WO2008011805A1 - Vinblastines compounds, the preparation and the pharmaceutical use thereof - Google Patents
Vinblastines compounds, the preparation and the pharmaceutical use thereof Download PDFInfo
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- WO2008011805A1 WO2008011805A1 PCT/CN2007/002176 CN2007002176W WO2008011805A1 WO 2008011805 A1 WO2008011805 A1 WO 2008011805A1 CN 2007002176 W CN2007002176 W CN 2007002176W WO 2008011805 A1 WO2008011805 A1 WO 2008011805A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Vinblastine compound preparation method thereof and use thereof in medicine
- the present invention relates to a novel vinblastine-like compound, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use in the preparation of a medicament for treating a cell proliferation-related disease or other diseases in a mammal.
- Vinblastine also known as vinblastine, is a kind of alkaloid contained in the vinca flower of the oleander family. Vinblastine and Vincristine isolated from the periwinkle (RL Noble, etal, Biochem. Pharmacol, 1958, 1, 347-348; GH Svoboda, Lloydia, 1961, 24, 173-178 ), was first used to treat Hodgkins lymphoma in i960. Since then, studies have begun on the synthesis of vinblastine and its derivatives and their anti-tumor mechanisms. Two of these semi-synthetic vinblastine derivatives have a major impact on the treatment of cancer.
- Vindesine and Vinorelbine are Vindesine and Vinorelbine (R ⁇ Gersosimo, eatl, Pharmacotherapy, 1983, 3, 259- 274; Langlois N., et al. J. Am. Chem. Soc. 197, 98, 7017-7024; Mangeney P., et al Tetrahedron 1979, 35, 2175-2179).
- these drugs have been widely used in clinical applications, mainly for the treatment of non-small cell lung cancer, small cell carcinoma, malignant lymphoma, breast cancer, esophageal cancer and malignant melanoma.
- the vinblastines are similar in structure and consist of two complex polycyclic systems connected by a carbon-carbon bridge. Years of research have shown that the cytotoxicity of these drugs is achieved by binding to tubulin. They share a common binding site on the microtubule dimer. Since the binding of the drug to the tubulin dimer inhibits microtubule polymerization, the dividing cells cannot form a spindle and the mitosis stops in the middle. Therefore, these microtubule depolymerizations are cell cycle specific drugs (SA Johnson, etal, Cancer Treat Rev. 1996, 22, 127-142; RK Gregory, et al, Br. J. Cancer 200, 82, 1901-1903) .
- vinblastine can inhibit tubulin from forming microtubules at lower doses and can depolymerize normal microtubules, which may be inhibited by binding to microtubule ends. GTP hydrolysis inhibits mitosis by kinetic stabilization of the spinel bulk microtubule polymerization function. At higher doses, vinblastine causes tubulin to form a helical polymer and eventually form a crystalloid.
- these drugs In addition to beneficial pharmacological activities, these drugs also have some side effects.
- the usual side effects are bone marrow loss, nausea, hair loss, diarrhea, constipation, numbness of hands and feet, headaches, and the like. This is related to its anti-tumor activity mechanism of cytotoxicity. Therefore, maintaining its original anti-tumor activity while reducing its toxic side effects has been a research direction of interest to pharmaceutical chemists.
- a more prominent example in this regard is vinflunine (J.-C. Jacquecy, et al, US 5,620,985).
- the vinorelbine is a double bond of the C 3 ' and C 4 positions of vinorelbine, and two fluorine atoms are introduced at the C 2Q position.
- Changchun Flunan is currently in Phase III clinical trials, and the results indicate that vinflunine exhibits significant antitumor activity against a variety of tumor lineages (A. Kruc Z yn S ki, BTHill, Critical Review in Oncology/Hematology 2001, 40, 159- 173). Especially vinflunine l It can also guide the tumor regression of small cell lung cancer and kidney cancer, and is superior to the best vinblastine anticancer drug vinorelbine in many comprehensive evaluation indexes such as efficacy, toxicity and anti-tumor lineage. Therefore, it can be expected to have a good market prospect.
- the present invention relates to a compound represented by the formula (I) or a salt thereof:
- R 2 is selected from alkyl or -CH O);
- R 3 is selected from a hydrogen atom, an alkyl group or -C(0)R 5 ;
- R 5 and each are respectively selected from a hydrogen atom, an alkyl group, a decyloxy group, a cycloalkyl group, a halogenated fluorenyl group, an aryl group An aryl or heterocyclic fluorenyl group; wherein the fluorenyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may be further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cycloalkyl, Substituted by an aryl group, a heteroaryl group, a halogen or a - hydrazine;
- R 5 may form a 4 to 8 membered heterocyclic group together with a halogen atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms;
- R 7 is a sulfhydryl group
- Z is selected from -OR 5 , - R5R6 or -NHNHC(0)R 5 ;
- R4 and Z can form a ring with the inserted atoms
- n 0 ⁇ 4.
- R 3 is a hydrogen atom or an acetyl group.
- it is a hydrogen atom in the compound of the formula (I) or a salt thereof.
- Z is a methoxy group in the compound of the formula (I) or a salt thereof.
- R 3 is a hydrogen atom or an acetyl group, which is a hydrogen atom, and Z is a methoxy group.
- R 2 is a formyl group or an alkyl group in the compound of the formula (I) or a salt thereof.
- R 2 is an alkyl group in the compound of the formula (I) or a salt thereof.
- the formula (I) is present in the form of a pharmaceutically acceptable free form or an acid addition salt selected from the group consisting of sulfuric acid, nitric acid, hydrobromic acid, hydrogen An inorganic acid such as iodic acid or phosphoric acid, or an organic acid selected from the group consisting of tartaric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, maleic acid, fumaric acid or lactic acid, preferably tartaric acid.
- the compounds to which the present invention relates include:
- the present invention relates to a process for the preparation of a compound of the formula (I), comprising the steps of: using vinflunine (I-la) as a raw material at a suitable temperature (-20 ° C to 3 (TC), at Reaction with a halogenating reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid to obtain a halogen-substituted compound of the formula (I-lb);
- the vinflunine (I-la) is reacted with hexamethylenetetramine in an oil bath at a suitable temperature (20O to 100 ° C) in a solvent of trifluoroacetic acid to obtain a compound of the formula (I-lc). ;
- the compound of the formula (I-ld) obtained above is in toluene, in tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphine-2',4',6'-triisopropyl - hydrazine, hydrazine-biphenyl catalyzed reaction with different amines to give a compound of the formula (I-lf);
- the compound of the formula (I-lc) is reacted with a different Grignard reagent in a tetrahydrofuran solution in the presence of a catalytic amount of a transition metal reagent to obtain a compound of the formula (I-le);
- - is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl with halogen, amino, cyano, trifluoromethyl, -N 3, - C(0)R 5 , -COOR 5 , -NR 5 C(0)R 6 , -NR 5 S(0) 2 R6, -NHC(S)NR 5 R 6 , -C(OH)R 5 , - (C3 ⁇ 4) n NR 5 , -NHC(0)NR 5 R 6 , -CSCSi(R 7 ) 3 , -C(0)NR 5 R 6 , -C(0)NHOH, -S0 2 NR 5 R 6 , -NHS(0) 2 R 5 , -S(0) 2 NR 5 R 6 , -SR 5 , -S(0)R 5 , -S(0) 2 R 5 , -SSR 5 , -B(OR 5 2 , -
- R 3 is selected from a hydrogen atom, an alkyl group or -C(0)R 5 ;
- R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated fluorenyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein alkyl group, cycloalkyl group, aryl group, hetero group
- the aryl or heterocycloalkyl group may be further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cyclodecyl, aryl, heteroaryl, halogen or -NR 5 groups;
- a 4 to 8 membered heterocyclic group may be formed together with the N atom: wherein 5 to 8 members of the heterocyclic ring may contain one or more N, 0, S atoms;
- R 7 is an alkyl group
- R 8 is selected from alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group may be further substituted by one or more mercapto, alkenyl, cycloalkyl or halogen;
- Z is selected from -OR 5 , -NRsi ⁇ or -NH HC(0)R 5 ;
- X is a halogen
- n is. ⁇ 4.
- it is selected from the group consisting of an anthracenyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a halogen, an amino group, a cyano group, and a trifluoromethyl group.
- R 2 is a sulfhydryl group
- R 3 is a hydrogen atom or an acetyl group
- R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated fluorenyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein alkyl group, cycloalkyl group, aryl group, hetero group
- the aryl or heterocycloalkyl group may be further substituted by one or more heptyl, decyloxy, alkenyl, hydroxy, cyclodecyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
- a 4 to 8 membered heterocyclic group may be formed together with the N atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms; R 7 is an alkyl group;
- R 8 is selected from alkyl or cycloalkyl, wherein the indenyl or cycloalkyl can be further substituted by one or more mercapto, alkenyl, cyclodecyl or halogen;
- Z is an alkoxy group
- X is a halogen
- n 0 to 4.
- the present invention relates to a process for the preparation of a compound of the formula (I):
- the compound of the formula (I-lb) is subjected to a coupling reaction by heating at 40 to 150 ° C under a transition metal catalysis to finally obtain a compound of the formula (I);
- X is a halogen
- the compound of the formula (I-lc) is subjected to reductive amination reaction with RiNH 2 and sodium triacetoxyborohydride at 25 to 80 Torr in anhydrous dichloromethane to obtain a compound of the formula (I);
- the compound of the formula (I-le) is oxidized by Dess-Martin in dichloromethane at room temperature to obtain a compound of the formula (I);
- alkyl group or a cycloalkyl group is selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group may be further substituted with one or more alkyl groups, alkenyl groups, cycloalkyl groups or halogens.
- Rs is selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group may be further substituted with one or more alkyl groups, alkenyl groups, cyclodecyl groups or groups;
- X is a halogen
- the transition metal catalyst used in the above preparation method 1) is selected from the group consisting of palladium acetate, cuprous iodide, palladium carbon, triphenylphosphine, tetrakis(triphenylphosphine)palladium chloride, di-(three Phenylphosphine) palladium chloride, rhodium, ruthenium-bis-(diphenylphosphino)ferrocene or tris(dibenzylideneacetone)dipalladium.
- the halogenating agent used in Process 4) is selected from the group consisting of ⁇ -bromosuccinimide, hydrazine-iodosuccinimide or iodine monochloride.
- the ratio of anhydrous dichloromethane to trifluoroacetic acid in the mixed solvent used in the method 4) is from 10:1 to 1:10, preferably 1:1.
- the present invention relates to a compound represented by the following formula (I-lb) and (I-lc) which is an intermediate for the synthesis of the compound of the formula (I):
- X is a halogen. Still further, the present invention relates to a process for producing a compound of the above formula (I-lb) or formula (I-lc), which comprises the steps of:
- the long flufenine (I-la) is reacted with hexamethylenetetramine in a solvent of trifluoroacetic acid at a suitable temperature (20 ° C to 100 Torr) to obtain a compound of the formula (1-1 c). ;
- halogenating agent is selected from the group consisting of: N-bromosuccinimide, N-iodosuccinimide or iodine monochloride.
- a thioprene (I-la) is used as a raw material, and a halogenating reagent is reacted in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid to obtain a halogen-substituted formula (I-lb).
- the compound; wherein the ratio of anhydrous dichloromethane to trifluoroacetic acid in the mixed solvent is from 10:1 to 1:10, preferably 1:1.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof, and a pharmaceutically acceptable carrier or excipient .
- R 3 is a hydrogen atom or an acetyl group.
- the pharmaceutical composition containing the compound of the formula (I) or a salt thereof it is a hydrogen atom.
- Z is a methoxy group.
- the pharmaceutical composition containing the compound of the formula (I) or a salt thereof it is a hydrogen atom or an acetyl group, and is a hydrogen atom, and Z is a methoxy group.
- the pharmaceutical composition containing the compound of the formula (I) or a salt thereof it is a formyl group.
- it is an anthracenyl group.
- the present invention relates to the use of the compound of the formula (I) or a salt thereof for the preparation of a medicament for treating a cell proliferation-related disease or other diseases in a mammal.
- the present invention relates to a use of a composition comprising the compound of the formula (I) or a salt thereof for the preparation of a medicament for treating a cell proliferation-related disease or other diseases in a mammal.
- diseases or other diseases associated with mammalian cell proliferation include cancer, bacterial infection diseases, allergies, heart disease, AIDS, human T lymphocyte virus type 1 infection, human herpes disease Toxic type 3, human herpesvirus type 4, human papillomavirus, diabetes, rheumatoid arthritis, Alzheimer's disease, inflammation, arthritis, malaria, autoimmune diseases, eczema, lupus, psoriasis, Rheumatic diseases, dry keratoconjunctivitis syndrome or viral infections.
- the cell proliferation-related disease is cancer
- the cancer is selected from the group consisting of lung cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, thyroid cancer, melanoma, brain cancer, bladder cancer, non-small cell lung cancer, small cell carcinoma, malignant Lymphoma, breast cancer or malignant melanoma.
- the present invention relates to a method for inhibiting proliferation of a mammalian cell comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formula (I) or a salt thereof, and a pharmaceutically acceptable Carrier or excipient.
- the mammal is an animal having cancer.
- the cancer of the above mammals includes solid tumors, cancer, lymphoma, Hodgkin's disease, neoplastic diseases, neoplastic diseases and the like.
- R 2 is selected from alkyl or -CH(O);
- R 3 is selected from a hydrogen atom, a fluorenyl group or -C(0)R 5 ;
- the cycloalkyl group may be further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cycloalkyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
- R 5 may form a 4 to 8 membered heterocyclic group together with the N atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms;
- R 7 is an alkyl group
- Z is selected from -OR 5 , -NRsRe or -NHNHC(0)R 5 ;
- n 0 ⁇ 4.
- the present invention also relates to a compound represented by the following formulas (I-lb) and (I-lc) which are intermediates for the synthesis of the compound of the formula (I):
- R 2 is selected from alkyl or -CH(O);
- R 3 is selected from a hydrogen atom, a fluorenyl group or -C(0)R 5 ;
- R4 is selected from a hydrogen atom, -C(0)R 5 or -Si(R 7 ) 3 ;
- R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated alkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein a fluorenyl group, a cycloalkyl group, an aryl group or a heteroaryl group; Or a heterocyclic fluorenyl group may be further substituted by one or more fluorenyl, alkoxy, alkenyl, hydroxy, cycloalkyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
- a 4 to 8 membered heterocyclic group may be formed together with the N atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms;
- R 7 is an alkyl group
- Z is selected from -OR 5 , -NRsRe or -NHNHC(0)R 5 ;
- X is a halogen.
- the hydrogen atom or the acetyl group is preferred.
- z is preferably a methoxy group.
- the hydrogen atom or the acetyl group is preferably a hydrogen atom and Z is a methoxy group.
- an alkyl group is preferred.
- the formula (I) is present in the form of a pharmaceutically acceptable free form or an acid addition salt, the salt comprising a mineral acid salt such as a sulfate, a nitrate, Hydrobromide, hydroiodide, phosphate, etc. and organic acid salts such as tartrate, acetate, methanesulfonate, besylate, tosylate, citrate, maleate, rich Citrate, lactate, etc. Preferred is tartrate.
- the present invention adopts the following technical scheme - a preparation method of the compound of the formula (I) or a salt thereof of the present invention, comprising the following steps:
- vinflunine (I-la) as a raw material, reacting with a halogenated reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid at an appropriate temperature (-20 ° C to 30 ° C).
- the alkylsilyl ester is reacted to obtain a compound of the formula (I-ld); or the vinflunine (I-la) is hexamethyltetramine in a solvent of trifluoroacetic acid at a suitable temperature (20°) C ⁇ 100 ° C) oil bath reaction to obtain a compound of the formula (I-lc); the compound of the formula (I-ld) obtained above in toluene, in tris(dibenzylideneacetone) dipalladium (0) and 2-Dicyclohexylphosphine-2',4,6'-triisopropyl-1,1'-biphenyl catalyzed by reaction with different amines to give a
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier or excipient, and to a preparation of a compound of the formula (I) or a salt thereof according to the invention Antineoplastic agents Use in T/CN2007/002176.
- the present invention provides a composition comprising a pharmaceutically effective amount of the above compound, and the use of the composition for the preparation of an antitumor drug.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- ⁇ is given in parts per million (ppm).
- the NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 3 ), the internal standard was trimethylsilane (TMS), and the chemical shift was given in units of 1 (T 6 (ppm).
- the MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer.
- Vinflunine a compound represented by the following structure (la);
- vinflunine la 2.0 g, 2.07 mmol
- a mixed solvent of 80 ml/80 ml of dichloromethane/trifluoroacetic acid 80 ml/80 ml
- the temperature in the reaction system was maintained at -15 ° C, and iodosuccinimide (0.605 g, 2.69 mmol) of dichloromethane was added dropwise.
- hydroxylamine hydrochloride 168 mg, 2.4 mmol
- 12,-formyl vinflunine 2 in acetonitrile 0.338 g, 0.40 mmol, dissolved in 40 ml of acetonitrile
- triethylamine 352 ul, 2.56 mmol
- the oil bath was heated to reflux at 100 to 110 ° C for 1.5 hours, then phthalic anhydride (0.352 mg, 2.4 mmol) was added, and the mixture was heated to reflux overnight.
- 12'-iodovinfluramine 1 (0.35 g, 0.37 mmol) was dissolved in 20 ml of anhydrous tetrachlorofuran in a dry three-necked flask, and palladium acetate (8.3 mg, 0.037 mmol) was added. And a solution of triphenylphosphine (19.4 mg, 0.074 mmol) in tetrahydrofuran (3 ml).
- Another dry reaction flask was prepared by dissolving hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (21 mg, 0.037 mmol) and palladium acetate (8 mg, 0.037 mmol) in 3.5 ml of 1,4 In the dioxane, 3.5 ml of this catalyst solution was added to the above round bottom flask. The oil bath was stirred at 60 ° C for 24 hours, and the reaction was quenched by ethyl acetate (100 ml). The mixture was filtered under reduced pressure. EtOAc EtOAc m. The obtained residue was purified by chromatography to give the title product 12'-(2-trifluoromethyl Phenyl) vinflunine 11 (0.138 g, yellow solid), yield 38.8%.
- 12'-iodovinfluramine 1 (0.377 g, 0.4 mmol) was dissolved in 12 ml of anhydrous toluene and 3 ml of anhydrous tetrahydrofuran in a dry round bottom flask. Copper (22.8 mg, 0.12 mmol), bis(triphenylphosphine)palladium chloride (30 mg, 0.04 mmol), triethylamine (0.55 ml, 3.2 mmol) and trimethylsilylacetylene (0.24 ml, 1.6 mmol) . The oil bath was stirred at 60 ° C for 18 hours, and the reaction was tracked by a spot plate, and the raw materials disappeared.
- reaction solution was extracted with ethyl acetate (100 ml ⁇ 4).
- the combined organic phases were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH%.
- °068 [I+I ⁇ ]:IS3 ' ⁇ nmm ⁇ mm ⁇ ''s''' - ⁇ mm ⁇ ° r/i oui ro)3 ⁇ 43 ⁇ 4* ti3 ⁇ 4Bai3 ⁇ 4i3 ⁇ 4i ⁇ i ra t 'd/i ora ⁇ ) 3 ⁇ 43 ⁇ 43 ⁇ 4 ⁇ 53 3 ⁇ 4 ⁇ ⁇ 3 ⁇ 4 fence II - i ra si ' ⁇ ⁇ f M ox - ⁇
- 12'-Amino-vinflurine 28 (0.09 g, 0.11 mmol) and 4-indole-indole-dimethylaminopyridine (3 mg, 0.024 mmol) were dissolved in tetrahydrofuran under a argon atmosphere in a dry round bottom flask. 10 ml), a solution of triethylamine (20 ul, 0.14 mmol) and methanesulfonyl chloride in tetrahydrofuran (1.4 ml, 0.14 mmol, 0.1 mol/L). The mixture was stirred at room temperature overnight, and the mixture was applied to the mixture. The mixture was evaporated. The mixture was concentrated.
- reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Filtration, the filtrate was concentrated under reduced pressure and purified to silica gel elution elution elution elution elution
- 12'-iodovinfluramine 1 (0.63 g, 0.668 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran under stirring in a round bottom flask, and 27 ml of methyl bromide was added dropwise in portions.
- 3-triethylsiloxy-12'-iodovinfluramine 50 (0.338 g, 0.32 mmol) and sodium tert-butoxide (0.101 mg, 1.056 mmol), dissolved in 10 ml of toluene with stirring, added pyrrolidine (0.64 ul, 0.8 mmol), stirred at room temperature for 3 minutes, and added tris(dibenzylideneacetone)dipalladium(0) (29.2 mg, 0.032 mmol) And a solution of 2-dicyclohexylphosphine-2,,4',6,-triisopropyl-1,1,-biphenyl (30.4 mg, 0.064 mmol) in toluene (5 ml).
