcohol micro-emulsion, taxol microballoon and taxol albumin nano
Grain etc..Although above-mentioned drug-loading system improves the water solubility of medicine to a certain extent, many defects are there is also, such as：
Only Paclitaxel liposome of the content less than 2% is stable on physical and chemical state, and taxol microballoon is also proved exist
Toxicity problem, and the method for change formulation can only mitigate adverse reaction, but cannot fundamentally improve drug effect.
Chemical modification technology is drug modified technology the most frequently used during modern medicines are modified.The water solubility carried out to taxol
The most commonly used water soluble group of transformation includes various organic acids and water-soluble amino acids, and it is exactly it that this kind of carrier has a big advantage
With the hydroxyl of active compound into can further be made salt, such as carboxylate after ester, sulfonate, phosphate or ammonium salt etc. are significantly carried
Water solubility high.But the improper chemical instability for being possible to that prodrug can be caused of selection of carrier, or ester bond is excessively stablized,
Generation active compound cannot be cracked in vivo.Some carriers can also cause adverse reaction in itself, or even produce toxic and side effect.So carrier
Selection is extremely important, and carrier is in addition to water miscible feature is improved, it is necessary to possess nontoxic, and accretion rate is suitable, biological
The characteristic such as compatibility is good.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of constitutionally stable hydrophily paclitaxel analog compound and its
Preparation method.
We are selected containing two and three micromolecular compounds of carboxylic acid as carrier, and difference is carried out to Docetaxel
The derivatization of hydroxyl.Containing two and three micromolecular compounds of carboxylic acid, one carboxyl and taxol into after ester, another
Free carboxyl group can again be made sodium salt, further improve water-soluble.According to above mentality of designing, selected hydrophilic small molecules chemical combination
Thing, directly carrying out reaction with taxol can produce multiple accessory substances.In order that the hydroxyl selectivity of taxol is small with hydrophily
One carboxyl of molecule first carries out the protection of side chain into ester to micromolecular compound.The structure of taxol is analyzed it can be found that dividing
Containing the unstable groups such as benzoyloxy, ester group, amide groups and multiple chiral carbons in son, these cause the change of taxol
Learn unstability；Additionally, in molecule house have four alcoholic extract hydroxyl groups, except 1-OH due to steric hindrance influence reactivity very it is low it
Outward, other three reactivities of hydroxyl are approached.Lot of unstable factor proposes higher to the malic acid derivatization of taxol
It is required that.Therefore, it is necessary to select relatively mild reaction condition in order to avoid destroying taxol parent nucleus, and reaction is set to be in regioselectivity.Through
The investigation that system is carried out into ester method to bearing taxanes is crossed, violent esterification condition such as chloride method, acid is found
Acid anhydride method is not suitable for Docetaxel；Most popular method is such as dicyclohexylcarbodiimide (DCC) in carbodiimide class dehydrating agent,
In the presence of DIC (DIC) etc. and catalyst DMAP (DMAP), the ester of acid and alcohol is directly carried out
Change.
A kind of hydrophily paclitaxel analog compound of the present invention, the concrete structure of the compound is as follows：
Wherein, R1It is small molecule hydrophilic compounds carboxylate, R2It is hydrogen.
The step of preparation method of hydrophily paclitaxel analog compound of the present invention, preparation method, is specific as follows：
By taxol and hydrophilic small molecules compound, reaction obtains hydrophily taxol compound precursor under base catalyst catalysis,
Then slough protectiveness group and obtain final product hydrophily taxol compound.
The step of preparation method of hydrophily paclitaxel analog compound of the present invention, preparation method, is specific as follows：
During 20-100mg taxols and hydrophilic small molecules carboxylic acid compound 5-50mg added into 2-10mL anhydrous methylene chlorides in proportion,
Dehydrating condensation agent and base catalyst, low temperature is added to stir under cryogenic conditions 5-10 hours, suction filtration, washing, saturated common salt washing
Wash, anhydrous sodium sulfate drying；Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate is wash-out
Agent, obtains water-soluble paclitaxel compound precursor 1；The 50-100mg of water-soluble paclitaxel compound precursor 1 is dissolved in HOAc, THF
And H2The mixed solution of O, is recovered under reduced pressure removing organic solvent, plus 5-20mL water dilution residue, lyophilized to obtain crude product, through preparing
Efficient liquid phase is isolated and purified, with acetonitrile:Water (1:1) it is mobile phase, obtains water-soluble paclitaxel compound precursor 2；Will be water-soluble purple
The 50-100mg of China fir alcoholic compound precursor 2 is dissolved in acetone 2-10ml, is stirred l-3 hours in the NaHCO3 aqueous solution；It is recovered under reduced pressure and removes
Acetone, residue is gone to freeze, obtain final product.