- 3-triethylsiloxy-12,-iodovinfluramine 0.5 g, 0.47 mmol
- sodium tert-butoxide 0.162 mg, 1.692 mmol
- the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, the reaction was quenched by ethyl acetate (50 ml). The mixture was filtered with EtOAc (EtOAc m.) The obtained residue was purified to purified crystalljjjjjjj
- Another dry reaction flask was prepared by dissolving hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (11 mg, 0.02 mmol) and palladium acetate (4.5 mg, 0.02 mmol) in 3 ml of 1,4 In the dioxane, the catalyst solution was added to the above reaction flask. The oil bath was stirred at 70 Torr overnight, and the reaction was stopped by clicking on the plate, and the raw materials disappeared. The reaction was quenched by the addition of ethyl acetate (50 mL).
- the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, ethyl acetate (50 ml) was added to quench. The mixture was filtered under reduced pressure. EtOAc (EtOAc m. The obtained residue was purified to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, the reaction was followed by spotting, the material disappeared, and ethyl acetate (50 ml) was added to quench the reaction. The mixture was filtered with EtOAc (EtOAc m.) The residue obtained was purified by chromatography to give the title product 12,-[2-(3-methyl-butyl)-pyrazol-4-yl]-vinflunine 61 (0.142 g, white solid: 74%.
- 12'-iodovinfluramine 1 (0.734 g, 0.78 mmol) was added to a dry round bottom flask, dissolved in 20 ml of anhydrous toluene, and bis(tributyltin) reagent (1.57 ml) was added. And a solution of palladium acetate (35 mg, 0.16 mmol) and triphenylphosphine (82 mg, 0.32 mmol) in toluene (10 ml). The oil bath was stirred at 102 ° C overnight, and the reaction was stopped by clicking on the plate, and the raw materials disappeared.
- Cell line A549 (human non-small cell lung cancer)
- the SRB method was used to evaluate the degree of inhibition of cell proliferation by the compound, and the inhibition rate was calculated.
- the IC50 was calculated by Logit method according to the inhibition rate, and the in vitro antitumor activity of the compound was compared. Calculation method of inhibition rate:
- Inhibition rate () (control group OD value - medication OD value) / control group OD value xlOO
- the IC50 of the sample to be tested is examined in two parallel experiments, and the inhibition rate of the compound on A549 cells (human non-small cell lung cancer) is shown in Table 1. Inhibition rate of vinblastine compounds on A549 cells (human non-small cell lung cancer)
- vinflunine la the tartrate salts of Examples 3 and 13 Formulation: vinflunine la tartrate: starting material, white powder; Example 3 tartrate: starting material, white powder; Example 13 tartrate: starting material, pale yellow.
- V l/2xaxb 2 where a and b represent length and width, respectively.
- Table 1 Effect of intravenous injection of vinflunine la, Examples 3 and 13 on human lung cancer A549 nude mice xenografts. Group dose animals after tumor weight TV RTV T/C (%)
- Example 13 40 5 17.2 20.3 218 ⁇ 50 2262 ⁇ 446 10.67 ⁇ 2.29 87.1
- Example 13 60 5 15.5 18.3 186 ⁇ 32 1577 ⁇ 733 8.90 ⁇ 4.83 72.7
- Example 13 80 5 17.8 18.2 211 ⁇ 21 1204 ⁇ 515 5.82 ⁇ 2.80 47.5 a
- Example 3 60 5 17.5 20.9 192 ⁇ 50 2134 ⁇ 372 11.84 ⁇ 4.15 96.7
- Drug name vinflunine la, tartrates of Examples 27, 33 and 49.
- Formulation vinflunine la tartrate: starting material, white powder; Example 27 tartrate: starting material, white powder; Example 33 tartrate: starting material, white powder.
- mice were subcutaneously inoculated with human lung cancer A549 tumor masses, and after the tumors were grown to 100-300 mm 3 , the animals were randomly divided into groups (d0).
- the doses of SHR1011, SHR1012, SHR1013, and SHR1014 were 10 mg/kg, 20 mg/kg, and 40 mg/kg; intravenous administration, d0, and 7 times.
- the tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded.
- the tumor volume (V) is calculated as:
- V l/2xaxb 2 where a and b represent length and width, respectively.
- Table 1 Intravenous injection of Example 17, 33, 49 and vinflunine la for human lung cancer A549 nude mice xenografts. Group dose animal number tumor-bearing mouse body TV RTV T/C
- Example 27 From the toxicological point of view, vinflunine la is the most toxic, the toxicity of Example 27 is weak, and the toxicity of Example 49 is between them. Overall evaluation, the effect on lung cancer A549, Example 27> vinflunine la> Example 49> Example 33.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses new vinblastines compounds represented by formula (I), the preparation thereof, pharmaceutical compositions containing such compounds and the use of such compounds as therapeutic agents, especially as antitumor agents, wherein each substituent in formula (I) is same as defined in the description.
Description
长春碱类化合物、 其制备方法及其在医药上的用途 技术领域 Vinblastine compound, preparation method thereof and use thereof in medicine
本发明涉及一种新的长春碱类化合物、其制备方法及含有该化合物的药物组 合物以及其在制备治疗哺乳动物细胞增殖相关疾病或其它疾病的药物中的用途。 背景技术 The present invention relates to a novel vinblastine-like compound, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use in the preparation of a medicament for treating a cell proliferation-related disease or other diseases in a mammal. Background technique
长春碱又称长春花碱，是夹竹桃科植物长春花中所含生物碱的一种。人们从 长春花中分离出来的长春碱 (Vinblastine)和长春新碱 (Vincristine) (R. L. Noble, etal, Biochem. Pharmacol, 1958, 1, 347-348; G. H. Svoboda, Lloydia, 1961, 24, 173-178)， 于 i960年首次被用于治疗 Hodgkins lymphoma。 从那时起人们开始研究长春碱 及其衍生物的合成及其抗肿瘤机理。这其中有两种半合成长春碱衍生物在治疗癌 症方面产生较大影响， 它们是长春地辛 (Vindesine)和长春瑞宾 (Vinorelbine)(R丄 Gersosimo, eatl, Pharmacotherapy, 1983, 3, 259-274; Langlois N., etal. J. Am. Chem. Soc. 197, 98, 7017-7024; Mangeney P., etal Tetrahedron 1979， 35, 2175-2179)。 目前 这几种药已被广泛地应用临床， 主要用于治疗非小细胞肺癌， 小细胞癌，恶性淋 巴瘤， 乳腺癌， 食管癌及恶性黑色素瘤等恶性肿瘤。 Vinblastine, also known as vinblastine, is a kind of alkaloid contained in the vinca flower of the oleander family. Vinblastine and Vincristine isolated from the periwinkle (RL Noble, etal, Biochem. Pharmacol, 1958, 1, 347-348; GH Svoboda, Lloydia, 1961, 24, 173-178 ), was first used to treat Hodgkins lymphoma in i960. Since then, studies have begun on the synthesis of vinblastine and its derivatives and their anti-tumor mechanisms. Two of these semi-synthetic vinblastine derivatives have a major impact on the treatment of cancer. They are Vindesine and Vinorelbine (R丄Gersosimo, eatl, Pharmacotherapy, 1983, 3, 259- 274; Langlois N., et al. J. Am. Chem. Soc. 197, 98, 7017-7024; Mangeney P., et al Tetrahedron 1979, 35, 2175-2179). At present, these drugs have been widely used in clinical applications, mainly for the treatment of non-small cell lung cancer, small cell carcinoma, malignant lymphoma, breast cancer, esophageal cancer and malignant melanoma.
长春碱类药物的结构相似， 由碳一碳桥连接的二个复杂的多环系统构成。多 年的研究表明这类药物的细胞毒性通过与微管蛋白的结合来实现。它们在微管蛋 白二聚体上有共同的结合位点。 由于药物与微管蛋白二聚体的结合抑制微管聚 合， 使分裂的细胞不能形成纺锤体而使有丝分裂停止于中期。因此，这些微管解 聚是属细胞周期特异性药物 (S. A. Johnson, etal, Cancer Treat Rev. 1996, 22, 127-142; R. K. Gregory,etal, Br. J. Cancer 200, 82, 1901-1903)。 The vinblastines are similar in structure and consist of two complex polycyclic systems connected by a carbon-carbon bridge. Years of research have shown that the cytotoxicity of these drugs is achieved by binding to tubulin. They share a common binding site on the microtubule dimer. Since the binding of the drug to the tubulin dimer inhibits microtubule polymerization, the dividing cells cannot form a spindle and the mitosis stops in the middle. Therefore, these microtubule depolymerizations are cell cycle specific drugs (SA Johnson, etal, Cancer Treat Rev. 1996, 22, 127-142; RK Gregory, et al, Br. J. Cancer 200, 82, 1901-1903) .
这些药物的抗癌活性与其剂量有很大关系，如长春碱在较低剂量它能抑制微 管蛋白形成微管， 并能使正常的微管解聚， 这可能是通过与微管末端结合抑制 GTP水解， 通过对纺綞体微管聚合机能的动力学稳定化处理来抑制有丝分裂。 在较高剂量时， 长春碱可使微管蛋白形成螺旋形聚合体并最终形成类晶体。 The anticancer activity of these drugs has a lot to do with its dosage. For example, vinblastine can inhibit tubulin from forming microtubules at lower doses and can depolymerize normal microtubules, which may be inhibited by binding to microtubule ends. GTP hydrolysis inhibits mitosis by kinetic stabilization of the spinel bulk microtubule polymerization function. At higher doses, vinblastine causes tubulin to form a helical polymer and eventually form a crystalloid.
除了有益的药理活性外，这类药物也有一些副作用，通常表现的副作用是骨 髓损耗、 恶心、 脱发、 腹泻、便秘、 手脚麻木、 头疼等。 这与其细胞毒性的抗肿 瘤活性机制有关。 因此， 在保持其原有的抗肿瘤活性的同时又降低其毒副作用， 一直是药物化学家感兴趣的研究方向。 在这方面， 比较突出的例子是长春氟宁 (J.-C. Jacquecy, etal, US5620985)。长春氟宁是把长春瑞宾的 C3'和 C4，位的双键还 原， 同时在 C2Q，位上引入二个氟原子。长春氟宁目前处于三期临床， 研究结果表 明长春氟宁对多种肿瘤谱系表现出显著的抗肿瘤活性 (A. KrucZynSki， B.T.Hill, Critical Review in Oncology/Hematology 2001 , 40， 159—173)。 尤其是长春氟宁 l
还能引导小细胞肺癌和肾癌的肿瘤衰退，并且在药效、毒性和抗肿瘤谱系等多个 综合评价指标中优于现有最好的长春碱类抗肿瘤药物长春瑞宾。因而可以预料它 具有良好的市场前景。 In addition to beneficial pharmacological activities, these drugs also have some side effects. The usual side effects are bone marrow loss, nausea, hair loss, diarrhea, constipation, numbness of hands and feet, headaches, and the like. This is related to its anti-tumor activity mechanism of cytotoxicity. Therefore, maintaining its original anti-tumor activity while reducing its toxic side effects has been a research direction of interest to pharmaceutical chemists. A more prominent example in this regard is vinflunine (J.-C. Jacquecy, et al, US 5,620,985). The vinorelbine is a double bond of the C 3 ' and C 4 positions of vinorelbine, and two fluorine atoms are introduced at the C 2Q position. Changchun Flunan is currently in Phase III clinical trials, and the results indicate that vinflunine exhibits significant antitumor activity against a variety of tumor lineages (A. Kruc Z yn S ki, BTHill, Critical Review in Oncology/Hematology 2001, 40, 159- 173). Especially vinflunine l It can also guide the tumor regression of small cell lung cancer and kidney cancer, and is superior to the best vinblastine anticancer drug vinorelbine in many comprehensive evaluation indexes such as efficacy, toxicity and anti-tumor lineage. Therefore, it can be expected to have a good market prospect.
尽管取得了较为显著的进步，进一步改善长春碱类药物的药效及降低其毒性 的研究工作仍在继续。最近， 对长春碱， 长春新碱， 长春瑞滨上半部的芳环上进 行结构改造，也取得了一些进展 (LL.Scott, eatl. WO2005/055939A2; I.L.Scott, eatl. WO2005/055943A2)。 报道的实验结果显示出潜在的有前景的药效， 但构效关系 不明确。 Despite significant progress, research efforts to further improve the efficacy and reduce the toxicity of vinblastine continue. Recently, structural improvements have been made to the aromatic rings of vinblastine, vincristine, and vinorelbine in the upper half (LL. Scott, eatl. WO2005/055939A2; I.L. Scott, eatl. WO2005/055943A2). The reported experimental results show potential promising effects, but the structure-activity relationship is not clear.
总之， 根据已有的研究， 可以发现： 尽管对这类药物分子进行极细微的结构 改造， 都可能引起抗肿瘤活性， 毒副作用以及抗肿瘤谱系的显著差异。 In summary, based on previous studies, it can be found that, despite the minimal structural modification of such drug molecules, significant anti-tumor activity, toxic side effects, and significant differences in anti-tumor lineage may be caused.
在现有文献中， 迄今尚未有对长春氟宁上半部的芳环进行结构修饰的报道， 而如上所述， 长春氟宁在药效及毒性等方面较之现有的长春碱、长春新碱、长春 地辛、长春瑞滨均有优越之处， 因此， 对长春氟宁的芳环进行结构改造， 将有可 能发现新的更具潜力的药物分子。 发明内容 In the existing literature, there has been no report on the structural modification of the aromatic ring in the upper part of vinflunine. As mentioned above, vinflunine is more effective than vinblastine and vinca in the efficacy and toxicity. Alkali, vindesine, and vinorelbine have advantages. Therefore, structural modification of the aromatic ring of vinflunine will reveal new and more potential drug molecules. Summary of the invention
本发明涉及一种由通式 (I)表示的化合物或其盐: The present invention relates to a compound represented by the formula (I) or a salt thereof:
其中： 选自烷基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基 环垸基、 杂环 烷基、 卤素、 氨基、 氰基、 三氟甲基、 -N3、 -C(0)R5、 -COOR5、 -NR5C(0)R6, -NR5S(0)2R6 -NHC(S)NR5R6 , -C(OH)R5、 -(CH2)nNR5R6、 -NHC(0)NR5R6、 -CsCSi(R7)3、 -C(0)NR5R6、 -C(0)NHOH、 -S02NR5R6、 -NHS(0)2R5、 -S(0)2NR5R6、 -SR5、 -S(0)R5、 -S(0)2R5、 -SSR5、 -B(OR5)2、 -Sn(R7)3 ; 其中烷基、 烷氧基、 烯 基、炔基、 芳基、 杂芳基、杂环垸基可以进一步被一个或多个烷基、烷氧基、炔 基、 羟基、羟烷基、 氨基、 胺烷基、 氰基、 卤素、 三氟甲基、 乙酰基、 环烷基或 杂环垸基所取代； Wherein: selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroarylcyclodecyl, heterocycloalkyl, halogen, amino, cyano, trifluoromethyl, -N 3 , -C (0) R 5 , -COOR 5 , -NR 5 C(0)R 6 , -NR 5 S(0) 2 R 6 -NHC(S)NR 5 R 6 , -C(OH)R 5 , -( CH 2 ) n NR 5 R 6 , -NHC(0)NR 5 R 6 , -CsCSi(R 7 ) 3 , -C(0)NR 5 R 6 , -C(0)NHOH, -S0 2 NR 5 R6 -NHS(0) 2 R 5 , -S(0) 2 NR 5 R6, -SR 5 , -S(0)R 5 , -S(0) 2 R 5 , -SSR 5 , -B(OR 5 2 , -Sn(R 7 ) 3 ; wherein alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl can be further substituted by one or more alkyl, alkoxy, Alkynyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, halogen, trifluoromethyl, acetyl, cycloalkyl or heterocyclic thiol;
R2选自烷基或 -CH O); R 2 is selected from alkyl or -CH O);
R3选自氢原子、 烷基或 -C(0)R5 ; R 3 is selected from a hydrogen atom, an alkyl group or -C(0)R 5 ;
选自氢原子、 -C(0)R5或 -Si(R7)3； Selected from a hydrogen atom, -C(0)R 5 or -Si(R 7 ) 3 ;
R5和 各自分别选自氢原子、 烷基、 垸氧基、 环烷基、 卤代垸基、 芳基杂
芳基或杂环垸基； 其中垸基、环烷基、芳基、杂芳基或杂环烷基可以进一步被一 个或多个烷基、 烷氧基、 烯基、 羟基、 环烷基、 芳基、 杂芳基、 卤素或 -Ν 所取代； R 5 and each are respectively selected from a hydrogen atom, an alkyl group, a decyloxy group, a cycloalkyl group, a halogenated fluorenyl group, an aryl group An aryl or heterocyclic fluorenyl group; wherein the fluorenyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may be further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cycloalkyl, Substituted by an aryl group, a heteroaryl group, a halogen or a - hydrazine;
同时， R5与 可以与 Ν原子一起形成一个 4〜8元的杂环基； 其中 5〜8元 杂环内可以含有一个或多个 N、 0、 S原子； Meanwhile, R 5 may form a 4 to 8 membered heterocyclic group together with a halogen atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms;
R7为垸基； R 7 is a sulfhydryl group;
Z选自 -OR5、 - R5R6或 -NHNHC(0)R5； Z is selected from -OR 5 , - R5R6 or -NHNHC(0)R 5 ;
同时， R4和 Z可成键与插入的原子形成一个环； At the same time, R4 and Z can form a ring with the inserted atoms;
n是 0~4。 优选地， 在通式 (I)所述的化合物或其盐中 R3为氢原子或乙酰基。 n is 0~4. Preferably, in the compound of the formula (I) or a salt thereof, R 3 is a hydrogen atom or an acetyl group.
优选地， 在通式 (I)所述的化合物或其盐中 为氢原子。 Preferably, it is a hydrogen atom in the compound of the formula (I) or a salt thereof.
优选地， 在通式 (I)所述的化合物或其盐中 Z为甲氧基。 Preferably, Z is a methoxy group in the compound of the formula (I) or a salt thereof.
优选地， 在通式 (I)所述的化合物或其盐中 R3为氢原子或乙酰基， 为氢 原子， Z为甲氧基。 Preferably, in the compound of the formula (I) or a salt thereof, R 3 is a hydrogen atom or an acetyl group, which is a hydrogen atom, and Z is a methoxy group.
优选地， 在通式 (I)所述的化合物或其盐中 R2为甲酰基或烷基。 Preferably, R 2 is a formyl group or an alkyl group in the compound of the formula (I) or a salt thereof.
优选地， 在通式 (I)所述的化合物或其盐中 R2为烷基。 在通式 (I)所述的化合物或其盐中，通式 (I)以药学上可接受的游离态或者酸加 成盐的形式存在， 所述酸选自硫酸、 硝酸、 氢溴酸、 氢碘酸或磷酸等的无机酸， 或选自酒石酸、 乙酸、 甲磺酸、 苯磺酸、 甲苯磺酸、 柠檬酸、 马来酸、 富马酸或 乳酸等的有机酸， 优选为酒石酸。 具体地， 本发明涉及的的化合物包括: Preferably, R 2 is an alkyl group in the compound of the formula (I) or a salt thereof. In the compound of the formula (I) or a salt thereof, the formula (I) is present in the form of a pharmaceutically acceptable free form or an acid addition salt selected from the group consisting of sulfuric acid, nitric acid, hydrobromic acid, hydrogen An inorganic acid such as iodic acid or phosphoric acid, or an organic acid selected from the group consisting of tartaric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, maleic acid, fumaric acid or lactic acid, preferably tartaric acid. Specifically, the compounds to which the present invention relates include:
丁基长春氟宁
苯基长春氟宁 。、 Butyl vinflunine Phenyl vinflunine. ,
。 。、 甲基苯基)长春氟 宁
氯苯基)长春氟宁 . . , methylphenyl) vinflunine Chlorophenyl) vinflunine
氯苯基)长春氟宁 、
12'-氨基长春氟宁Chlorophenyl) vinflunine, 12'-amino vinflunine
28 28
F F F F
12，-(2,2,2-三氟乙酰胺) 12,-(2,2,2-trifluoroacetamide)
29 / 0 、 长春気宁 29 / 0 , Changchun Suining
？ ?
12，-(2,2-二氯乙酰胺基） 12,-(2,2-dichloroacetamido)
30 / ¾"。、 ^^ 30 / 3⁄4"., ^^
。 .
12'- (甲氧基甲酰胺基)长12'-(methoxyformamide) long
31 春氟宁
31 Chun Fanning
12'- (甲磺酰氨基)长春氟12'- (Methanesulfonylamino) vinca fluoride
32 宁 32 Ning
¾。 ¾。 3⁄4. 3⁄4.
12'-(N,N-二甲氨基)长春12'-(N,N-dimethylamino) Changchun
33 、 氟宁
(甲氨基)长春氟宁 33, flunin (methylamino) vinflunine
，- (乙酰氨基)长春氟宁 ,-(Acetylamino) vinflunine
° 甲氧基羰基长春氟 宁 ° methoxycarbonyl vinflunine
，-乙氧基羰基长春氟 宁
异丙氧基羰基长春 -ethoxycarbonyl vinflunine Isopropoxycarbonyl Changchun
， 乙基-硫脲）长舂 氟宁 、
N2007/002176 , ethyl-thiourea) N2007/002176
46 46
¾¾。 3⁄43⁄4.
12'-环丙基长春氟宁12'-cyclopropyl vinflunine
47 47
12'-(4-氟苯基)长春氟宁12'-(4-fluorophenyl) vinflunine
48 。、 48. ,
12'-甲基长春氟宁12'-methyl vinflunine
/ 0 N / 0 N
49 49
3-三乙基硅氧 -12，-碘代3-triethylsiloxy-12,-iodo
50 人 、 50 people,
3-三乙基硅氧 -12，- (；吡咯3-triethylsiloxy-12,- (;pyrrole
51 烷基 -1-)长春氟宁
进一步， 本发明涉及通式 (I)所示化合物的制备方法， 包括以下步骤： 以长春氟宁 (I-la)为原料， 在适当的温度 (-20°C〜3(TC)下， 在无水二氯甲垸 及三氟乙酸的混合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物；
51 alkyl-1-) vinflunine Further, the present invention relates to a process for the preparation of a compound of the formula (I), comprising the steps of: using vinflunine (I-la) as a raw material at a suitable temperature (-20 ° C to 3 (TC), at Reaction with a halogenating reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid to obtain a halogen-substituted compound of the formula (I-lb);
(I-la) (Mb) (I-la) (Mb)
或者将所述的长春氟宁 (I-la)在三氟乙酸溶剂中与六亚甲基四胺在适当的温 度 (20O〜100°C)下油浴反应得到通式 (I-lc)化合物； Alternatively, the vinflunine (I-la) is reacted with hexamethylenetetramine in an oil bath at a suitable temperature (20O to 100 ° C) in a solvent of trifluoroacetic acid to obtain a compound of the formula (I-lc). ;
(I-la) (Mc) 得到的通式化合物 (I-lb)在适当的温度 (-20°C〜40°C)下在二氯甲烷中与三氟 甲磺酸烷基硅烷基酯反应， 得到通式 (I-ld)化合物； (I-la) (Mc) The obtained compound (I-lb) is reacted with an alkylsilyl triflate at a suitable temperature (-20 ° C to 40 ° C) in dichloromethane. , obtaining a compound of the formula (I-ld);
如上所得的通式 (I-ld)化合物在甲苯中， 在三 (二亚苄基丙酮)二钯 (0)和 2-二 环己基膦 -2',4',6'-三异丙基 -Ι,Γ-联苯催化下与不同的胺反应得到通式 (I-lf)化合 物； The compound of the formula (I-ld) obtained above is in toluene, in tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphine-2',4',6'-triisopropyl - hydrazine, hydrazine-biphenyl catalyzed reaction with different amines to give a compound of the formula (I-lf);
通式化合物 (I-lc)在四氢呋喃溶液中， 在催化量的过渡金属试剂存在下， 与 不同的格氏试剂反应得到通式 (I-le)化合物；
The compound of the formula (I-lc) is reacted with a different Grignard reagent in a tetrahydrofuran solution in the presence of a catalytic amount of a transition metal reagent to obtain a compound of the formula (I-le);
将所述的通式化合物 (I-lb)， (I-lc), (I-le), (I-lf)分别在过渡金属催化下加热 40〜150°C进行偶联反应， 或与不同的胺在 25〜80Ό下还原胺化， 或在室温条件 下在二氯甲烷中进行戴斯一马丁 (Dess martin)氧化， 或在四氢呋喃溶剂中与四丁 基氟化铵反应脱掉垸基硅最终得到通式 (I)化合物； The above-mentioned compound (I-lb), (I-lc), (I-le), (I-lf) are respectively subjected to a coupling reaction under a transition metal catalysis of 40 to 150 ° C for coupling reaction, or different The amine is reductively aminated at 25 to 80 Torr, or Dess Martin oxidized in dichloromethane at room temperature, or reacted with tetrabutylammonium fluoride in tetrahydrofuran solvent to remove sulfonium silicon. Finally obtaining a compound of the formula (I);
其中- 选自烷基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、 环烷基、 杂环垸基、 卤素、氨基、氰基、三氟甲基、 -N3、 -C(0)R5、 -COOR5、 -NR5C(0)R6、 -NR5S(0)2R6、 -NHC(S)NR5R6、 -C(OH)R5、 -(C¾)nNR5 、 -NHC(0)NR5R6、 -CSCSi(R7)3、 -C(0)NR5R6、 -C(0)NHOH、 -S02NR5R6、 -NHS(0)2R5、 -S(0)2NR5R6、 -SR5、 -S(0)R5、 -S(0)2R5、 -SSR5、 -B(OR5)2、 -Sn(R7)3; 其中烷基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、杂环烷基可以进一步被一个或多个垸基、烷氧基、炔基、羟基、羟烷基、
氨基、 胺烷基、 氰基、 卤素、 三氟甲基、 乙酰基、 环烷基或杂环烷基所取代； ¾选自烷基或 -CH(0); Wherein - is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl with halogen, amino, cyano, trifluoromethyl, -N 3, - C(0)R 5 , -COOR 5 , -NR 5 C(0)R 6 , -NR 5 S(0) 2 R6, -NHC(S)NR 5 R 6 , -C(OH)R 5 , - (C3⁄4) n NR 5 , -NHC(0)NR 5 R 6 , -CSCSi(R 7 ) 3 , -C(0)NR 5 R 6 , -C(0)NHOH, -S0 2 NR 5 R 6 , -NHS(0) 2 R 5 , -S(0) 2 NR 5 R 6 , -SR 5 , -S(0)R 5 , -S(0) 2 R 5 , -SSR 5 , -B(OR 5 2 , -Sn(R 7 ) 3 ; wherein alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl may be further substituted by one or more mercapto, alkoxy, Alkynyl, hydroxy, hydroxyalkyl, Substituted by amino, aminoalkyl, cyano, halogen, trifluoromethyl, acetyl, cycloalkyl or heterocycloalkyl; 3⁄4 is selected from alkyl or -CH(0) ;
R3选自氢原子、 烷基或 -C(0)R5 ; R 3 is selected from a hydrogen atom, an alkyl group or -C(0)R 5 ;
选自氢原子丁基 -C(0)R5或 -Si(R7)3 ; Selected from hydrogen butyl-C(0)R 5 or -Si(R 7 ) 3 ;
R5和 各自分别选自氢原子、 烷基、 烷氧基、 环垸基、 卤代垸基、 芳基、 杂芳基或杂环烷基； 其中烷基、环烷基、芳基、杂芳基或杂环烷基可以进一步被 一个或多个烷基、烷氧基、烯基、 羟基、 环浣基、 芳基、 杂芳基、 卤素或 -NR5 所取代； R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated fluorenyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein alkyl group, cycloalkyl group, aryl group, hetero group The aryl or heterocycloalkyl group may be further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cyclodecyl, aryl, heteroaryl, halogen or -NR 5 groups;
同时， 与 可以与 N原子一起形成一个 4〜8元的杂环基： 其中 5〜8元 杂环内可以含有一个或多个 N、 0、 S原子； Meanwhile, a 4 to 8 membered heterocyclic group may be formed together with the N atom: wherein 5 to 8 members of the heterocyclic ring may contain one or more N, 0, S atoms;
R7为烷基； R 7 is an alkyl group;
R8选自烷基或环烷基， 其中烷基或环烷基可以进一步被一个或多个垸基、 烯基、 环烷基或卤素所取代； R 8 is selected from alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group may be further substituted by one or more mercapto, alkenyl, cycloalkyl or halogen;
Z选自 -OR5、 -NRsi^或 -NH HC(0)R5； Z is selected from -OR 5 , -NRsi^ or -NH HC(0)R 5 ;
同时， 和 Z可成键与插入的原子形成一个环； At the same time, and Z can form a ring with the inserted atoms;
X为卤素； X is a halogen;
n是。〜 4。 优选地， 在上述制备方法中， 选自垸基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、环烷基、杂环烷基、卤素、氨基、氰基、三氟甲基、 -N3、-C(0)R5、 -COOR5、 -NRsCCO)!^、 -NR5S(0)2R6、 -NHC(S)NR5¾、 -C(0H)R5、 -(CH2)nNR5R6、 -NHC(0)NRSR6、 -CsCSi(R7)3、 -C(0)NR5R6、 -C(0)NH0H、 -802 5 、 - HS(0)2R5、 - S(0)2NR5R6、 -SR5、 -S(0)R5、 -S(0)2R5、 -SSR5、 -B(OR5)2或 -Sn(R7)3 ; 其中烷基、垸氧基、烯基、 炔基、 芳基、 杂芳基、 杂环烷基可以进一步被一个或 多个烷基、 烷氧基、 炔基、 羟基、 羟烷基、 氨基、 胺烷基、 氰基、 卤素、三氟甲 基、 乙酰基、 环烷基或杂环烷基所取代； n is. ~ 4. Preferably, in the above preparation method, it is selected from the group consisting of an anthracenyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a halogen, an amino group, a cyano group, and a trifluoromethyl group. Base, -N 3 , -C(0)R 5 , -COOR 5 , -NRsCCO)!^, -NR 5 S(0) 2 R6, -NHC(S)NR 5 3⁄4, -C(0H)R 5 -(CH 2 ) n NR 5 R6, -NHC(0)NR S R 6 , -CsCSi(R 7 ) 3 , -C(0)NR 5 R 6 , -C(0)NH0H, -80 2 5 - HS(0) 2 R 5 , - S(0) 2 NR 5 R 6 , -SR 5 , -S(0)R 5 , -S(0) 2 R 5 , -SSR 5 , -B(OR 5 ) 2 or -Sn(R 7 ) 3 ; wherein alkyl, decyloxy, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl may be further substituted by one or more alkyl groups, alkoxy groups Substituted with alkynyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, halogen, trifluoromethyl, acetyl, cycloalkyl or heterocycloalkyl;
R2是焼基； R 2 is a sulfhydryl group;
R3是氢原子或乙酰基； R 3 is a hydrogen atom or an acetyl group;
为氢原子； Is a hydrogen atom;
R5和 各自分别选自氢原子、 烷基、 烷氧基、 环烷基、 卤代垸基、 芳基、 杂芳基或杂环烷基； 其中烷基、环烷基、芳基、杂芳基或杂环烷基可以进一步被 一个或多个綜基、 垸氧基、 烯基、 羟基、环垸基、 芳基、杂芳基、 卤素或 -NR5R6 所取代； R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated fluorenyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein alkyl group, cycloalkyl group, aryl group, hetero group The aryl or heterocycloalkyl group may be further substituted by one or more heptyl, decyloxy, alkenyl, hydroxy, cyclodecyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
同时， 与 可以与 N原子一起形成一个 4〜8元的杂环基； 其中 5〜8元 杂环内可以含有一个或多个 N、 0、 S原子；
R7为烷基； Meanwhile, a 4 to 8 membered heterocyclic group may be formed together with the N atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms; R 7 is an alkyl group;
R8选自烷基或环烧基， 其中垸基或环垸基可以进一步被一个或多个垸基、 烯基、 环垸基或卤素所取代； R 8 is selected from alkyl or cycloalkyl, wherein the indenyl or cycloalkyl can be further substituted by one or more mercapto, alkenyl, cyclodecyl or halogen;
Z为烷氧基； Z is an alkoxy group;
同时， 和 Z可成键与插入的原子形成一个环； At the same time, and Z can form a ring with the inserted atoms;
X为卤素； X is a halogen;
n是 0〜4。 具体地， 本发明涉及通式 (I)所示化合物的制备方法： n is 0 to 4. In particular, the present invention relates to a process for the preparation of a compound of the formula (I):
1) 以长春氟宁 (I-la)为原料，在 -20°C〜30°C下，在无水二氯甲垸及三氟乙酸 的混合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物； 1) Using vinflunine (I-la) as a raw material, reacting with a halogenated reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid at -20 ° C to 30 ° C to obtain a halogen-substituted pass. a compound of formula (I-lb);
(I-la) (I-lb) (I-la) (I-lb)
将所述的通式化合物 (I-lb)在过渡金属催化下加热 40〜150°C进行偶联反应， 最终得到通式 (I)化合物； The compound of the formula (I-lb) is subjected to a coupling reaction by heating at 40 to 150 ° C under a transition metal catalysis to finally obtain a compound of the formula (I);
其中， 各个取代基的定义如上所述； Wherein each substituent is as defined above;
X为卤素。 X is a halogen.
2) 以长春氟宁 (I-la)为原料， 在三氟乙酸溶剂中与六亚甲基四胺在 20°C〜 100Ό下油浴反应得到通式 (I-lc)化合物；
2) using vinflunine (I-la) as a raw material, reacting with hexamethylenetetramine in an oil bath at 20 ° C ~ 100 Torr in a solvent of trifluoroacetic acid to obtain a compound of the formula (I-lc);
(Ha) (I-lc) (Ha) (I-lc)
将所述的通式 (I-lc)化合物在无水二氯甲烷中， 与 RiNH2、三乙酰基硼氢化 钠在 25〜80Ό下进行还原胺化反应得到通式 (I)化合物； The compound of the formula (I-lc) is subjected to reductive amination reaction with RiNH 2 and sodium triacetoxyborohydride at 25 to 80 Torr in anhydrous dichloromethane to obtain a compound of the formula (I);
其中， 各个取代基的定义如上所述; Wherein each substituent is as defined above;
3) 以长春氟宁 (I-la)为原料， 在三氟乙酸溶剂中与六亚甲基四胺在 20Ό 下油浴进行反应得到通式 (I-lc)化合物； 3) using vinflunine (I-la) as a raw material, reacting with hexamethylenetetramine in a 20 Ό oil bath in a solvent of trifluoroacetic acid to obtain a compound of the formula (I-lc);
(I-la) (I-lc) 通式 (I-lc)化合物在无水四氢呋喃溶液中与 R8MgBr格氏反应得到通式 (I-le) 化合物；
(I-la) (I-lc) The compound of the formula (I-lc) is reacted with R 8 MgBr in an anhydrous tetrahydrofuran solution to obtain a compound of the formula (I-le);
将所述的通式 (I-le)化合物在室温条件下在二氯甲烷中进行戴斯一马丁氧 化， 得到通式 (I)化合物； The compound of the formula (I-le) is oxidized by Dess-Martin in dichloromethane at room temperature to obtain a compound of the formula (I);
其中， 各个取代基的定义如上所述； Wherein each substituent is as defined above;
选自烷基或环烷基， 其中烷基或环烷基可以进一步被一个或多个烷基、 烯基、 环烷基或卤素所取代。 It is selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group may be further substituted with one or more alkyl groups, alkenyl groups, cycloalkyl groups or halogens.
4) 以长舂氟宁 (I-la)为原料，在 -20°C〜30°C下，在无水二氯甲烷及三氟乙酸的混 合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物； 4) Using a long fluorination (I-la) as a raw material, reacting with a halogenated reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid at -20 ° C to 30 ° C to obtain a halogen-substituted pass. a compound of formula (I-lb);
(I-la) (I-lb) 得到的通式化合物 (I-lb)在 -2(TC〜40O下在二氯甲烷中与三氟甲磺酸烷基 硅烷基酯进行反应， 得到通式 (I-ld)化合物；
(I-la) (I-lb) The obtained compound of the formula (I-lb) is reacted with an alkylsilyl triflate at -2 (TC~40O in dichloromethane to give a formula (I-ld) compound;
如上所得的通式 (I-ld)化合物在甲苯中， 在三 (二亚苄基丙酮)二钯 (0)和 2-二 环己基膦 -2，，4，,6，-三异丙基-1,1，-联苯催化下与1 ^]¾反应得到通式(1-1£)化合物； The compound of the formula (I-ld) obtained above is in toluene, in tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphine-2,4,6,-triisopropyl -1,1,-biphenyl catalyzed reaction with 1 ^]3⁄4 to give a compound of the formula (1-1£);
将所述的通式化合物 (I-lf)在四氢呋喃溶剂中与四丁基氟化铵反应脱掉烷基 硅最终得到通式 (I)化合物； The compound of the formula (I-lf) is reacted with tetrabutylammonium fluoride in tetrahydrofuran solvent to remove the alkyl silicon to finally obtain the compound of the formula (I);
其中， 各个取代基的定义如上所述; Wherein each substituent is as defined above;
Rs选自烷基或环烷基， 其中烷基或环烷基可以进一步被一个或多个烷基、 烯基、 环垸基或^素所取代； Rs is selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group may be further substituted with one or more alkyl groups, alkenyl groups, cyclodecyl groups or groups;
X为卤素。 X is a halogen.
其中， 在上述制备方法 1 ) 中所使用的过渡金属催化剂选自： 醋酸钯、 碘化 亚铜、钯碳、三苯基膦、四- (三苯基膦)氯化钯、二- (三苯基膦)氯化钯、 Ι,Γ-双- (二 苯基膦)二茂铁或三 (二亚苄基丙酮)二钯。 在方法 4) 中所使用的卤代试剂选自 Ν-溴代琥珀酰亚胺、 Ν-碘代琥珀酰亚胺或一氯化碘。 在方法 4)所使用的混合溶 剂中无水二氯甲烷与三氟乙酸的比例为 10:1~1 :10， 优选为 1:1。 进一步， 本发明涉及一种如下列通式 (I-lb)和 (I-lc)所示的化合物， 其作为通 式 (I)化合物合成的中间体：
Wherein the transition metal catalyst used in the above preparation method 1) is selected from the group consisting of palladium acetate, cuprous iodide, palladium carbon, triphenylphosphine, tetrakis(triphenylphosphine)palladium chloride, di-(three Phenylphosphine) palladium chloride, rhodium, ruthenium-bis-(diphenylphosphino)ferrocene or tris(dibenzylideneacetone)dipalladium. The halogenating agent used in Process 4) is selected from the group consisting of Ν-bromosuccinimide, hydrazine-iodosuccinimide or iodine monochloride. The ratio of anhydrous dichloromethane to trifluoroacetic acid in the mixed solvent used in the method 4) is from 10:1 to 1:10, preferably 1:1. Further, the present invention relates to a compound represented by the following formula (I-lb) and (I-lc) which is an intermediate for the synthesis of the compound of the formula (I):
(I-lb) (I-lc) (I-lb) (I-lc)
其中： 各个取代基的定义如上所述； Wherein: the definition of each substituent is as described above;
X为卤素。 又进一步， 在本发明本涉及一种制备如上述通式 (I-lb)或者通式 (I-lc)所示化 合物的方法， 包括以下步骤： X is a halogen. Still further, the present invention relates to a process for producing a compound of the above formula (I-lb) or formula (I-lc), which comprises the steps of:
(I-lb) (I-lc) 以长春氟宁 (I-la)为原料， 在适当的温度 (-20°C〜30°C)下， 在无水二氯甲烷 及三氟乙酸的混合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物； (I-lb) (I-lc) using vinflunine (I-la) as a raw material, at a suitable temperature (-20 ° C ~ 30 ° C), in a mixture of anhydrous dichloromethane and trifluoroacetic acid Reacting with a halogenating reagent in a solvent to obtain a halogen-substituted compound of the formula (I-lb);
(I-la) (I-lb) (I-la) (I-lb)
或者将所述的长舂氟宁 (I-la)在三氟乙酸溶剂中与六亚甲基四胺在适当的温 度 (20°C〜 100Ό)下反应得到通式 (1-1 c)化合物；
Alternatively, the long flufenine (I-la) is reacted with hexamethylenetetramine in a solvent of trifluoroacetic acid at a suitable temperature (20 ° C to 100 Torr) to obtain a compound of the formula (1-1 c). ;
(I-la) (He) 又进一步， 在上述制备方法中， 以长春氟宁 (I-la)为原料， 与卤化试剂反应， 得到卤素取代的通式 (I-lb)化合物； 其中所述的卤化试剂选自： N-溴代琥珀酰亚 胺、 N-碘代琥珀酰亚胺或一氯化碘。 (I-la) (He) Still further, in the above preparation method, using vinflunine (I-la) as a raw material, and reacting with a halogenating reagent to obtain a halogen-substituted compound of the formula (I-lb); The halogenating agent is selected from the group consisting of: N-bromosuccinimide, N-iodosuccinimide or iodine monochloride.