The preparation method of hydrophily paclitaxel analog compound of the present invention, the base catalyst is triethylamine, 4- bis-
One or more in methylamino pyridine, N- oxidation lycopodines M, sodium carbonate, potassium carbonate and sodium acid carbonate.
The preparation method of hydrophily paclitaxel analog compound of the present invention, the hydrophilic small molecules compound is apple
Acid, citric acid, tartaric acid, succinic acid, lactic acid, metatartaric acid, adipic acid, fumaric acid, 2- hydroxyl glutaric acids.
The preparation method of hydrophily paclitaxel analog compound of the present invention, the dehydrating condensation agent is DCC or/and DIC.
The preparation method of hydrophily paclitaxel analog compound of the present invention, described HOAc, THF and H2The mixed solution of O
Middle HOAc, THF and H2The ratio of O is (1-2):(1-2):1.
Compared with prior art, hydrophily paclitaxel analog compound preparation method of the present invention have it is easy, quick,
The advantages of high income；After taxol is through the method structural modification, stable chemical nature, water solubility improves a lot.
Brief description of the drawings
Fig. 1 is the synthetic route chart of the hydrophily paclitaxel analog compound in embodiment 1.
Specific embodiment
With reference to specific embodiment hydrophily paclitaxel analog compound of the present invention and preparation method thereof is made into
One step is illustrated, but protection scope of the present invention is not limited to this.
Embodiment 1
Malic acid 1.86g (13.8mmol) is added in acetone 72ml, and p-methyl benzenesulfonic acid 86mg is added in reaction solution
(0.5mmol), mixedliquor is stirred at room temperature 24 hours.Triethylamine neutralization reaction liquid is concentrated under reduced pressure to pH 6.7, and residue is with silica gel
Column chromatography is purified, with petroleum ether:Acetone (3:1) it is eluant, eluent, obtains slurry, drying under reduced pressure overnight obtains white solid 1,2- afterwards
O- isopropylidenes-malic acid 1.20g.
Under argon gas protection, by taxol 80.8mg (0.1mmol) and 1,2-O- isopropylidene-malic acid 19.1mg
(0.11mmol) is added in 2.5mL anhydrous methylene chlorides, is cooled to -10 DEG C.Then add DCC 30.9mg (0.15mmol) and
DMAP l8.3mg (0.15mmol), keep -10 DEG C of low temperature to stir 7 hours, suction filtration, washing, saturated common salt water washing, anhydrous sulphur
Sour sodium is dried.Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate (2:1) it is eluant, eluent,
Obtain white solid 2'- (1,2-O- isopropylidene-malic acid -4- bases)-taxol 67.4mg, yield 70%.
Compound 2'- (1,2-O- isopropylidenes-malic acid -4- bases)-taxol 96.4mg (0.10mmol) is dissolved in mixed
Close Solution H OAc-THF-H2O(5:5:5mL), stir 20 hours at 25 DEG C, be recovered under reduced pressure removing organic solvent, plus 10mL water is dilute
Residue is released, it is lyophilized to obtain crude product, isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, obtains white
Solid 2'- (malic acid -4- bases)-taxol 79.5mg.
Compound 2'- (malic acid -4- bases)-taxol 92.4mg (0.10mmol) is dissolved in acetone 4ml, by NaHC03
The aqueous solution 8ml of 8.4mg (0.10mmol) adds reaction solution.Reaction solution is stirred l hours at 25 DEG C.Removing third is recovered under reduced pressure
Ketone, residue is lyophilized to obtain white solid Docetaxel 2 '-natrium malicum 94.6mg, yield 93.2%.
Embodiment 2
2- hydroxyls-glutaric acid 2.07g (13.8mmol) is added in acetone 75ml, and p-methyl benzenesulfonic acid 86mg is added in reaction solution
(0.5mmol), mixedliquor is stirred at room temperature 24 hours.Triethylamine neutralization reaction liquid is concentrated under reduced pressure to pH 6.7, and residue is with silica gel
Column chromatography is purified, with petroleum ether:Acetone (3:1) it is eluant, eluent, obtains slurry, drying under reduced pressure overnight obtains white solid 1,2- afterwards
O- isopropylidenes-valeric acid 1.27g.