又进一步， 在上述的制备方法中， 以长春氟宁 (I-la)为原料， 在无水二氯甲 烷及三氟乙酸的混合溶剂中与卤化试剂反应， 得到卤素取代通式 (I-lb)化合物； 其中混合溶剂中无水二氯甲烷与三氟乙酸的比例为 10:1〜1:10， 优选为 1 : 1。 Further, in the above preparation method, a thioprene (I-la) is used as a raw material, and a halogenating reagent is reacted in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid to obtain a halogen-substituted formula (I-lb). The compound; wherein the ratio of anhydrous dichloromethane to trifluoroacetic acid in the mixed solvent is from 10:1 to 1:10, preferably 1:1.
(I-la) (I-lb) 进一步，本发明涉及一种药物组合物，有含有治疗有效剂量的通式 (I)所述的 化合物或其盐， 以及药学可接受的载体或赋形剂。 (I-la) (I-lb) Further, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof, and a pharmaceutically acceptable carrier or excipient .
优选地， 在含有通式 (I)所述化合物或其盐的药物组合物中， R3为氢原子或 乙酰基。 Preferably, in the pharmaceutical composition containing the compound of the formula (I) or a salt thereof, R 3 is a hydrogen atom or an acetyl group.
优选地， 在含有通式 (I)所述化合物或其盐的药物组合物中， 为氢原子。 优选地， 在含有通式 (I)所述化合物或其盐的药物组合物中， Z为甲氧基。 优选地， 在含有通式 (I)所述化合物或其盐的药物组合物中， 为氢原子或 乙酰基， 为氢原子， Z为甲氧基。 Preferably, in the pharmaceutical composition containing the compound of the formula (I) or a salt thereof, it is a hydrogen atom. Preferably, in the pharmaceutical composition containing the compound of the formula (I) or a salt thereof, Z is a methoxy group. Preferably, in the pharmaceutical composition containing the compound of the formula (I) or a salt thereof, it is a hydrogen atom or an acetyl group, and is a hydrogen atom, and Z is a methoxy group.
优选地， 在含有通式 (I)所述化合物或其盐的药物组合物中， 为甲酰基。 优选地， 在含有通式 (I)所述化合物或其盐的药物组合物中， 为垸基。 进一步，本发明涉及通式 (I)所述化合物或其盐在制备治疗哺乳动物细胞增殖 相关疾病或其它疾病的药物中的用途。 Preferably, in the pharmaceutical composition containing the compound of the formula (I) or a salt thereof, it is a formyl group. Preferably, in the pharmaceutical composition containing the compound of the formula (I) or a salt thereof, it is an anthracenyl group. Further, the present invention relates to the use of the compound of the formula (I) or a salt thereof for the preparation of a medicament for treating a cell proliferation-related disease or other diseases in a mammal.
进一步，本发明涉及含有通式 (I)所述化合物或其盐的组合物在制备治疗哺乳 动物细胞增殖相关疾病或其它疾病的药物中的用途。 Further, the present invention relates to a use of a composition comprising the compound of the formula (I) or a salt thereof for the preparation of a medicament for treating a cell proliferation-related disease or other diseases in a mammal.
进一步，在上述与哺乳动物细胞增殖相关疾病或其它疾病包括癌症、细菌感 染疾病、 过敏症、 心脏病、 AIDS、 噬人体 T淋巴细胞病毒 1型感染、 人疱疹病
毒 3型、人疱疹病毒 4型、人乳头状瘤病毒、糖尿病、类风湿性关节炎、 阿耳茨 海默病、 发炎、 关节炎、 疟疾、 自身免疫性疾病、 湿疹、 红斑狼疮、 牛皮癣、 风 湿性疾病、 干燥角膜结膜炎综合征或病毒感染等疾病。 Further, the above diseases or other diseases associated with mammalian cell proliferation include cancer, bacterial infection diseases, allergies, heart disease, AIDS, human T lymphocyte virus type 1 infection, human herpes disease Toxic type 3, human herpesvirus type 4, human papillomavirus, diabetes, rheumatoid arthritis, Alzheimer's disease, inflammation, arthritis, malaria, autoimmune diseases, eczema, lupus, psoriasis, Rheumatic diseases, dry keratoconjunctivitis syndrome or viral infections.
其中， 所述细胞增殖相关疾病为癌症， 所述癌症选自肺癌、 肝癌、 胰腺癌、 食管癌、 胃癌、 甲状腺癌、黑色素癌、脑癌、膀胱癌、非小细胞肺癌、小细胞癌、 恶性淋巴瘤、 乳腺癌或恶性黑色素瘤。 Wherein the cell proliferation-related disease is cancer, and the cancer is selected from the group consisting of lung cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, thyroid cancer, melanoma, brain cancer, bladder cancer, non-small cell lung cancer, small cell carcinoma, malignant Lymphoma, breast cancer or malignant melanoma.
进一步，本发明涉及一种抑制哺乳动物细胞增殖的方法，包括对哺乳动物施 用治疗有效量的药物组合物，该组合物中含有通式 (I)所述化合物或其盐， 以及药 学可接受的载体或赋形剂。 Further, the present invention relates to a method for inhibiting proliferation of a mammalian cell comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formula (I) or a salt thereof, and a pharmaceutically acceptable Carrier or excipient.
进一步，在上述含有通式 (I)所述化合物或其盐的药物组合物所涉及的方法中 中， 哺乳动物为患有癌症的动物。 Further, in the method of the above pharmaceutical composition comprising the compound of the formula (I) or a salt thereof, the mammal is an animal having cancer.
进一步， 上述哺乳动物所患有的癌症包括实体瘤， 癌， 淋巴瘤， 霍奇金病， 肿瘤疾病，新生瘤疾病等。 换言之，本发明的目的在于提供一种下述通式 (I)所提供的长春碱类衍生物以 及它们互变异构体、对映体、非对映体、 消旋体和药学上可接受的盐， 以及代谢 产物和代谢前体或前药。 Further, the cancer of the above mammals includes solid tumors, cancer, lymphoma, Hodgkin's disease, neoplastic diseases, neoplastic diseases and the like. In other words, it is an object of the present invention to provide a vinblastine derivative of the following formula (I) and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable Salt, as well as metabolites and metabolic precursors or prodrugs.
其中： 选自垸基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、 环烷基、 杂环 垸基、 卤素、 氨基、 氰基、 三氟甲基、 -N3、 -C(0)R5、 -COOR5、 -NR5C(0)R6、 -NR5S(0)2R6、 -NHC(S)NR5R6、 -C(OH)R5、 -(C¾)nNR5R6、 -NHC(0)NR5R6、 -CHCSi(R7)3 -C(0)NR5R6、 -C(0)NHOH, -S02NR5R6、 -NHS(0)2R5. -S(0)2NR5R6、 -SR5、 -S(0)R5、 -S(0)2R5、 -SSR5、 -B(OR5)2、 -Sn(R7)3; 其中垸基、 烷氧基、 烯 基、炔基、 芳基、 杂芳基、 杂环烷基可以进一步被一个或多个烧基、烷氧基、炔 基、 羟基、 羟烧基、 氨基、 胺烷基、 氰基、 卤素、 三氟甲基、 乙酰基、 环烷基或 杂环烷基所取代；
N2007/002176 Wherein: is selected from the embankment, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl with halogen, amino, cyano, trifluoromethyl, -N 3, - C(0)R 5 , -COOR 5 , -NR 5 C(0)R 6 , -NR 5 S(0) 2 R6, -NHC(S)NR 5 R 6 , -C(OH)R 5 , - (C3⁄4) n NR 5 R 6 , -NHC(0)NR 5 R 6 , -CHCSi(R 7 ) 3 -C(0)NR 5 R 6 , -C(0)NHOH, -S0 2 NR 5 R6, -NHS(0) 2 R 5 . -S(0) 2 NR 5 R6, -SR 5 , -S(0)R 5 , -S(0) 2 R 5 , -SSR 5 , -B(OR 5 ) 2 , -Sn(R 7 ) 3 ; wherein fluorenyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl may be further substituted by one or more alkyl, alkoxy, alkyne Substituted with a hydroxy group, a hydroxyalkyl group, an amino group, an aminoalkyl group, a cyano group, a halogen, a trifluoromethyl group, an acetyl group, a cycloalkyl group or a heterocycloalkyl group; N2007/002176
R2选自烷基或 -CH(O); R 2 is selected from alkyl or -CH(O);
R3选自氢原子、 垸基或 -C(0)R5 ; R 3 is selected from a hydrogen atom, a fluorenyl group or -C(0)R 5 ;
选自氢原子、 -C(0)R5或 -Si(R7)3； Selected from a hydrogen atom, -C(0)R 5 or -Si(R 7 ) 3 ;
和 各自分别选自氢原子、 烷基、 烷氧基、 环烷基、 卤代烷基、 芳基、 杂芳基或杂环垸基； 其中垸基、环垸基、芳基、杂芳基或杂环烷基可以进一步被 一个或多个烷基、 烷氧基、 烯基、 羟基、 环烷基、 芳基、 杂芳基、 卤素或 -NR5R6 所取代； And each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated alkyl group, an aryl group, a heteroaryl group or a heterocyclic fluorenyl group; wherein a fluorenyl group, a cyclodecyl group, an aryl group, a heteroaryl group or a hetero group The cycloalkyl group may be further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cycloalkyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
同时， R5与 可以与 N原子一起形成一个 4〜8元的杂环基； 其中 5〜8元 杂环内可以含有一个或多个 N、 0、 S原子； Meanwhile, R 5 may form a 4 to 8 membered heterocyclic group together with the N atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms;
R7为烷基； R 7 is an alkyl group;
Z选自 -OR5、 -NRsRe或 -NHNHC(0)R5； Z is selected from -OR 5 , -NRsRe or -NHNHC(0)R 5 ;
同时， 和 Z可成键与插入的原子形成一个环； At the same time, and Z can form a ring with the inserted atoms;
n是 0~4。 本发明还涉及一种如下列通式 (I-lb)和 (I-lc)所示的化合物， 其作为通式 (I)化 合物合成的中间体： n is 0~4. The present invention also relates to a compound represented by the following formulas (I-lb) and (I-lc) which are intermediates for the synthesis of the compound of the formula (I):
(I-lb) (I-lc) (I-lb) (I-lc)
其中： R2选自烷基或 -CH(O); Wherein: R 2 is selected from alkyl or -CH(O);
R3选自氢原子、 垸基或 -C(0)R5 ; R 3 is selected from a hydrogen atom, a fluorenyl group or -C(0)R 5 ;
R4选自氢原子、 -C(0)R5或 -Si(R7)3； R4 is selected from a hydrogen atom, -C(0)R 5 or -Si(R 7 ) 3 ;
R5和 各自分别选自氢原子、 烷基、 烷氧基、 环烷基、 卤代烷基、 芳基、 杂芳基或杂环烷基； 其中垸基、环烷基、芳基、杂芳基或杂环垸基可以进一步被 一个或多个焼基、烷氧基、 烯基、羟基、环烷基、 芳基、 杂芳基、 卤素或 -NR5R6 所取代； R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated alkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein a fluorenyl group, a cycloalkyl group, an aryl group or a heteroaryl group; Or a heterocyclic fluorenyl group may be further substituted by one or more fluorenyl, alkoxy, alkenyl, hydroxy, cycloalkyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
同时， 与 可以与 N原子一起形成一个 4〜8元的杂环基； 其中 5〜8元 杂环内可以含有一个或多个 N、 0、 S原子； Meanwhile, a 4 to 8 membered heterocyclic group may be formed together with the N atom; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms;
R7为烷基； R 7 is an alkyl group;
Z选自 -OR5、 -NRsRe或 -NHNHC(0)R5； Z is selected from -OR 5 , -NRsRe or -NHNHC(0)R 5 ;
同时， 和 Z可成键与插入的原子形成一个环；
P T/CN2007/002176 At the same time, and Z can form a ring with the inserted atoms; PT/CN2007/002176
X为卤素。 在本发明通式 (I)所述的化合物或其盐中， 优选 为氢原子或乙酰基。 X is a halogen. In the compound of the formula (I) or a salt thereof, the hydrogen atom or the acetyl group is preferred.
在本发明通式 (I)所述的化合物或其盐中， 优选 为氢原子。 In the compound of the formula (I) of the present invention or a salt thereof, a hydrogen atom is preferred.
在本发明通式 (I)所述的化合物或其盐中， 优选 z为甲氧基。 In the compound of the formula (I) of the present invention or a salt thereof, z is preferably a methoxy group.
在本发明通式 (I)所述的化合物或其盐中， 优选 为氢原子或乙酰基， 为 氢原子， Z为甲氧基。 In the compound of the formula (I) or a salt thereof, the hydrogen atom or the acetyl group is preferably a hydrogen atom and Z is a methoxy group.
在本发明通式 (I)所述的化合物或其盐中， 优选 为甲酰基。 In the compound of the formula (I) of the present invention or a salt thereof, a formyl group is preferred.
在本发明通式 (I)所述的化合物或其盐中， 优选 为烷基。 In the compound of the formula (I) of the present invention or a salt thereof, an alkyl group is preferred.
在通式 (I)所述的化合物或其盐中，通式 (I)以药学上可接受的游离态或者酸加 成盐的形式存在，所述盐包括无机酸盐如硫酸盐、硝酸盐、氢溴酸盐、氢碘酸盐、 磷酸盐等和有机酸盐如酒石酸盐、 乙酸盐、 甲磺酸盐、 苯磺酸盐、 甲苯磺酸盐、 柠檬酸盐、 马来酸盐、 富马酸盐、 乳酸盐等。 优选为酒石酸盐。 本发明化合物的合成方法 In the compound of the formula (I) or a salt thereof, the formula (I) is present in the form of a pharmaceutically acceptable free form or an acid addition salt, the salt comprising a mineral acid salt such as a sulfate, a nitrate, Hydrobromide, hydroiodide, phosphate, etc. and organic acid salts such as tartrate, acetate, methanesulfonate, besylate, tosylate, citrate, maleate, rich Citrate, lactate, etc. Preferred is tartrate. Method for synthesizing the compound of the present invention
为了完成本发明的目的， 本发明采用如下技术方案- 本发明通式 (I)所述的化合物或其盐的制备方法， 包括以下步骤：
In order to accomplish the object of the present invention, the present invention adopts the following technical scheme - a preparation method of the compound of the formula (I) or a salt thereof of the present invention, comprising the following steps:
本发明涉及一种药物组合物，其含有治疗有效剂量的通式 (I)化合物或其盐和 药学可接受的载体或赋形剂，还涉及本发明通式 (I)化合物或其盐在制备抗肿瘤药
T/CN2007/002176 物中的用途。另外， 本发明还提供含有药物有效剂量的上述化合物的组合物， 以 及所述的组合物在制备抗肿瘤药物中的用途。 具体实施方式 The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier or excipient, and to a preparation of a compound of the formula (I) or a salt thereof according to the invention Antineoplastic agents Use in T/CN2007/002176. Further, the present invention provides a composition comprising a pharmaceutically effective amount of the above compound, and the use of the composition for the preparation of an antitumor drug. detailed description
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的 范围。 实施例 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. Example
化合物的结构是通过核磁共振 (NMR)或质谱 (MS)来确定的。 NMR位移 (δ)以 百万分之一 (ppm)的单位给出。 NMR的测定是用 Bruker AVANCE-400核磁仪， 测定溶剂为氘代氯仿 (CDC13)，内标为三甲基硅烷 (TMS)，化学位移是以 l(T6(ppm) 作为单位给出。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 3 ), the internal standard was trimethylsilane (TMS), and the chemical shift was given in units of 1 (T 6 (ppm).
MS的测定用 FINNIGAN LCQAd (ESI)质谱仪。 The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer.
薄层硅胶使用烟台黄海 HSGF254或青岛 GF254硅胶板 Thin layer of silica gel using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate
柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体。 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
CDC13: 氘代氯仿； CDC1 3 : deuterated chloroform;
长春氟宁： 如下列结构 (la)所表示的化合物； Vinflunine: a compound represented by the following structure (la);
12'-碘代长春氟宁 12'-iodo-vinflurine
氩气氛下， 在干燥的三口烧瓶中， 将长春氟宁 la(2.0 g， 2.07 mmol)搅拌下 溶解于 80 ml/80 ml的二氯甲烷 /三氟乙酸的混合溶剂中。干冰 -丙酮浴下，维持反 应体系内温度在 -15°C， 逐滴滴加碘代琥珀酰亚胺 (0.605 g， 2.69 mmol)的二氯甲
院 /三氟乙酸 (10 ml/10 ml)混合溶液， 30分钟滴完， 继续搅拌 30分钟， 点板跟踪 反应， 原料消失， 将反应液倒入冰水 (400 ml)中以淬灭反应， 加入饱和亚硫酸氢 钠溶液 (50 ml)， 用氨水调节溶液 pH值为 8， 用乙酸乙酯 (300 ml><4)萃取反应液。 合并有机相， 依次用饱和碳酸氢钠溶液 (200 ml)及饱和氯化钠溶液 (200 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得 残余物， 得到标题产物 12'-碘代长春氟宁 1(1.84 g， 白色固体)， 产率 94%。 Under a argon atmosphere, vinflunine la (2.0 g, 2.07 mmol) was dissolved in a mixed solvent of 80 ml/80 ml of dichloromethane/trifluoroacetic acid in a dry three-necked flask. Under dry ice-acetone bath, the temperature in the reaction system was maintained at -15 ° C, and iodosuccinimide (0.605 g, 2.69 mmol) of dichloromethane was added dropwise. In a mixed solution of trifluoroacetic acid (10 ml/10 ml), the mixture was stirred for 30 minutes, stirring was continued for 30 minutes, the reaction was stopped by clicking on the plate, the starting material disappeared, and the reaction solution was poured into ice water (400 ml) to quench the reaction. Saturated sodium hydrogen sulfite solution (50 ml) was added, the pH of the solution was adjusted to 8 with aqueous ammonia, and the mixture was extracted with ethyl acetate (300 ml >< 4). The combined organic layers were washed with EtOAc EtOAc (EtOAc) The obtained residue was purified to give the title product 12'- iodothiophene 1 (1.84 g, white solid).
ESI:[M+1]=943。 ESI: [M+1] = 943.
1H NMR (CDC13, 400MHz)59.69(brs, IH), 8.44(s, IH), 7.99(s, IH), 7.40(dd, 1H: J尸 8.4Hz, J2=1.2Hz), 6.9 l(d, IH, J=8.4Hz), 6.28(s, IH), 6.08(s, IH), 5.85(dd, IH, J!=10.4Hz, J2=4.0Hz), 5.40(s, IH), 5.27(d, IH, J=10.4Hz), 4.48(d, IH, J=13.2Hz), 4.25(d, IH, J=12.8Hz), 3.81(s, 3H), 3.78(s, 3H), 3.72(s, 4H), 3.38-3.25(m, 4H)， 3.04(dd, IH, Ji= 12.4Hz, J2=13.2Hz), 2.94(dd3 IH, J!=14.4Hz, J2=13.6Hz), 2.82-2.74(m, IH), 2.74(m, IH), 2.7 l(s, 3H), 2.57(dd, IH,
J2=6.4Hz), 2.47(s, IH), 2.40-2.30(m, IH), 2.26(d, IH, J=13.2Hz), 2.13-2.08(m, IH), 2.08(s, 3H), 1.84-1.79(m, 2H), 1.80-1.70(m, IH), 1.70-1.60(m, IH), 1.61(dd, 3H, J!=18.8Hz, J2=18.8Hz), 1.36-1.22(m, IH), 1.16-1.12(m, IH), 0.66(m, 3H, J!=7.2Hz, J2=7.2Hz)。 实施例 2 1H NMR (CDC1 3 , 400MHz) 59.69 (brs, IH), 8.44 (s, IH), 7.99 (s, IH), 7.40 (dd, 1H: J 8.4 Hz, J 2 = 1.2 Hz), 6.9 l ( d, IH, J=8.4Hz), 6.28(s, IH), 6.08(s, IH), 5.85(dd, IH, J!=10.4Hz, J 2 =4.0Hz), 5.40(s, IH), 5.27(d, IH, J=10.4Hz), 4.48(d, IH, J=13.2Hz), 4.25(d, IH, J=12.8Hz), 3.81(s, 3H), 3.78(s, 3H), 3.72(s, 4H), 3.38-3.25(m, 4H), 3.04(dd, IH, Ji= 12.4Hz, J 2 = 13.2Hz), 2.94(dd 3 IH, J!=14.4Hz, J 2 =13.6 Hz), 2.82-2.74(m, IH), 2.74(m, IH), 2.7 l(s, 3H), 2.57(dd, IH, J 2 = 6.4 Hz), 2.47 (s, IH), 2.40-2.30 (m, IH), 2.26 (d, IH, J = 13.2 Hz), 2.13-2.08 (m, IH), 2.08 (s, 3H) , 1.84-1.79(m, 2H), 1.80-1.70(m, IH), 1.70-1.60(m, IH), 1.61(dd, 3H, J!=18.8Hz, J 2 = 18.8Hz), 1.36-1.22 (m, IH), 1.16-1.12 (m, IH), 0.66 (m, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz). Example 2
12'-甲酰基长春氟宁 12'-formyl vinflunine
氩气氛下， 在干燥的三口烧瓶中， 将长春氟宁 la(1.80 g， 1.6 mmol)搅拌下 溶解于 60 ml三氟乙酸中，加入六亚甲基四胺 (0.75 g， 5.3 mmol), 油浴 75°C加热 回流 20分钟， 点板跟踪反应， 原料消失， 自然冷却倒入碎冰中。 用氨水调节溶 液 pH为 7〜8，再用乙酸乙酯 (200 mlx4)萃取反应液，合并有机相，依次用水 (100 ml)及饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液 减压浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-甲酰基长春氟宁 2(0.991 g, 白色固体)， 产率 73 %。 Under a argon atmosphere, vinflunine la (1.80 g, 1.6 mmol) was dissolved in 60 ml of trifluoroacetic acid in a dry three-necked flask, and hexamethylenetetramine (0.75 g, 5.3 mmol) was added. The bath was heated to reflux at 75 ° C for 20 minutes, the reaction was tracked by a spot plate, the raw material disappeared, and it was naturally cooled and poured into crushed ice. The pH of the solution was adjusted to 7 to 8 with aqueous ammonia, and the reaction mixture was extracted with ethyl acetate (200 ml×4). The organic phase was combined and washed with water (100 ml) and saturated sodium chloride (100 ml). The residue was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
ESI:[M+l]=845 o ESI: [M+l]=845 o
1H NMR (CDCI3, 400MHz)510.95(s, IH), 9.55(brs, IH), 8.03(s, IH), 8.14(s, IH), 7.67(d, IH, J=8.4Hz), 7.15(d, IH, J=8.4Hz), 6.2 l(s, IH), 6.02(s, IH), 5.78(dd,
N2007/002176 1H NMR (CDCI3, 400MHz) 510.95 (s, IH), 9.55 (brs, IH), 8.03 (s, IH), 8.14 (s, IH), 7.67 (d, IH, J = 8.4 Hz), 7.15 (d , IH, J=8.4Hz), 6.2 l(s, IH), 6.02(s, IH), 5.78(dd, N2007/002176
1H， J^lO.OHz, J2=4.0Hz), 5.33(s, IH), 5.20(d, IH, J=10.4Hz), 4.49(d, IH, J=12.8Hz): 4.33(d, 1H， J=12.8Hz)， 3.75(s, 3H), 3.71(s, 3H), 3.65(s, 3H), 3.60(s, IH), 3.29-3.20(m: 3H), 3.18-3.15(m, IH), 3.00(dd, 1H，
1H, J^lO.OHz, J 2 =4.0Hz), 5.33(s, IH), 5.20(d, IH, J=10.4Hz), 4.49(d, IH, J=12.8Hz) : 4.33(d, 1H, J=12.8Hz), 3.75(s, 3H), 3.71(s, 3H), 3.65(s, 3H), 3.60(s, IH), 3.29-3.20(m : 3H), 3.18-3.15(m , IH), 3.00 (dd, 1H,
J2=14.4Hz), 2.80-2.70(m, IH), 2.64(s, 3H), 2.60-2.50(m, 2H), 2.37(s, 1H)， 2.24-2.19(m, 2H), 2.10-2.04(m, IH), 2.02(s, 3H), 1.72-1.70(m, IH), 1.80-1.61(m, 4H): 1.55(dd, 3H, J尸 18.4Hz， J2=19.2Hz), l.ll(m， IH), 0.60(dd, 3H， K.2HZ, J2=7.6Hz)。 实施例 3 J 2 = 14.4 Hz), 2.80-2.70 (m, IH), 2.64 (s, 3H), 2.60-2.50 (m, 2H), 2.37 (s, 1H), 2.24-2.19 (m, 2H), 2.10- 2.04(m, IH), 2.02(s, 3H), 1.72-1.70(m, IH), 1.80-1.61(m, 4H): 1.55(dd, 3H, J corp. 18.4Hz, J 2 = 19.2Hz), L.ll(m, IH), 0.60 (dd, 3H, K.2HZ, J 2 = 7.6 Hz). Example 3
12'-氰基长春氟宁 12'-cyano vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 搅拌下依次加入盐酸羟胺 (168 mg， 2.4 mmol), 12，-甲酰基长春氟宁 2的乙腈溶液 (0.338 g， 0.40 mmol,溶于 40 ml乙腈) 及三乙胺 (352 ul， 2.56 mmol)。 油浴 100〜110°C下加热回流 1.5小时， 再加入邻 苯二甲酸酐 (0.352 mg， 2.4 mmol), 继续加热回流过夜。 次日点板跟踪反应， 原 料消失， 冷却反应液， 减压蒸除溶剂， 用乙酸乙酯稀释 (400 ml)， 依次用饱和碳 酸氢钠溶液 (100 ml)及饱和氯化钠溶液 (50 ml)洗涤， 乙酸乙酯层用无水硫酸镜干 燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'- 氰基长春氟宁 3(0.157 g， 白色固体)， 产率 47%。 Under a argon atmosphere, a dry round bottom flask was charged with hydroxylamine hydrochloride (168 mg, 2.4 mmol), 12,-formyl vinflunine 2 in acetonitrile (0.338 g, 0.40 mmol, dissolved in 40 ml of acetonitrile). And triethylamine (352 ul, 2.56 mmol). The oil bath was heated to reflux at 100 to 110 ° C for 1.5 hours, then phthalic anhydride (0.352 mg, 2.4 mmol) was added, and the mixture was heated to reflux overnight. The next day, the reaction was stopped, the starting material disappeared, the reaction solution was cooled, the solvent was evaporated under reduced pressure, and diluted with ethyl acetate (400 ml), followed by saturated sodium hydrogen carbonate solution (100 ml) and saturated sodium chloride solution (50 ml) After washing, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. , yield 47%.
ESI:[M+1]=842。 ESI: [M+1] = 842.
1H NMR (CDC13, 400MHz)58.72(s, IH), 8.06(s, IH), 7.40(dd, 1H， J尸 8.4Hz， J2=1.4Hz), 7.19(d， IH, J=8.4Hz), 6.24(s, IH), 6.10(s, IH), 5.86(dd, IH, J^lO.OHz, J2-4.0Hz), 5.39(s, IH), 5.28(d, IH, J=10.0Hz), 4.53(d, IH, J=12.8Hz), 4.37(d, IH, J=12.8Hz), 3.82(s, 3H), 3.78(s, 3H), 3.76(s, 1H)， 3.74(s, 3H), 3.38-3.24(m, 4H), 3.08(dd, IH, J!=12.8Hz, J2=13.2Hz), 2.94(dd, IH, J^H^Hz, J2=13.6Hz), 2.82(m, IH), 2.74(m, IH), 2.72(s, 3H), 2.64(m, IH), 2.47(s, IH), 2.37-2.3 l(m, 2H), 2.12(m, IH), 2.10(s, 3H), 1.87-1.74(m, 2H), 1.74-1.62(m, 2H)， 1.62(dd, 3H, J尸 18.8Hz, J2=l 8.8Hz), 1.28-1.22(m, 2H), 0.66(dd, 3H, J!=7.2Hz, J2=7.2Hz)。 实施例 4 1H NMR (CDC1 3 , 400MHz) 58.72 (s, IH), 8.06 (s, IH), 7.40 (dd, 1H, J 8.4 Hz, J 2 = 1.4 Hz), 7.19 (d, IH, J = 8.4 Hz) ), 6.24(s, IH), 6.10(s, IH), 5.86(dd, IH, J^lO.OHz, J 2 -4.0Hz), 5.39(s, IH), 5.28(d, IH, J= 10.0 Hz), 4.53 (d, IH, J = 12.8 Hz), 4.37 (d, IH, J = 12.8 Hz), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 (s, 1H), 3.74 (s, 3H), 3.38-3.24(m, 4H), 3.08(dd, IH, J!=12.8Hz, J 2 = 13.2Hz), 2.94(dd, IH, J^H^Hz, J 2 =13.6 Hz), 2.82(m, IH), 2.74(m, IH), 2.72(s, 3H), 2.64(m, IH), 2.47(s, IH), 2.37-2.3 l(m, 2H), 2.12( m, IH), 2.10(s, 3H), 1.87-1.74(m, 2H), 1.74-1.62(m, 2H), 1.62(dd, 3H, J corp. 18.8Hz, J 2 =l 8.8Hz), 1.28 -1.22 (m, 2H), 0.66 (dd, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz). Example 4
12'-丁基长春氟宁
12'-butyl vinflunine
氩气氛下，在干燥的三口烧瓶中，将 12'-碘代长春氟宁 1 (0.35 g， 0.37 mmol) 搅拌下溶解于 20 ml无水四氯呋喃中，加入醋酸钯 (8.3 mg， 0.037 mmol)和三苯基 膦 (19.4 mg, 0.074 mmol)的四氢呋喃 (3 ml)溶液。 另取一干燥反应瓶， 将氯化锌 (0.303 g， 2.22 imnol)搅拌下溶解于 4 ml四氢呋喃中，随后逐滴滴加正丁基锂 (0.93 ml, 1.48 mmol), 室温搅拌， 随后滴加到上述三口瓶中。 室温搅拌 24小时后， 加入乙酸乙酯 (200 ml)淬灭反应。减压抽滤，滤液依次用饱和碳酸氢钠溶液 (50 ml) 及饱和氯化钠溶液 (50 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压 浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-丁基长春氟宁 4(71 mg, 白色固体)， 产率 22%。 Under an argon atmosphere, 12'-iodovinfluramine 1 (0.35 g, 0.37 mmol) was dissolved in 20 ml of anhydrous tetrachlorofuran in a dry three-necked flask, and palladium acetate (8.3 mg, 0.037 mmol) was added. And a solution of triphenylphosphine (19.4 mg, 0.074 mmol) in tetrahydrofuran (3 ml). Another dry reaction flask was taken, and zinc chloride (0.303 g, 2.22 imnol) was dissolved in 4 ml of tetrahydrofuran with stirring, followed by dropwise addition of n-butyllithium (0.93 ml, 1.48 mmol), stirring at room temperature, followed by dropwise addition. Go to the above three bottles. After stirring at room temperature for 24 hours, the reaction was quenched with ethyl acetate (200 ml). The filtrate was filtered with EtOAc (EtOAc)EtOAc. The resulting residue was purified by chromatography to crystalljjjjjjjj
ESI:[M+1]=873。 ESI: [M+1] = 873.
1H NMR (CDC13, 400MHz)59.75(brs, 1H), 8.30(s, 1H), 7.45(s, 1H), 7.04(d, 1H, J=8.0Hz), 7.00(d, 1H, J=8.4Hz), 6.39(s, 1H), 6.09(s, 1H), 5.84(dd, 1H, J^lO^Hz, J2=4.0Hz), 5.41(s, 1H), 5.27(d, 1H, J=10.4Hz), 4.49(d, 1H, J=12.4Hz), 4.36(d, 1H, J=12.8Hz), 3.81(s, 3H), 3.78(s, 3H), 3.71(s, 1H), 3.68(s, 3H), 3.40-3.29(m, 3H), 3.29-3.20(m, 1H), 3.05(dd, 1H, Ji=12.4Hz, J!=12.4Hz), 2.97(dd， 1H, Ji=14.8Hz, J2=14.0Hz), 2.85-2.75(m, 1H), 2.74-2.67(m, 3H), 2.7 l(s, 3H), 2.60-2.50(m, 1H)， 2.53(s, 1H), 2.40-2.33(m, 1H), 2.25(d, 1H, J=14.0Hz), 2.15-2.05(m, 1H), 2.09(s, 3H), 1.87-1.77(m, 2H), 1.77-1.70(m, 1H), 1.70-1.50(m, 3H), 1.61(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.50-1.30(m, 2H), 1.30-1.20(m, 1H), 1.20-1.10(m, 1H), 1.00-0.80(m, 3H); 0.70(dd, 3H, J尸 6.8Hz, J2=7.2Hz)。 实施例 5 1H NMR (CDC1 3 , 400MHz) 59.75 (brs, 1H), 8.30 (s, 1H), 7.45 (s, 1H), 7.04 (d, 1H, J = 8.0 Hz), 7.00 (d, 1H, J = 8.4 Hz), 6.39(s, 1H), 6.09(s, 1H), 5.84(dd, 1H, J^lO^Hz, J 2 =4.0Hz), 5.41(s, 1H), 5.27(d, 1H, J = 10.4 Hz), 4.49 (d, 1H, J = 12.4 Hz), 4.36 (d, 1H, J = 12.8 Hz), 3.81 (s, 3H), 3.78 (s, 3H), 3.71 (s, 1H), 3.68(s, 3H), 3.40-3.29(m, 3H), 3.29-3.20(m, 1H), 3.05(dd, 1H, Ji=12.4Hz, J!=12.4Hz), 2.97(dd, 1H, Ji =14.8 Hz, J 2 =14.0 Hz), 2.85-2.75 (m, 1H), 2.74-2.67 (m, 3H), 2.7 l(s, 3H), 2.60-2.50 (m, 1H), 2.53 (s, (1), 2.40-2. -1.70 (m, 1H), 1.70-1.50 (m, 3H), 1.61 (dd, 3H, J corp. 18.8 Hz, J 2 = 18.8 Hz), 1.50-1.30 (m, 2H), 1.30-1.20 (m, 1H), 1.20-1.10 (m, 1H), 1.00-0.80 (m, 3H) ; 0.70 (dd, 3H, J 6.8 Hz, J 2 = 7.2 Hz). Example 5
12'-苯基长春氟宁 12'-phenyl vinflunine
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S08I膽 00Z OAV
1H NMR (CDC13, 400MHz)59.80(brs, IH), 8.4 l(s, IH), 7.86(s, IH), 7.56(d, 2H, J=7.6Hz), 7.42(d, IH, J=8.0Hz), 7.23(d, 2H, J=7.6Hz), 7.18(d, IH, J=8.4Hz), 6.40(s, 1H)， 6.10(s, IH), 5.85(dd, IH, J^lO.ffiz, J2=4.0Hz), 5.28(d, IH, J=10.8Hz), 4.52-4.40(m, 2H), 3.82(s, 3H)， 3.78(s, 3H), 3.73(s, IH), 3.71(s, 3H), 3.36-3.32(m, 3H), 3.29-3.25(m, IH), 3.02-2.95(m, 2H), 2.82 (m, IH), 2.74(m, IH), 2.72(s, 3H), 2.63-2.55(m, 2H), 2.39(s, 3H), 2.45-2.34(m, 2H), 2.17(m, IH), 2.10(s, 3H)， 1.88-1.83(m, 2H), 1.79-1.70(m, IH), 1.70-1.66(m, IH), 1.62(dd, 3H, Ji=18.4Hz, J2=18.8Hz), 1.26-1.15(m, 2H), 0.73 (dd, 3H, J尸 6.8Hz, J2=7.2Hz)。 实施例 7 S08I 00Z OAV 1H NMR (CDC1 3 , 400MHz) 59.80 (brs, IH), 8.4 l(s, IH), 7.86(s, IH), 7.56(d, 2H, J=7.6Hz), 7.42(d, IH, J= 8.0Hz), 7.23(d, 2H, J=7.6Hz), 7.18(d, IH, J=8.4Hz), 6.40(s, 1H), 6.10(s, IH), 5.85(dd, IH, J^ lO.ffiz, J 2 =4.0Hz), 5.28(d, IH, J=10.8Hz), 4.52-4.40(m, 2H), 3.82(s, 3H), 3.78(s, 3H), 3.73(s, IH), 3.71(s, 3H), 3.36-3.32(m, 3H), 3.29-3.25(m, IH), 3.02-2.95(m, 2H), 2.82 (m, IH), 2.74(m, IH) , 2.72(s, 3H), 2.63-2.55(m, 2H), 2.39(s, 3H), 2.45-2.34(m, 2H), 2.17(m, IH), 2.10(s, 3H), 1.88-1.83 (m, 2H), 1.79-1.70(m, IH), 1.70-1.66(m, IH), 1.62(dd, 3H, Ji=18.4Hz, J 2 = 18.8Hz), 1.26-1.15(m, 2H) , 0.73 (dd, 3H, J 6.8 Hz, J 2 = 7.2 Hz). Example 7
12'-(4-氯苯基)长春氟宁 12'-(4-chlorophenyl) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1 (0.35 g， 0.37 mmol) 搅拌下溶解于无水 35 ml 1,4-二氧六环中， 加入碳酸铯 (0.606 g， 1.85 mmol)和 4- 氯苯基硼酸 (0.116 g， 0.74 mmol)。 另取一干燥反应瓶， 将 Ι,Γ-双- (二苯基膦)二 茂铁 (21 mg, 0.037 mmol)和醋酸钯 (8 mg， 0.037 mmol)搅拌下溶解于 3.5 ml的 1， 4-二氧六环中， 取 3.5 ml此催化剂溶液加入上述圆底烧瓶中。 油浴 60Ό下搅拌 24小时后， 加入乙酸乙酯 (100 ml)淬灭反应。 减压抽滤， 滤液依次用饱和碳酸氢 钠溶液 (30 ml)及饱和氯化钠溶液 (30 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥，过 滤，滤液减压浓縮，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-(4-氯苯 基)长春氟宁 7(0.18 g， 白色固体)， 产率 52.5 %。 Under an argon atmosphere, 12'-iodovinfluramine 1 (0.35 g, 0.37 mmol) was dissolved in anhydrous 35 ml of 1,4-dioxane under stirring in a round bottom flask, and cesium carbonate was added. (0.606 g, 1.85 mmol) and 4-chlorophenylboronic acid (0.116 g, 0.74 mmol). Another dry reaction flask was taken, and hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (21 mg, 0.037 mmol) and palladium acetate (8 mg, 0.037 mmol) were dissolved in 3.5 ml of 1, 4 with stirring. In the dioxane, 3.5 ml of this catalyst solution was added to the above round bottom flask. The oil bath was stirred at 60 ° C for 24 hours and then quenched with ethyl acetate (100 ml). The mixture was filtered with EtOAc (EtOAc m.) The resulting residue was purified to purified crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
ESI:[M+1]=927。 ESI: [M+1] = 927.
1H NMR (CDC13, 400MHz)59.67(brs, IH), 8.45(s, IH), 7.82(s, IH) ,7.57(d, 2H, J=8.4Hz), 7.36-7.39(m, 3H), 7.19(d, IH, J=8.4Hz), 6.38(s, IH), 6.10(s, IH), 5.84(dd, 1H， J尸 10.4Hz, J2=4.0Hz), 5.42(s, IH), 5.28(d, IH, J=10.0Hz), 4.54(d, IH, J=12.4Hz): 4.40(m, IH), 3.82(s, 3H), 3.78(s, 3H), 3.72(s, 3H), 3.70(s, IH), 3.37-3.3 l(m, 3H), 3.28-3.24(m, IH), 3.07(dd, 1H， J!=12.4Hz, J2=13.2Hz), 2.99(dd, IH, J尸 14.8Hz, J2=13.6Hz), 2.81(m, IH), 2.72(s， 3H), 2.67(m, IH), 2.60 (dd, IH, J!=15.6Hz, J2=5.6Hz), 2.5 l(s, IH), 2.35-2.30(m, IH), 2.28(d, IH, J=15.6Hz), 2.16-2.12(m, IH), 2.10(s, 3H)， 1.86-1.83(m, 2H), 1.80-1.72(m, IH), 1.70-1.64(m, IH), 1.61(dd, IH, J尸 18.4Hz, J2=19.2Hz), 1.31-1.27(m, IH), 1.15-1.14(m, IH), 0.72(dd, 3H, =7.2Uz,
实施例 8 1H NMR (CDC1 3 , 400MHz) 59.67 (brs, IH), 8.45 (s, IH), 7.82 (s, IH), 7.57 (d, 2H, J = 8.4 Hz), 7.36-7.39 (m, 3H), 7.19(d, IH, J=8.4Hz), 6.38(s, IH), 6.10(s, IH), 5.84(dd, 1H, J corp. 10.4Hz, J 2 =4.0Hz), 5.42(s, IH) , 5.28(d, IH, J=10.0Hz), 4.54(d, IH, J=12.4Hz) : 4.40(m, IH), 3.82(s, 3H), 3.78(s, 3H), 3.72(s, 3H), 3.70(s, IH), 3.37-3.3 l(m, 3H), 3.28-3.24(m, IH), 3.07(dd, 1H, J!=12.4Hz, J 2 = 13.2Hz), 2.99( Dd, IH, J corpse 14.8 Hz, J 2 =13.6 Hz), 2.81 (m, IH), 2.72 (s, 3H), 2.67 (m, IH), 2.60 (dd, IH, J! = 15.6 Hz, J 2 = 5.6 Hz), 2.5 l (s, IH), 2.35-2.30 (m, IH), 2.28 (d, IH, J = 15.6 Hz), 2.16-2.12 (m, IH), 2.10 (s, 3H) , 1.86-1.83 (m, 2H), 1.80-1.72 (m, IH), 1.70-1.64 (m, IH), 1.61 (dd, IH, J corp. 18.4 Hz, J 2 = 19.2 Hz), 1.31-1.27 ( m, IH), 1.15-1.14(m, IH), 0.72(dd, 3H, =7.2Uz, Example 8
12'-(2-氯苯基)长春氟宁 12'-(2-chlorophenyl) vinflunine
ESI:[M+1]=927。 ESI: [M+1] = 927.