Under argon gas protection, by taxol 80.8mg (0.1mmol) and 1,2-O- isopropylidene-valeric acid 20.4mg
(0.11mmol) is added in 2.5mL anhydrous methylene chlorides, is cooled to -10 DEG C.Then add DCC 30.9mg (0.15mmol) and
DMAP l8.3mg (0.15mmol), keep -10 DEG C of low temperature to stir 7 hours, suction filtration, washing, saturated common salt water washing, anhydrous sulphur
Sour sodium is dried.Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate (2:1) it is eluant, eluent,
Obtain white solid 2'- (1,2-O- isopropylidene-valeric acid -4- bases)-taxol 65.8mg, yield 68.3%.
Compound 2'- (1,2-O- isopropylidenes-valeric acid -4- bases)-taxol 94.2mg (0.10mmol) is dissolved in mixing
Solution H OAc-THF-H2O(5:5:5mL), stir 20 hours at 25 DEG C, removing organic solvent, plus the dilution of 10mL water is recovered under reduced pressure
Residue, it is lyophilized to obtain crude product, isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, obtains white solid
Body 2'- (valeric acid -4- bases)-taxol 78.2mg.
Compound 2'- (valeric acid -4- bases)-taxol 92.4mg (0.10mmol) is dissolved in acetone 4ml, by NaHC03
The aqueous solution 8ml of 8.4mg (0.10mmol) adds reaction solution.Reaction solution is stirred l hours at 25 DEG C.Removing third is recovered under reduced pressure
Ketone, residue is lyophilized to obtain white solid Docetaxel 2 '-natrium malicum 91.8mg, yield 90.5%.
Embodiment 3
2- hydroxyls-glutaric acid 2.07g (13.8mmol) is added in acetone 75ml, and p-methyl benzenesulfonic acid 86mg is added in reaction solution
(0.5mmol), mixedliquor is stirred at room temperature 24 hours.N- aoxidizes lycopodine M neutralization reaction liquid to pH6.7, is concentrated under reduced pressure, residue
Purified with silica gel column chromatography, with petroleum ether:Acetone (3:1) be eluant, eluent, obtain slurry, drying under reduced pressure overnight afterwards it is white solid
Body 1,2-O- isopropylidenes-valeric acid 1.51g.
Under argon gas protection, by taxol 80.8mg (0.1mmol) and 1,2-O- isopropylidene-valeric acid 20.4mg
(0.11mmol) is added in 2.5mL anhydrous methylene chlorides, is cooled to -10 DEG C.Then add DCC 30.9mg (0.15mmol) and
DMAP l8.3mg (0.15mmol), keep -10 DEG C of low temperature to stir 7 hours, suction filtration, washing, saturated common salt water washing, anhydrous sulphur
Sour sodium is dried.Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate (2:1) it is eluant, eluent,
Obtain white solid 2'- (1,2-O- isopropylidene-valeric acid -4- bases)-taxol 65.8mg, yield 68.3%.
Compound 2'- (1,2-O- isopropylidenes-valeric acid -4- bases)-taxol 94.2mg (0.10mmol) is dissolved in mixing
Solution H OAc-THF-H2O(5:5:5mL), stir 20 hours at 25 DEG C, removing organic solvent, plus the dilution of 10mL water is recovered under reduced pressure
Residue, it is lyophilized to obtain crude product, isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, obtains white solid
Body 2'- (valeric acid -4- bases)-taxol 78.2mg.
Compound 2'- (valeric acid -4- bases)-taxol 92.4mg (0.10mmol) is dissolved in acetone 4ml, by NaHC03
The aqueous solution 8ml of 8.4mg (0.10mmol) adds reaction solution.Reaction solution is stirred l hours at 25 DEG C.Removing third is recovered under reduced pressure
Ketone, residue is lyophilized to obtain white solid Docetaxel 2 '-natrium malicum 91.8mg, yield 90.5%.
Claims (7)
1. a kind of hydrophily paclitaxel analog compound, it is characterised in that the concrete structure of the compound is as follows：
Wherein, R1It is small molecule hydrophilic compounds carboxylate, R2It is hydrogen.