1H NMR (CDC13, 400MHz)59.80(brs, 1H), 8.46(s, 1H), 7.74-7.69(m, 2H), 7.49-7.41 (mj 2H), 7.31-7.23(m, 2H), 7.18(d, 1H, J=8.4Hz), 6.44(s, 1H), 6.10(s, 1H), 5.86(dd, 1H, =9.SRz, J2=3.8Hz), 5.43(s, 1H), 5.29(d, 1H, J=10.0Hz), 4.51-4.3 l(m, 2H), 3.82(s, 3H), 3.79(s, 3H), 3.73(s, 1H), 3.72(s, 3H), 3.39-3.27(m, 4H), 3.08-2.96(m, 2H), 2.85-2.77(m, 2H), 2.72(s, 3H), 2.63-2.56(m, 2H), 2.97-2.88(m, 1H), 2.28(d, 1H, J=15.2Hz), 2.17-2.10(m, 1H), 2.10(s, 3H), 1.90-1.83(m, 2H), 1.76-1.65(m, 2H), 1.60(dd, 3H, J!=l 8.8Hz, J2=18.8Hz), 1.35-1.26(m, 1H), 1.19-1.13(m, 1H)， 0.73(dd, 3H,】尸7.21¾】2=7.21¾)。 实施例 9 1H NMR (CDC1 3 , 400MHz) 59.80 (brs, 1H), 8.46 (s, 1H), 7.74-7.69 (m, 2H), 7.49-7.41 ( mj 2H), 7.31-7.23 (m, 2H), 7.18 ( d, 1H, J=8.4Hz), 6.44(s, 1H), 6.10(s, 1H), 5.86(dd, 1H, =9.SRz, J 2 =3.8Hz), 5.43(s, 1H), 5.29 (d, 1H, J=10.0Hz), 4.51-4.3 l(m, 2H), 3.82(s, 3H), 3.79(s, 3H), 3.73(s, 1H), 3.72(s, 3H), 3.39 -3.27(m, 4H), 3.08-2.96(m, 2H), 2.85-2.77(m, 2H), 2.72(s, 3H), 2.63-2.56(m, 2H), 2.97-2.88(m, 1H) , 2.28(d, 1H, J=15.2Hz), 2.17-2.10(m, 1H), 2.10(s, 3H), 1.90-1.83(m, 2H), 1.76-1.65(m, 2H), 1.60(dd , 3H, J!=l 8.8Hz, J 2 = 18.8Hz), 1.35-1.26(m, 1H), 1.19-1.13(m, 1H), 0.73(dd, 3H, corp.7.213⁄4) 2 =7.213⁄4 ). Example 9
12'-(2,4-二氟苯基)长春氟宁
12'-(2,4-difluorophenyl) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.35 g， 0.37 mmol) 搅拌下溶解于 35 ml的 1,4-二氧六环中， 加入碳酸铯 (0.606 g, 1.85 mmol)和 2,4- 二氟苯基硼酸 (0.117 g， 0.74 mmol)。 另取一干燥反应瓶， 将 1，1 '-双- (二苯基膦） 二茂铁 (21 mg, 0.037 mmol)和醋酸钯 (8 mg， 0.37 mmol)搅拌下溶解于 3.5 ml的 1,4-二氧六环中，取 3.5 ml此催化剂溶液加入上述圆底烧瓶中。油浴 60°C下搅拌 24小时， 加入乙酸乙酯 (200 ml)淬灭反应。 减压抽滤， 滤液依次用饱和碳酸氢钠 溶液 (100 ml)及饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥，过 滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-(2,4- 二氟苯基)长春氟宁 9(0.194 g， 黄色固体)， 产率 56.6%。 Under an argon atmosphere, 12'-iodovinflurine 1 (0.35 g, 0.37 mmol) was dissolved in 35 ml of 1,4-dioxane with stirring in a round bottom flask, and cesium carbonate was added. 0.606 g, 1.85 mmol) and 2,4-difluorophenylboronic acid (0.117 g, 0.74 mmol). Another dry reaction flask was taken, and 1,1 '-bis-(diphenylphosphino)ferrocene (21 mg, 0.037 mmol) and palladium acetate (8 mg, 0.37 mmol) were dissolved in 3.5 ml of 1, In the 4-dioxane, 3.5 ml of this catalyst solution was added to the above round bottom flask. The oil bath was stirred at 60 ° C for 24 hours and then quenched by ethyl acetate (200 ml). The mixture was filtered with EtOAc (EtOAc m.) The obtained residue was purified to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
ESI:[M+1]=929。 ESI: [M+1] = 929.
1H NMR (CDC13, 400MHz)89.86(brs, IH), 8.47(s, IH), 7.71 (s, IH), 7.46(dd, IH, Ji=15.2Hz, J2=8.4Hz), 7.3 l(d, IH, J=8.4Hz), 7.19(d, IH, J=8.4Hz), 6.96-6.88(m, 2H), 6.42(s, IH), 6.10(s, IH), 5.86(dd, IH, J!=10.4Hz, J2-4.0Hz), 5.42(s, IH), 5.29(d, IH, J=4.0Hz), 4.53(d, IH, J=12.8Hz), 4.38(m, IH), 3.82(s, 3H), 3.79(s, 3H), 3.74(s, IH), 3.72(s, 3H), 3.38-3.25(m, 4H), 3.08-2.95(m, 2H), 2.84-2.78(m, IH), 2.73(m, IH), 2.72(s, 3H), 2.64-2.60(m, IH), 2.56(s, 1H)， 2.42(m, IH), 2.28(d, IH, J=13.6Hz), 2.18-2.14(m, IH), 2.11(s, 3H), 1.90-1.79(m, 2H), 1.77-1.70(m, IH), 1.68-1.64(m, IH), 1.61(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.33-1.24(m, 1H)， 1.18-1.14(m5 IH), 0.73(dd, 3H, Ji=7.6Hz, J2=7.2Hz)。 实施例 10 1H NMR (CDC1 3 , 400MHz) 89.86 (brs, IH), 8.47 (s, IH), 7.71 (s, IH), 7.46 (dd, IH, Ji = 15.2 Hz, J 2 = 8.4 Hz), 7.3 l ( d, IH, J=8.4Hz), 7.19(d, IH, J=8.4Hz), 6.96-6.88(m, 2H), 6.42(s, IH), 6.10(s, IH), 5.86(dd, IH , J!=10.4Hz, J 2 -4.0Hz), 5.42(s, IH), 5.29(d, IH, J=4.0Hz), 4.53(d, IH, J=12.8Hz), 4.38(m, IH ), 3.82(s, 3H), 3.79(s, 3H), 3.74(s, IH), 3.72(s, 3H), 3.38-3.25(m, 4H), 3.08-2.95(m, 2H), 2.84- 2.78(m, IH), 2.73(m, IH), 2.72(s, 3H), 2.64-2.60(m, IH), 2.56(s, 1H), 2.42(m, IH), 2.28(d, IH, J=13.6Hz), 2.18-2.14(m, IH), 2.11(s, 3H), 1.90-1.79(m, 2H), 1.77-1.70(m, IH), 1.68-1.64(m, IH), 1.61 (dd, 3H, J corpse 18.8 Hz, J 2 = 18.8 Hz), 1.33-1.24 (m, 1H), 1.18-1.14 (m 5 IH), 0.73 (dd, 3H, Ji = 7.6 Hz, J 2 = 7.2 Hz). Example 10
12'-(4-氰基苯基)长春氟宁 12'-(4-cyanophenyl) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.35 g， 0.37 mmol)
07 002176 搅拌下溶解于 35 ml无水 1,4-二氧六环中， 加入碳酸铯 (0.606 g， 1.85 mmol)和 4- 氰基苯基硼酸 (109 mg, 0.74 mmol)。 另取一干燥反应瓶， 将 1，Γ-双- (二苯基膦） 二茂铁 (21 mg, 0.037 mmol)和醋酸钯 (8 mg, 0.037 mmol)搅拌下溶解于 3.5 ml的 l 54-二氧六环中， 取 3.5 ml此催化剂溶液加入上述圆底烧瓶中。油浴 60Ό下搅拌 24小时， 加入乙酸乙酯 (200 ml)淬灭反应。 减压抽滤， 滤液依次用饱和碳酸氢钠 溶液 (100 ml)， 饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸缓干燥， 过 滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-(4-氰基 苯基)长春氟宁 10(0.153 g， 黄色固体)， 产率 45.6%。 12'-iodovinfluramine 1 (0.35 g, 0.37 mmol) in a dry round bottom flask under argon 07 002176 was dissolved in 35 ml of anhydrous 1,4-dioxane with stirring, and cesium carbonate (0.606 g, 1.85 mmol) and 4-cyanophenylboronic acid (109 mg, 0.74 mmol) were added. Another dry reaction flask was taken, and 1, Γ-bis-(diphenylphosphino)ferrocene (21 mg, 0.037 mmol) and palladium acetate (8 mg, 0.037 mmol) were dissolved in 3.5 ml of l 5 4 with stirring. In the dioxane, 3.5 ml of this catalyst solution was added to the above round bottom flask. The oil was stirred at 60 ° C for 24 hours and then quenched by ethyl acetate (200 mL). The mixture was filtered under reduced pressure. EtOAc EtOAc m. The resulting residue was purified by chromatography to crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
ESI:[M+1]=918。 ESI: [M+1] = 918.
1H NMR (CDC13, 400MHz)59.69(brs, IH), 8.52(s, 1H), 7.90(s, 1H), 7.60(d, 2H, J=8.0Hz), 7.42(d, 1H， J=8.4Hz), 7.23(d, 1H， J=8.8Hz), 7.00(d， 2H, J=8.4Hz), 6.36(s, IH), 6.10(s, IH), 5.85(dd, IH, J^lO^Hz, J2=4.8Hz), 5.41(s, IH), 5.30(s, IH), 4.56(d, IH, J=13.2Hz), 4.43(d, IH, J=12.4Hz), 3.83(s, 3H), 3.79(s, 3H), 3.73(s, 4H)， 3.33-3.37(m, 3H), 3.29-3.23(m, IH), 3.08(dd, IH, J尸 12.4Hz, J2=12.8Hz), 2.99(dd, IH, J!=14.0Hz, J2=14.4Hz), 2.85-2.79(m, IH), 2.72(s, 3H), 2.72-2.67(m, IH), 2.61(dd, IH, Ji=14.4Hz, J2=5.2Hz), 2.51(s, IH), 2.36-2.29(m, 2H), 2.17-2.10(m, IH), 2.10(s, 3H), 1.87-1.80(m, 2H), 1.80-1.70(m, 1H)， 1.70-1.65(m, IH), 1.62(dd， 3H, ^=18.8Hz, J2=18.8Hz), 1.33-1.26(m, IH), 1.20-1.12(m, IH), 0.62(dd, 3H, J!=7.2Hz, J2=7.2Hz)。 实施例 11 1H NMR (CDC1 3 , 400MHz) 59.69 (brs, IH), 8.52 (s, 1H), 7.90 (s, 1H), 7.60 (d, 2H, J = 8.0 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.23(d, 1H, J=8.8Hz), 7.00(d, 2H, J=8.4Hz), 6.36(s, IH), 6.10(s, IH), 5.85(dd, IH, J^lO ^Hz, J 2 =4.8Hz), 5.41(s, IH), 5.30(s, IH), 4.56(d, IH, J=13.2Hz), 4.43(d, IH, J=12.4Hz), 3.83( s, 3H), 3.79(s, 3H), 3.73(s, 4H), 3.33-3.37(m, 3H), 3.29-3.23(m, IH), 3.08(dd, IH, J corp. 12.4Hz, J 2 = 12.8 Hz), 2.99 (dd, IH, J! = 14.0 Hz, J 2 = 14.4 Hz), 2.85-2.79 (m, IH), 2.72 (s, 3H), 2.72-2.67 (m, IH), 2.61 (dd, IH, Ji=14.4Hz, J 2 =5.2Hz), 2.51(s, IH), 2.36-2.29(m, 2H), 2.17-2.10(m, IH), 2.10(s, 3H), 1.87 -1.80 (m, 2H), 1.80-1.70 (m, 1H), 1.70-1.65 (m, IH), 1.62 (dd, 3H, ^=18.8 Hz, J 2 = 18.8 Hz), 1.33-1.26 (m, IH), 1.20-1.12 (m, IH), 0.62 (dd, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz). Example 11
12'-(2-三氟甲基苯基)长春氟宁 12'-(2-trifluoromethylphenyl) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.35 g， 0.37 mmol) 搅拌下溶解于 35 ml的 1，4-二氧六环中， 加入碳酸铯 (0.606 g， 1.85 mmol)和 2-三 氟甲基苯基硼酸 (0.14 g， 0.74 mmol)。 另取一干燥反应瓶， 将 Ι,Γ-双- (二苯基膦) 二茂铁 (21 mg, 0.037 mmol)和醋酸钯 (8 mg, 0.037 mmol)搅拌下溶解于 3.5 ml的 1,4-二氧六环中，取 3.5 ml此催化剂溶液加入上述圆底烧瓶中。油浴 60°C下搅拌 24小时， 加入乙酸乙酯 (100 ml)淬灭反应。 减压抽滤， 滤液依次用饱和碳酸氢钠 溶液 (30 ml)，饱和氯化钠溶液 (30 ml)洗涤，乙酸乙酯层用无水硫酸镁干燥，过滤， 滤液减压浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-(2-三氟甲基
苯基)长春氟宁 11(0.138 g, 黄色固体)， 产率 38.8%。 Under an argon atmosphere, 12'-iodovinflurine 1 (0.35 g, 0.37 mmol) was dissolved in 35 ml of 1,4-dioxane with stirring in a round bottom flask, and cesium carbonate was added. 0.606 g, 1.85 mmol) and 2-trifluoromethylphenylboronic acid (0.14 g, 0.74 mmol). Another dry reaction flask was prepared by dissolving hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (21 mg, 0.037 mmol) and palladium acetate (8 mg, 0.037 mmol) in 3.5 ml of 1,4 In the dioxane, 3.5 ml of this catalyst solution was added to the above round bottom flask. The oil bath was stirred at 60 ° C for 24 hours, and the reaction was quenched by ethyl acetate (100 ml). The mixture was filtered under reduced pressure. EtOAc EtOAc m. The obtained residue was purified by chromatography to give the title product 12'-(2-trifluoromethyl Phenyl) vinflunine 11 (0.138 g, yellow solid), yield 38.8%.
ESI:[M+1]=961。 ESI: [M+1] = 961.
1H NMR (CDC13, 400MHz)59.65(brs, IH), 7.74(s, IH, J=8.0Hz), 7.58(s, IH), 7.52(d， IH, J==7.2Hz), 7.45-7.39(m, 2H), 7.14(m, 2H)， 6.38 (s, IH), 6.10(s, IH), 5.86(dd, 1H， Ji=9.6Hz, J2=4.0Hz), 5.43(s, IH), 5.28(d, IH, J=10.0Hz)3 4.52(d, IH, J=12.8Hz), 4.3 l(m, IH), 3.82(s, 3H)， 3.79(s, 3H), 3.74(s, 3H), 3.72(s, IH), 3.39-3.26(m, 4H), 3.07-2.94(m, 2H), 2.80(m, IH), 2.72(s, 3H), 2.70(m, IH), 2.61(dd, IH, J^l 6.8Hz, J2=5.6Hz), 2.50(s, IH), 2.30(m, 2H), 2.13(m, 1H)， 2.10(s, 3H), 1.90-1.83(m, 2H), 1.78-1.65(m, 2H), 1.60(dd, 3H,
J2=l 9.2Hz), 1.26(m, IH), 1.15(m, IH), 0.71(dd, 3H, J尸 7.2Hz, J2=7.6Hz)。 实施例 12 1H NMR (CDC1 3 , 400MHz) 59.65 (brs, IH), 7.74 (s, IH, J = 8.0 Hz), 7.58 (s, IH), 7.52 (d, IH, J == 7.2 Hz), 7.45-7.39 (m, 2H), 7.14(m, 2H), 6.38 (s, IH), 6.10(s, IH), 5.86(dd, 1H, Ji=9.6Hz, J 2 =4.0Hz), 5.43(s, IH ), 5.28(d, IH, J=10.0Hz) 3 4.52(d, IH, J=12.8Hz), 4.3 l(m, IH), 3.82(s, 3H), 3.79(s, 3H), 3.74( s, 3H), 3.72(s, IH), 3.39-3.26(m, 4H), 3.07-2.94(m, 2H), 2.80(m, IH), 2.72(s, 3H), 2.70(m, IH) , 2.61 (dd, IH, J^l 6.8Hz, J 2 =5.6Hz), 2.50(s, IH), 2.30(m, 2H), 2.13(m, 1H), 2.10(s, 3H), 1.90- 1.83(m, 2H), 1.78-1.65(m, 2H), 1.60(dd, 3H, J 2 = l 9.2 Hz), 1.26 (m, IH), 1.15 (m, IH), 0.71 (dd, 3H, J 7.2 Hz, J 2 = 7.6 Hz). Example 12
12，-三甲基硅乙炔基长春氟宁 12,-trimethylsilylacetylene vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.377 g， 0.4 mmol) 搅拌下溶解于 12 ml无水甲苯及 3 ml无水四氢呋喃中， 加入碘化亚铜 (22.8 mg， 0.12 mmol)、二 (三苯基膦)氯化钯 (30 mg， 0.04 mmol)、三乙胺 (0.55 ml， 3.2 mmol) 和三甲基硅乙炔 (0.24 ml， 1.6 mmol)。 油浴 60°C下搅拌 18小时， 点板跟踪反应， 原料消失。 搅拌下向反应液中加入 50 ml饱和碳酸氢钠， 乙酸乙酯 (100 mix 4) 萃取反应体系， 合并有机相， 用饱和氯化钠水溶液 (25 mlX 1)洗， 乙酸乙酯层用 无水硫酸缓干燥 1小时， 过滤， 滤液减压浓缩， 得到标题产物 12，-三甲基硅乙炔 基长春氟宁 12(0.35 g， 黄色固体)， 产率 95%。 Under an argon atmosphere, 12'-iodovinfluramine 1 (0.377 g, 0.4 mmol) was dissolved in 12 ml of anhydrous toluene and 3 ml of anhydrous tetrahydrofuran in a dry round bottom flask. Copper (22.8 mg, 0.12 mmol), bis(triphenylphosphine)palladium chloride (30 mg, 0.04 mmol), triethylamine (0.55 ml, 3.2 mmol) and trimethylsilylacetylene (0.24 ml, 1.6 mmol) . The oil bath was stirred at 60 ° C for 18 hours, and the reaction was tracked by a spot plate, and the raw materials disappeared. 50 ml of saturated sodium hydrogencarbonate and ethyl acetate (100 mix 4) were added to the reaction mixture under stirring to extract the reaction system, and the organic phase was combined, washed with saturated aqueous sodium chloride (25 ml×1), The sulfuric acid was slowly dried for 1 hour, filtered, and the filtrate was concentrated to dryness to give the title product 12,-trimethylsilylacetyl vinflunine 12 (0.35 g, yellow solid), yield 95%.
ESI:[M+1]=913。 实施例 13 ESI: [M+1] = 913. Example 13
12，-乙炔基长春氟宁
12,-ethynyl vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-三甲基硅乙炔基长春氟宁 12(0.35 g， 0.4 mmol)搅拌下溶解于 20 ml无水四氢呋喃中，加入三水合四丁基氟化铵的四氢 呋喃溶液 (0.5 g， 1.6 mmol, 溶于 15 ml四氢呋喃)。 冰盐浴下反应 30分钟， 点板 跟踪反应， 原料消失。 加入饱和食盐水 (50 ml)淬灭反应， 搅拌 10分钟。 用乙酸 乙酯 (100 mlx4)萃取反应液。 合并有机相， 用无水硫酸镁干燥， 过滤， 滤液减压 浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12，-乙炔基长春氟宁 13(0.19 g， 白色固体)， 产率 60%。 Under a argon atmosphere, 12'-trimethylsilylacetyl vinflunine 12 (0.35 g, 0.4 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran with stirring in a dry round bottom flask, and tetrabutyl trihydrate was added. A solution of ammonium fluoride in tetrahydrofuran (0.5 g, 1.6 mmol, dissolved in 15 ml of tetrahydrofuran). The reaction was carried out for 30 minutes in an ice salt bath, and the reaction was followed by a spotting, and the raw materials disappeared. The reaction was quenched by the addition of brine (50 ml) and stirred for 10 min. The reaction solution was extracted with ethyl acetate (100 ml×4). The combined organic phases were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 60%.
ESI:[M+1]=841。 ESI: [M+1] = 841.
1H NMR (CDC13, 400MHz)59.69(brs, IH), 8.42(s, 1H)， 7.80(brs, IH), 7.23(d， IH, J=8.8Hz), 7.00(d, IH, J=8.4Hz), 6.20(s, IH), 6.02(s, IH), 5.80-5.79(m, IH), 5.32(s, IH), 5.21(d, IH, J=10.4Hz), 4.46-4.44(m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.66(s: 3H), 3.63(s, IH), 3.31-3.26(m, 3H), 3.22-3.16(m, IH), 2.92(s, IH), 2.90-2.70(m, 2H), 2.76-2.63(m, 4H), 2.65(s, 3H), 2.62-2.44(m, 4H), 2.07-2.0 l(m, IH), 2.03(s, 3H), 1.56(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.25-1, 14(m, IH), 1.13-1.07(m, IH), 0.61 (dd, 3H, J尸 6.8Hz, J2=7.2Hz)。 实施例 14 1H NMR (CDC1 3 , 400MHz) 59.69 (brs, IH), 8.42 (s, 1H), 7.80 (brs, IH), 7.23 (d, IH, J = 8.8 Hz), 7.00 (d, IH, J=8.4 Hz), 6.20(s, IH), 6.02(s, IH), 5.80-5.79(m, IH), 5.32(s, IH), 5.21(d, IH, J=10.4Hz), 4.46-4.44(m , 2,,,,, 2.92(s, IH), 2.90-2.70(m, 2H), 2.76-2.63(m, 4H), 2.65(s, 3H), 2.62-2.44(m, 4H), 2.07-2.0 l(m, IH) , 2.03(s, 3H), 1.56(dd, 3H, J corp. 18.8 Hz, J 2 = 18.8 Hz), 1.25-1, 14 (m, IH), 1.13-1.07 (m, IH), 0.61 (dd, 3H, J 6.8 Hz, J 2 = 7.2 Hz). Example 14
12'-[N-(4-甲氧基苯基)氨基]甲基长春氟宁 12 '-[N-(4-Methoxyphenyl)amino]methyl vinflunine
氩气氛下，事 燥雜.圆底:烧瓶中，将 1 -甲酰基长春 宁 2(0.169 g， 0.20 mmol) 搅拌下溶解于 l mi ¾^^:甲醇中， 加入对甲苯磺酸 (3'8 mg, 0.20 mmol), 对甲氧 基苯胺 (74 mg， 0.60 mmol)。袖浴 65Ό搅拌 4小时后，加入氰基硼氢化钠 (75 mg， 0.60 mmol),继续反应 2小时，点板跟踪反应结束，加入饱和¾酸氢钠溶液 (50 ml) 淬灭反应， 用乙酸乙酯 (100 mlx3)萃取反应液。 合并有机相， 用饱和氯化钠溶液
(100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱 色谱法纯化所得残余物， 得到标题产物 12'-[N-(4-甲氧基苯基)氨基]甲基长春氟 宁 14(0.117 g， 白色固体)， 产率 61.5 %。 Under argon atmosphere, dryness. Round bottom: In a flask, 1-formyl vinorelbine 2 (0.1 6 9 g, 0.20 mmol) was dissolved in 1 mi 3⁄4^^ : methanol with stirring, and p-toluenesulfonic acid was added. 3'8 mg, 0.20 mmol), p-methoxyaniline (74 mg, 0.60 mmol). After stirring for 4 hours in a sleeve bath, stirring for 4 hours, sodium cyanoborohydride (75 mg, 0.60 mmol) was added, and the reaction was continued for 2 hours. The reaction was completed by spotting, and the reaction was quenched with saturated aqueous sodium hydrogen sulfate (50 ml). The reaction solution was extracted with ethyl acetate (100 ml x 3). Combine the organic phase with a saturated sodium chloride solution After washing with (100 ml), EtOAc EtOAcjjjjjjjjjjjjj Base amino]methyl vinflunine 14 (0.117 g, white solid), yield 61.5%.
ESI:[M+1]=952。 ESI: [M+1] = 952.
1H NMR (CDC13, 400MHz)59.68(brs, IH), 8.40(s5 IH), 7.70(s, IH), 7.19(d, IH, J=8.0Hz), 7.10(d, 1H， J=8.4Hz), 6.79-6.73(m, 2H), 6.64(d, 2H, J=8.4Hz), 6.36(s, 1H)， 6.09(s, IH), 5.84(dd, IH =9.2Uz, J2=3.2Hz), 5.41(s, IH), 5.27(d, IH, J=10.4Hz), 4.5 l(d, IH, J=12.4Hz), 4.33(m, IH), 3.81(s, 3H), 3.78(s, 3H), 3.74(s, 3H), 3.72(s, IH), 3.71(s， 3H), 3.36-3.28(m, 3H)， 3.28-3.25(m, IH), 3.07(dd, IH, J尸 11·6Ηζ, J2=13.2Hz), 2.97(dd, IH, J!=14.4Hz, J2=13.6Hz), 2.83-2.77(m, IH), 2.75-2.64(m, IH), 2.7 l(s, 3H), 2.58(dd, IH, J尸 14.0Hz, J2=4.8Hz), 2.50(s, 1H)， 2.17-2.00(m, IH), 1.26(m, 1H)， 2.40-2.30(m, IH), 2.29(d, IH, J=15.2Hz), 2.09(s, 3H), 1.85(m, 1H)， 1.82(m, IH), 1.78-1.70(m, IH), 1.70-1.60(m, IH), 1.61(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.19(brs, IH), 0.69(dd, 3H, J^T. Hz, J2=6.8Hz)。 实施例 15 1H NMR (CDC1 3 , 400MHz) 59.68 (brs, IH), 8.40 (s 5 IH), 7.70 (s, IH), 7.19 (d, IH, J = 8.0 Hz), 7.10 (d, 1H, J = 8.4 Hz), 6.79-6.73(m, 2H), 6.64(d, 2H, J=8.4Hz), 6.36(s, 1H), 6.09(s, IH), 5.84(dd, IH =9.2Uz, J 2 = 3.2Hz), 5.41(s, IH), 5.27(d, IH, J=10.4Hz), 4.5 l(d, IH, J=12.4Hz), 4.33(m, IH), 3.81(s, 3H), 3.78(s, 3H), 3.74(s, 3H), 3.72(s, IH), 3.71(s, 3H), 3.36-3.28(m, 3H), 3.28-3.25(m, IH), 3.07(dd, IH, J corpse 11.6 Ηζ, J 2 = 13.2 Hz), 2.97 (dd, IH, J! = 14.4 Hz, J 2 = 13.6 Hz), 2.83-2.77 (m, IH), 2.75-2.64 (m, IH) ), 2.7 l(s, 3H), 2.58 (dd, IH, J corp. 14.0 Hz, J 2 = 4.8 Hz), 2.50 (s, 1H), 2.17-2.00 (m, IH), 1.26 (m, 1H) , 2.40-2.30(m, IH), 2.29(d, IH, J=15.2Hz), 2.09(s, 3H), 1.85(m, 1H), 1.82(m, IH), 1.78-1.70(m, IH ), 1.70-1.60 (m, IH), 1.61 (dd, 3H, J corp. 18.8 Hz, J 2 = 18.8 Hz), 1.19 (brs, IH), 0.69 (dd, 3H, J^T. Hz, J 2 =6.8Hz). Example 15
12，-[N-(2-吗啡啉 -4-基乙基)氨基]甲基长春氟宁 12,-[N-(2-morpholine-4-ylethyl)amino]methyl vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 将 12'-甲酰基长春氟宁 2(0.169 g， 0.2 mmol), 搅拌下溶解于 20 ml二氯甲垸中， 加入 4-(2-乙胺基)吗啡啉 (75 ul， 0.60 mmol). 室温搅拌 4小时后， 加入三乙酰硼氢化钠 (0.127 g， 0.60 mmol), 继续反 应 3小时， 点板跟踪反应结束， 加入饱和碳酸氢钠溶液 (50 ml)淬灭反应，用乙酸 乙酯 (100 mlx3)萃取反应液。合并有机相，用饱和氯化钠溶液 (100 ml)洗涤， 乙酸 乙酯层用无水硫酸镁干燥， 过滤，滤液减压浓缩， 用硅胶柱色谱法纯化所得残余 物， 得到标题产物 12，-[ -(2-吗啡啉 -4-基乙基)氨基]甲基长春氟宁 15(99 mg， 白 色固体)， 产率 52%。 Under an argon atmosphere, 12'-formyl vinflunine 2 (0.169 g, 0.2 mmol) was dissolved in 20 ml of dichloromethane in a dry round bottom flask, and 4-(2-ethylamine) was added. Base morpholine (75 ul, 0.60 mmol). After stirring at room temperature for 4 hours, sodium triacetoxyborohydride (0.127 g, 0.60 mmol) was added, and the reaction was continued for 3 hours. The reaction was completed by spotting, and saturated sodium bicarbonate solution was added. 50 ml) was quenched and the reaction was extracted with ethyl acetate (100 ml×3). The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH [-(2-morpholine-4-ylethyl)amino]methyl vinflunine 15 (99 mg, white solid), yield 52%.
1H NMR (CDCI3, 400MHz)59.50(brs, IH), 8.37(s, IH), 7.58(s, IH), 7.14(d, IH, J=8.0Hz), 7.09(d, IH, J=8.4Hz), 6.36(s, IH), 6.09(s, IH), 5.85(dd, IH, J^lO.OHz, J2=4.0Hz), 5.41(s, IH), 5.28(d, IH, J=10.0Hz), 4.50(d, IH, J=12.8Hz), 4.33(d, IH, J=12.4Hz), 3.88(s5 2H), 3.81(s, 3H), 3.78(s, 3H), 3.71(s, IH), 3.70(s, 3H), 3.68(dd,
4H,
J2=13.6Hz), 2.97(dd, IH, J!=14.4Hz, J2=14.0Hz), 2.88-2.78(m, IH), 2.76(dd, 2H5 J!=6.0Hz, J2=6.0Hz), 2.71(s, 3H), 2.68(m, IH), 2.57(dd, IH, J!=15.2Hz, J2=6.0Hz), 2.52(dd, 2H, J!=6.0Hz, J2=5.6Hz), 2.50(s, IH), 2.40(dd, 4H, J!=4.0Hz, J2=4.4Hz), 2.37-2.32(m, IH), 2.25(d, IH, J=l 2.4Hz), 2.09(s， 3H), 2.07(m, IH), 1.85-1.81(m5 2H), 1.78-1.70(m, IH), 1.67-1.63(m, IH), 1.61(dd, 3H, Jfl S.SHz, J2=18.8Hz), 1.26(m, IH), 1.12(m, IH), 0.69(dd, 3H， J!=7.2Hz, J2=7.6Hz)。 实施例 16 1H NMR (CDCI3, 400MHz) 59.50 (brs, IH), 8.37 (s, IH), 7.58 (s, IH), 7.14 (d, IH, J = 8.0 Hz), 7.09 (d, IH, J = 8.4 Hz ), 6.36(s, IH), 6.09(s, IH), 5.85(dd, IH, J^lO.OHz, J 2 =4.0Hz), 5.41(s, IH), 5.28(d, IH, J= 10.0 Hz), 4.50 (d, IH, J = 12.8 Hz), 4.33 (d, IH, J = 12.4 Hz), 3.88 (s 5 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.71 (s, IH), 3.70(s, 3H), 3.68(dd, 4H, J 2 =13.6 Hz), 2.97 (dd, IH, J! = 14.4 Hz, J 2 = 14.0 Hz), 2.88-2.78 (m, IH), 2.76 (dd, 2H 5 J! = 6.0 Hz, J 2 = 6.0Hz), 2.71(s, 3H), 2.68(m, IH), 2.57(dd, IH, J!=15.2Hz, J 2 =6.0Hz), 2.52(dd, 2H, J!=6.0Hz, J 2 = 5.6 Hz), 2.50 (s, IH), 2.40 (dd, 4H, J! = 4.0 Hz, J 2 = 4.4 Hz), 2.37-2.32 (m, IH), 2.25 (d, IH, J=l 2.4Hz), 2.09(s, 3H), 2.07(m, IH), 1.85-1.81(m 5 2H), 1.78-1.70(m, IH), 1.67-1.63(m, IH), 1.61(dd, 3H , Jfl S.SHz, J 2 = 18.8 Hz), 1.26 (m, IH), 1.12 (m, IH), 0.69 (dd, 3H, J! = 7.2 Hz, J 2 = 7.6 Hz). Example 16
12，-[N-(3-吗啡啉 -4-基丙基)氨基]甲基长春氟宁 12,-[N-(3-morpholine-4-ylpropyl)amino]methyl vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 将 12'-甲酰基长春氟宁 2(0.169 g， 0.20 mmol),搅拌下溶解于 20 ml二氯甲烷中，加入 4-(3-丙胺基)吗啡啉 (0.117 ml, 0.80 mmol)。油浴 40°C搅拌 19小时后， 加入三乙酰硼氢化钠 (0.17 g， 0.80 mmol), 继 续反应 3小时， 点板跟踪反应结束， 加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 用 乙酸乙酯 (100 mlx3)萃取反应液。 合并有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得 残余物， 得到标题产物 12'-[N-(3-吗啡啉 -4-基丙基)氨基]甲基长春氟宁 16(0.102 g， 白色固体)， 产率 53 %。 Under an argon atmosphere, 12'-formyl vinflunine 2 (0.169 g, 0.20 mmol) was dissolved in 20 ml of dichloromethane with stirring in a dry round bottom flask, and 4-(3-propylamino) was added. Morpholine (0.117 ml, 0.80 mmol). After the oil bath was stirred at 40 ° C for 19 hours, sodium triacetoxyborohydride (0.17 g, 0.80 mmol) was added, and the reaction was continued for 3 hours. The reaction was completed by spotting, and the reaction was quenched with saturated sodium hydrogen carbonate (50 ml). The reaction solution was extracted with ethyl acetate (100 ml×3). The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH [N-(3-Phenylmorph-4-ylpropyl)amino]methyl vinflunine 16 (0.102 g, white solid), yield 53%.
ESI: [M+l]=973 o ESI: [M+l]=973 o
1H NMR (CDC13, 400MHz)59.27(brs, IH), 8.37(s, IH), 7.57(s, IH), 7.15(d, IH, J=8.4Hz), 7.09(d, IH, J=8.0Hz), 6.34(s, IH), 6.08(s, IH), 5.84(dd, IH, J尸 10.0Hz， J2=4.0Hz), 5.41(s, IH), 5.27(d, IH, J=10.0Hz), 4.50(d, IH, J=12.8Hz), 4.32(d， IH, J=12.4Hz), 3.87(s, 2H), 3.81(s, 3H), 3.78(s, 3H)， 3.71(s, IH), 3.70(s, 3H), 3.68(dd, 4H， J!=4.8Hz , J2=14.4Hz), 3.37-3.24(m, 4H), 3.04(dd, IH, J^l 2.0Hz, J2=13.6Hz), 2.97(dd, IH, J!=14.4Hz, J2=13.6Hz), 2.90-2.80(m, IH), 2.75(dd, 2H, J尸 6.8Hz, J2=6.8Hz), 2.71(s, 3H), 2.67(m, IH), 2.57(dd, IH,】尸15.21¾ J2=6.0Hz), 2.49(s, IH), 2.42-2.38(m, 6H), 2.36-2.32(m, IH), 2.24(d5 IH, J=13.2Hz), 2.18-2.09(m, IH), 2.09(s: 3H), 1.87-1.81(m, 2H), 1.77-1.72(m, 3H), 1.70-1.63(m, 1H)， 1.61(dd, 3H, J尸 19.2Hz, J2=18.8Hz), 1.32-1.23(m, IH), 1.19-1.12(m, IH), 0.69(dd, 3H,
。
T N2007/002176 实施例 17 1H NMR (CDC1 3 , 400MHz) 59.27 (brs, IH), 8.37 (s, IH), 7.57 (s, IH), 7.15 (d, IH, J = 8.4 Hz), 7.09 (d, IH, J = 8.0 Hz), 6.34(s, IH), 6.08(s, IH), 5.84(dd, IH, J corpse 10.0Hz, J 2 =4.0Hz), 5.41(s, IH), 5.27(d, IH, J= 10.0 Hz), 4.50 (d, IH, J = 12.8 Hz), 4.32 (d, IH, J = 12.4 Hz), 3.87 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.71 (s, IH), 3.70(s, 3H), 3.68(dd, 4H, J!=4.8Hz, J 2 = 14.4Hz), 3.37-3.24(m, 4H), 3.04(dd, IH, J^l 2.0Hz, J 2 =13.6Hz), 2.97(dd, IH, J!=14.4Hz, J 2 =13.6Hz), 2.90-2.80(m, IH), 2.75(dd, 2H, J 6.8Hz, J 2 = 6.8 Hz), 2.71 (s, 3H), 2.67 (m, IH), 2.57 (dd, IH, corpse 15.213⁄4 J 2 = 6.0 Hz), 2.49 (s, IH), 2.42-2.38 (m, 6H), 2.36-2.32(m, IH), 2.24(d 5 IH, J=13.2Hz), 2.18-2.09(m, IH), 2.09(s : 3H), 1.87-1.81(m, 2H), 1.77 -1.72 (m, 3H), 1.70-1.63 (m, 1H), 1.61 (dd, 3H, J corp. 19.2 Hz, J 2 = 18.8 Hz), 1.32-1.23 (m, IH), 1.19-1.12 (m, IH), 0.69 (dd, 3H, . T N2007/002176 Example 17
12'- (吗啉 -4-基)甲基长舂氟宁 12'-(morpholin-4-yl)methylglyoxiphine
氩气氛下， 在干燥的三口烧瓶中， 将 12'-甲酰基长春氟宁 2(0.169 g， 0.20 mmol), 搅拌下溶解于 20 ml二氯甲烷中， 加入吗啡啉 (70 ul， 0.80 mmol)和四异 丙基氧钛 (228 ul， 0.80 mmol)。 油浴 40°C搅拌 19小时后， 加入三乙酰硼氢化钠 (0.17 g, 0.80 mmol), 继续反应 3小时， 点板跟踪反应结束， 加入饱和碳酸氢钠 溶液 (50 ml)淬灭反应， 用乙酸乙酯 (100 mlx3)萃取反应液。 合并有机相， 用饱和 氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'- (吗啉 -4-基)甲基长春氟宁 Under an argon atmosphere, 12'-formyl vinflunine 2 (0.169 g, 0.20 mmol) was dissolved in 20 ml of dichloromethane with stirring, and morpholine (70 ul, 0.80 mmol) was added. And tetraisopropoxytitanium (228 ul, 0.80 mmol). After the oil bath was stirred at 40 ° C for 19 hours, sodium triacetoxyborohydride (0.17 g, 0.80 mmol) was added, and the reaction was continued for 3 hours. The reaction was completed by spotting, and the reaction was quenched with saturated sodium hydrogen carbonate (50 ml). The reaction solution was extracted with ethyl acetate (100 ml×3). The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (morpholin-4-yl)methyl vinflunine
17(46 mg, 白色固体)， 产率 25 %。 17 (46 mg, white solid), yield 25 %.
ESI: [M+l]=916。 ESI: [M+l]=916.