2. the preparation method of hydrophily paclitaxel analog compound according to claim 1, it is characterised in that the preparation method
The step of it is specific as follows：By taxol and hydrophilic small molecules compound, reaction obtains hydrophily purple under base catalyst catalysis
China fir alcoholic compound precursor, then sloughs protectiveness group and obtains final product hydrophily taxol compound.
3. the preparation method of hydrophily paclitaxel analog compound according to claim 2, it is characterised in that the preparation method
The step of it is specific as follows：20-100mg taxols and hydrophilic small molecules carboxylic acid compound 5-50mg are added into 2-10mL in proportion
In anhydrous methylene chloride, dehydrating condensation agent and base catalyst, low temperature is added to stir under cryogenic conditions 5-10 hours, suction filtration, water
Wash, saturated common salt water washing, anhydrous sodium sulfate drying；Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with oil
Ether:Ethyl acetate is eluant, eluent, obtains water-soluble paclitaxel compound precursor 1；By the 50- of water-soluble paclitaxel compound precursor 1
100mg is dissolved in mixed solution HOAc-THF-H2O, is recovered under reduced pressure removing organic solvent, plus 5-20mL water dilution residue, freezes
Crude product is obtained, is isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, before obtaining water-soluble paclitaxel compound
Body 2；The 50-100mg of water-soluble paclitaxel compound precursor 2 is dissolved in acetone 2-10ml, l-3 is stirred in the NaHCO3 aqueous solution
Hour；Removing acetone is recovered under reduced pressure, residue is freezed, obtained final product.
4. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the base catalysis
Agent is one or more in triethylamine, DMAP, sodium carbonate, potassium carbonate and sodium acid carbonate.
5. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the hydrophily is small
Molecular compound is malic acid, citric acid, tartaric acid, succinic acid, lactic acid, metatartaric acid, adipic acid, fumaric acid, 2- hydroxyls penta
Diacid.
6. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the dehydrating condensation
Agent is DCC or/and DIC.
7. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the HOAc-
THF-H2The ratio of O is (1-2):(1-2):1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115385875A (en) * | 2022-07-18 | 2022-11-25 | 中国药科大学 | Taxol derivative and preparation method and application thereof |
| CN119285582A (en) * | 2024-07-01 | 2025-01-10 | 浙江中医药大学金华研究院 | A highly water-soluble bisaconitic acid molecule chemically modified paclitaxel compound, synthesis method and application thereof |
| CN119285583A (en) * | 2024-10-11 | 2025-01-10 | 苏州摩笛尔科技有限公司 | A kind of difluoromethylated paclitaxel and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1059337A (en) * | 1990-08-28 | 1992-03-11 | 弗吉尼亚科技知识产权有限公司 | Water-soluble derivatives of paclitaxel |
| WO2000001682A1 (en) * | 1998-07-01 | 2000-01-13 | Bcm Developpement Inc. | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
| WO2000010988A1 (en) * | 1998-08-21 | 2000-03-02 | Pharmachemie B.V. | Water soluble analogs and prodrugs of paclitaxel |
-
2016
- 2016-12-31 CN CN201611264228.7A patent/CN106800542A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1059337A (en) * | 1990-08-28 | 1992-03-11 | 弗吉尼亚科技知识产权有限公司 | Water-soluble derivatives of paclitaxel |
| WO2000001682A1 (en) * | 1998-07-01 | 2000-01-13 | Bcm Developpement Inc. | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
| WO2000010988A1 (en) * | 1998-08-21 | 2000-03-02 | Pharmachemie B.V. | Water soluble analogs and prodrugs of paclitaxel |
Non-Patent Citations (1)
| Title |
|---|
| 杨恩慈 等: "改善紫杉醇水溶性方法的研究进展", 《中南药学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115385875A (en) * | 2022-07-18 | 2022-11-25 | 中国药科大学 | Taxol derivative and preparation method and application thereof |
| CN119285582A (en) * | 2024-07-01 | 2025-01-10 | 浙江中医药大学金华研究院 | A highly water-soluble bisaconitic acid molecule chemically modified paclitaxel compound, synthesis method and application thereof |
| CN119285583A (en) * | 2024-10-11 | 2025-01-10 | 苏州摩笛尔科技有限公司 | A kind of difluoromethylated paclitaxel and preparation method thereof |
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