1H NMR (CDC13, 400MHz)59.60(brs, IH), 8.31(brs, IH), 7.53(s, IH), 7.10(d, IH, J=8.0Hz), 7.01 (d, IH, J=8.4Hz), 6.29(s, IH), 6.02(s, IH), 5.78(dd, IH, J^lO.OHz, J2=4.4Hz), 5.34(s, IH), 5.21(d, IH, J=10.0Hz), 4.44(d, IH, J=12.4Hz), 4.35(m, IH), 3.74(s, 3H), 3.71(s, 3H), 3.65-3.60(m, 4H), 3.63(s, 3H), 3.64(s, IH), 3.51(s, 2H), 3.30-3.25(m, 3H), 3.21-3.15(m, IH), 3.02-2.98(m, IH), 2.89(dd, IH, Ji=14.4Hz, J2=13.6Hz), 2.80-2.70(m, IH), 2.70-2.60(m, IH), 2.64(s, 3H), 2.54(dd, IH, J^H.OHz, J2=4.8Hz), 2.50(s, IH), 2.50-2.38(m, 4H), 2.38-2.20(m, 2H), 2.05-1.95(m, IH), 2.02(s, 3H), 1.80-1.70(m, 2H), 1.70-1.60(m, IH), 1.60-1.55(m, IH), 1.55(dd, 3H, J!=18.8Hz, J2-18.8Hz), 1.20-1.00(m, 2H), 0.62(dd, 3H, Ji=6.8Hz, J2=7.2Hz)。 实施例 18 1H NMR (CDC1 3 , 400MHz) 59.60 (brs, IH), 8.31 (brs, IH), 7.53 (s, IH), 7.10 (d, IH, J = 8.0 Hz), 7.01 (d, IH, J=8.4 Hz), 6.29(s, IH), 6.02(s, IH), 5.78(dd, IH, J^lO.OHz, J 2 =4.4Hz), 5.34(s, IH), 5.21(d, IH, J =10.0Hz), 4.44(d, IH, J=12.4Hz), 4.35(m, IH), 3.74(s, 3H), 3.71(s, 3H), 3.65-3.60(m, 4H), 3.63(s , 3H), 3.64(s, IH), 3.51(s, 2H), 3.30-3.25(m, 3H), 3.21-3.15(m, IH), 3.02-2.98(m, IH), 2.89(dd, IH , Ji=14.4Hz, J 2 =13.6Hz), 2.80-2.70(m, IH), 2.70-2.60(m, IH), 2.64(s, 3H), 2.54(dd, IH, J^H.OHz, J 2 = 4.8 Hz), 2.50 (s, IH), 2.50-2.38 (m, 4H), 2.38-2.20 (m, 2H), 2.05-1.95 (m, IH), 2.02 (s, 3H), 1.80- 1.70(m, 2H), 1.70-1.60(m, IH), 1.60-1.55(m, IH), 1.55(dd, 3H, J!=18.8Hz, J 2 -18.8Hz), 1.20-1.00(m, 2H), 0.62 (dd, 3H, Ji = 6.8 Hz, J 2 = 7.2 Hz). Example 18
12，-[N- (乙醇基)氨基]甲基长春氟宁 12,-[N-(ethanolyl)amino]methyl vinflunine
ESI: [M+l]=890。 ESI: [M+l]=890.
1H NMR (CDC13, 400MHz)59.69(brs, 1H), 8.35(s, 1H), 7.63(s, 1H), 7.13(d, 1H, J=8.0Hz), 7.04(d, 1H, J=8.4Hz), 6.27(s, 3H), 6.02(s, 3H)， 5.78(dd, 1H, Ji=10.4Hz, J2=4.0Hz), 5.34(s, 1H), 5.21(d, 1H, J=10.4Hz), 4.44(d, 1H, J=13.2Hz), 4.32(d, 1H, J=13.2Hz), 3.94(m, 2H), 3.74(s, 3H), 3.71(s, 3H), 3.65(s, 1H), 3.57(s, 3H), 3.27-3.17(m, 6H), 2.98(dd, 1H, J^l 2.4Hz, J2=l 3.2Hz), 2.89(dd, 1H, J^M.OHz, J2-14.4Hz), 2.83(dd, 2H, 1^5.2Hz, J2=4.8Hz), 2.76-2.70(m, 1H), 2.67(m, 1H，), 2.64(s, 3H), 2.52(dd, 1H, Ji=15.6Hz, J2=6.0Hz), 2.45(s, 1H)， 2.32-2.26(m, 1H), 2.2 l(d, 1H, J=13.2Hz), 2.05-1.97(m, 1H) , 2.03(s, 3H), 1.78-1.75(m, 2H), 1.72-1.63(m, 1H), 1.63-1.55(m, 1H), 1.54(dd, 3H, J!=18.8Hz, J2=18.8Hz), 1.23-1.19(m, 1H), 1.13-1.07(m, 1H), 0.62(dd, 3H, Ji=7.2Hz, J2=7.2Hz)。 实施例 19 1H NMR (CDC1 3 , 400MHz) 59.69 (brs, 1H), 8.35 (s, 1H), 7.63 (s, 1H), 7.13 (d, 1H, J = 8.0 Hz), 7.04 (d, 1H, J=8.4 Hz), 6.27(s, 3H), 6.02(s, 3H), 5.78(dd, 1H, Ji=10.4Hz, J 2 =4.0Hz), 5.34(s, 1H), 5.21(d, 1H, J= 10.4Hz), 4.44(d, 1H, J=13.2Hz), 4.32(d, 1H, J=13.2Hz), 3.94(m, 2H), 3.74(s, 3H), 3.71(s, 3H), 3.65 (s, 1H), 3.57(s, 3H), 3.27-3.17(m, 6H), 2.98(dd, 1H, J^l 2.4Hz, J 2 =l 3.2Hz), 2.89(dd, 1H, J^ M.OHz, J 2 -14.4 Hz), 2.83 (dd, 2H, 1^5.2 Hz, J 2 = 4.8 Hz), 2.76-2.70 (m, 1H), 2.67 (m, 1H,), 2.64 (s, 3H), 2.52 (dd, 1H, Ji=15.6Hz, J 2 =6.0Hz), 2.45(s, 1H), 2.32-2.26(m, 1H), 2.2 l(d, 1H, J=13.2Hz), 2.05-1.97(m, 1H) , 2.03(s, 3H), 1.78-1.75(m, 2H), 1.72-1.63(m, 1H), 1.63-1.55(m, 1H), 1.54(dd, 3H, J !=18.8 Hz, J 2 = 18.8 Hz), 1.23-1.19 (m, 1H), 1.13-1.07 (m, 1H), 0.62 (dd, 3H, Ji = 7.2 Hz, J 2 = 7.2 Hz). Example 19
12，-[N- (正丁基)氨基]甲基长春氟宁 12,-[N-(n-butyl)amino]methyl vinflunine
氩气氛下， 在干燥的三口烧瓶中， 将 12'-甲酰基长春氟宁 2(0.169 g， 0.20 mmol), 搅拌下溶解于 20 ml二氯甲烷中， 加入正丁胺 (79 ul， 0.80 mmol)。 油浴 40°C搅拌 19小时后， 点板跟踪反应， 原料消失， 加入三乙酰硼氢化钠 (0.17 g, 0.80 mmol), 继续反应 2小时， 加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 用乙酸 乙酯 (100 mlx3)萃取反应液。合并有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸 乙酯层用无水硫酸镁干燥，过滤，滤液减压浓缩， 用硅胶柱色谱法纯化所得残余 物， 得到标题产物 12'-[N- (正丁基)氨基]甲基长春氟宁 19(31 mg， 白色固体)， 产 率 17%。 Under an argon atmosphere, 12'-formyl vinflunine 2 (0.169 g, 0.20 mmol) was dissolved in 20 ml of dichloromethane with stirring, and n-butylamine (79 ul, 0.80 mmol) was added. ). After the oil bath was stirred at 40 ° C for 19 hours, the reaction was followed by spotting, the starting material disappeared, sodium triacetoxyborohydride (0.17 g, 0.80 mmol) was added, the reaction was continued for 2 hours, and the reaction was quenched by the addition of saturated sodium hydrogen carbonate solution (50 ml). The reaction solution was extracted with ethyl acetate (100 ml×3). The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH [N-(n-butyl)amino]methyl vinflunine 19 (31 mg, white solid), yield 17%.
ESI: [M+l]=902。
Ή NMR (CDCI3, 400MHz)58.36(s, IH), 7.60(s, IH), 7.10(d, IH, J=8.8Hz)5 7.04(d, IH, J=8.8Hz), 6.27(s, IH), 6.02(s, IH), 5.78(dd, IH, Ji=10.0Hz, J2=4.0Hz), 5.33(s, IH), 5.20(d, IH, J=10.0Hz), 4.39(m, 2H), 3.91(s, 2H), 3.74(s, 3H), 3.71(s, 3H); 3.65(s, IH), 3.62(s, 3H), 3.47(brs, IH), 3.32-3.14(m, 4H), 3.00(dd, IH, J尸 12.4Hz, J2=13.2Hz), 2.89(dd, IH, J^H.OHz, J2=l 4.0Hz), 2.74-2.70(m, IH), 2.68-2.63(m, 3H); 2.64(s, 3H), 2.55(dd, IH, Ji=15.6Hz， J2=6.0Hz), 2.54(dd, 3H, Jx=l 8.8Hz, J2=18.8Hz), 2.46(s, IH), 2.32-2.26(m, IH), 2.2 l(d, IH, J=13.2Hz), 2.08-2.02(m, IH), 2.02(s, 3H), 1.80-1.70(m, 2H)， 1.70-1.60(m, IH), 1.60-1.50(m, 3H), 1.29-1.15(m, 4H), 0.84-0.80(m, 3H), 0.62(dd, 3H, Ji=7.2Hz, J2=7.2Hz)。 实施例 20 ESI: [M+l]=902. NMR NMR (CDCI3, 400MHz) 58.36(s, IH), 7.60(s, IH), 7.10(d, IH, J=8.8Hz) 5 7.04(d, IH, J=8.8Hz), 6.27(s, IH ), 6.02(s, IH), 5.78(dd, IH, Ji=10.0Hz, J 2 =4.0Hz), 5.33(s, IH), 5.20(d, IH, J=10.0Hz), 4.39(m, 2H), 3.91(s, 2H), 3.74(s, 3H), 3.71(s, 3H) ; 3.65(s, IH), 3.62(s, 3H), 3.47(brs, IH), 3.32-3.14(m , 4H), 3.00 (dd, IH, J corp. 12.4 Hz, J 2 = 13.2 Hz), 2.89 (dd, IH, J^H.OHz, J 2 = l 4.0 Hz), 2.74-2.70 (m, IH) , 2.68-2.63(m, 3H) ; 2.64(s, 3H), 2.55(dd, IH, Ji=15.6Hz, J 2 =6.0Hz), 2.54(dd, 3H, J x =l 8.8Hz, J 2 =18.8Hz), 2.46(s, IH), 2.32-2.26(m, IH), 2.2 l(d, IH, J=13.2Hz), 2.08-2.02(m, IH), 2.02(s, 3H), 1.80-1.70(m, 2H), 1.70-1.60(m, IH), 1.60-1.50(m, 3H), 1.29-1.15(m, 4H), 0.84-0.80(m, 3H), 0.62(dd, 3H , Ji=7.2Hz, J 2 =7.2Hz). Example 20
12，-(1-羟基) -乙基长春氟宁 12,-(1-hydroxy)-ethyl vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 将 12'-甲酰基长春氟宁 2(0.125 g， 0.148 mmol)搅拌下溶于 10 ml无水四氢呋喃中，滴加甲基溴化镁的甲苯-四氢呋喃溶液 (1.4 mol/L, 0.22 ml, 0.31 mmol),室温搅拌 1小时后，加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 用乙酸乙酯 (50 mlx4)萃取反应液。 合并有机相， 用饱和氯化钠溶 液 (50 mlxl)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩，用硅胶 柱色谱法纯化所得残余物， 得到标题产物 12'-(1-羟基) -乙基长春氟宁 20(73 mg， 白色固体)， 产率 57%。 Under a argon atmosphere, in a dry round bottom flask, 12'-formyl vinflunine 2 (0.125 g, 0.148 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran with stirring, and toluene of methyl magnesium bromide was added dropwise. A solution of tetrahydrofuran (1.4 mol/L, 0.22 ml, 0.31 mmol), EtOAc (EtOAc) The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (1-hydroxy)-ethyl vinflurine 20 (73 mg, white solid), yield 57%.
ESI:[M+1]=861。 实施例 21 ESI: [M+1] = 861. Example 21
12，-乙酰基长春氟宁 12,-acetyl vinflunine
ESI:[M+1]=859。 ESI: [M+1] = 859.
1H NMR (CDC13, 400MHz)59.65(brs, 1H), 8.62(s, 1H), 8.34(s, 1H), 7.86(dd, 1H, Ji=8.8Hz, J2=1.6Hz), 7.16(d, 1H, J=8.4Hz), 6.28(s, 1H), 6.09(s, 1H), 5.85(dd, 1H, J尸 10.4Hz, J2=4.4Hz), 5.40(s, 1H), 5.27(d, 1H, J=10.4Hz), 4.55(d, 1H, J=12.8Hz), 4.42(d, IH, J=12.8Hz), 3.82(s, 3H), 3.78(s, 3H), 3.74(s, 3H), 3.72(s, 1H), 3.40-3.27(m, 3H), 3.27-3.20(m, IH), 3.08(dd, IH,
J2=12.4Hz), 2.97(dd, 1H， Ji=14.4Hz, J2=14.0Hz), 2.90-2.77(m, IH), 2.71(s, 3H), 2.67(s, 3H), 2.67-2.59(m, 2H), 2.44(s, IH), 2.32(m, IH), 2.29(m, IH), 2.14-2.07(m, IH), 2.10(s, 3H), 1.87(m, IH), 1.83(m, IH), 1.80-1.70(m, 1H)， 1.70-1.65(m, IH), 1.62(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.33-1.26(m, 1H)， 1.20-1.12(m, IH), 0.7 (dd, 3H, J尸 7.2Hz, J2=7.6Hz)。 实施例 22 1H NMR (CDC1 3 , 400MHz) 59.65 (brs, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.86 (dd, 1H, Ji = 8.8 Hz, J 2 = 1.6 Hz), 7.16 (d) , 1H, J=8.4Hz), 6.28(s, 1H), 6.09(s, 1H), 5.85(dd, 1H, J corp. 10.4Hz, J 2 =4.4Hz), 5.40(s, 1H), 5.27( d, 1H, J = 10.4 Hz), 4.55 (d, 1H, J = 12.8 Hz), 4.42 (d, IH, J = 12.8 Hz), 3.82 (s, 3H), 3.78 (s, 3H), 3.74 ( s, 3H), 3.72(s, 1H), 3.40-3.27(m, 3H), 3.27-3.20(m, IH), 3.08(dd, IH, J 2 = 12.4 Hz), 2.97 (dd, 1H, Ji = 14.4 Hz, J 2 = 14.0 Hz), 2.90-2.77 (m, IH), 2.71 (s, 3H), 2.67 (s, 3H), 2.67- 2.59(m, 2H), 2.44(s, IH), 2.32(m, IH), 2.29(m, IH), 2.14-2.07(m, IH), 2.10(s, 3H), 1.87(m, IH) , 1.83(m, IH), 1.80-1.70(m, 1H), 1.70-1.65(m, IH), 1.62(dd, 3H, J corp. 18.8Hz, J 2 = 18.8Hz), 1.33-1.26(m, 1H), 1.20-1.12 (m, IH), 0.7 (dd, 3H, J 7.2 Hz, J 2 = 7.6 Hz). Example 22
12'-[(1-羟基) -环丙基甲基]长春氟宁 12'-[(1-hydroxy)-cyclopropylmethyl] vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-甲酰基长春氟宁 2(0.5 g， 0.59 mmol) 搅拌下溶于 15 ml无水四氢呋喃中， 滴加环丙基溴化镁的甲苯-四氢呋喃溶液 (1.4 mol/L, 4.7 ml, 2.37 mmol), 室温搅拌 1小时后， 点板跟踪反应， 原料消失。 加 入饱和碳酸氢钠溶液 (100 ml)淬灭反应，用乙酸乙酯 (100 mlx4)萃取反应液。合并 有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-[(1-羟基) - 环丙基甲基]长春氟宁 22(73 mg， 白色固体)， 产率 14%。 · Under a argon atmosphere, in a dry round bottom flask, 12'-formyl vinflunine 2 (0.5 g, 0.59 mmol) was dissolved in 15 ml of anhydrous tetrahydrofuran with stirring, and toluene of cyclopropylmagnesium bromide was added dropwise. - Tetrahydrofuran solution (1.4 mol/L, 4.7 ml, 2.37 mmol), stirred at room temperature for 1 hour, the reaction was followed by spotting, and the starting material disappeared. The reaction was quenched by EtOAc (EtOAc) (EtOAc) The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH [(1-Hydroxy)-cyclopropylmethyl] vinflunine 22 (73 mg, white solid), yield 14%. ·
ESI:[M+1]=887。 实施例 23
12'- (环丙基甲酰基)长春氟宁 ESI: [M+1] = 887. Example 23 12'-(cyclopropylformyl) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 将 12'-[(1-羟基) -环丙基甲基]长春氟宁 22(90 mg， 0.1 mtnol)搅拌下溶于 10 ml无水二氯甲烷中，缓慢滴加 DESS-MARTIN Periodinane的二氯甲烷溶液 (0.03 mol/L， 15 ml, 0.45 mmol), 室温搅拌 24小时 后， 点板跟踪反应， 原料消失， 加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 用乙酸 乙酯 (50 mlx4)萃取反应液。合并有机相， 用饱和氯化钠溶液 (50 ml)洗涤， 乙酸乙 酯层用无水硫酸镁千燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-环丙烷甲酰基长春氟宁 23(36 mg， 白色固体)， 产率 41 %。 Under a argon atmosphere, 12'-[(1-hydroxy)-cyclopropylmethyl] vinflunine 22 (90 mg, 0.1 mtnol) was dissolved in 10 ml of anhydrous dichloride under stirring in a round bottom flask. In methane, DESS-MARTIN Periodinane in dichloromethane (0.03 mol/L, 15 ml, 0.45 mmol) was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction was stopped by spotting, the starting material disappeared, and saturated sodium bicarbonate solution was added. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - cyclopropaneformyl vinflunine 23 (36 mg, white solid), yield 41%.
1H丽 R (CDC13, 400MHz)68.53(s, 1H), 8.40(s, 1H), 7.83(dd, 1H, J尸 8.4Hz, J2=1.4Hz), 7.11(d, 1H, J=8.4Hz), 6.2 l(s, 1H), 6.02(s, 1H), 5.77(dd, 1H， J^lO.OHz, J2=4.0Hz), 5.34(s, 1H), 5.20(d, 1H, J=10.4Hz), 4.46(m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.67(s, 3H), 3.65(s, 1H), 3.30-3.24(m, 3H), 3.18(m, 1H), 2.98(dd, 1H, 】尸12.81¾ J2=12.8Hz), 2.90(dd, 1H, J尸 14.0Hz, J2=14.4Hz), 2.76(m, 1H), 2.64(s, 3H), 2.60-2.52(dd, 2H), 2.39(s, 1H), 2.24-2.2 l(m, 3H)， 2.03(m, 1H), 2.02(s, 3H), 1.80-1.70(m, 2H), 1.70-1.57(m, 2H), 1.55(dd, 3H, Ji=18.8Hz, J2=18.8Hz), 1.23-1.12(m, 2H), 0.95-0.93(m, 4H), 0.61(dd, 3H, J!=7.2Hz, J2=7.2Hz)。 实施例 24 1H Li R (CDC1 3 , 400MHz) 68.53 (s, 1H), 8.40 (s, 1H), 7.83 (dd, 1H, J 8.4 Hz, J 2 = 1.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.2 l(s, 1H), 6.02(s, 1H), 5.77(dd, 1H, J^lO.OHz, J 2 =4.0Hz), 5.34(s, 1H), 5.20(d, 1H, J=10.4Hz), 4.46(m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.67(s, 3H), 3.65(s, 1H), 3.30-3.24(m, 3H), 3.18(m, 1H), 2.98(dd, 1H, 】 corpse 12.813⁄4 J 2 = 12.8 Hz), 2.90 (dd, 1H, J corp. 14.0 Hz, J 2 = 14.4 Hz), 2.76 (m, 1H), 2.64 (s, 3H), 2.60-2.52 (dd, 2H), 2.39(s, 1H), 2.24-2.2 l(m, 3H), 2.03(m, 1H), 2.02(s, 3H), 1.80-1.70 ( m, 2H), 1.70-1.57 (m, 2H), 1.55 (dd, 3H, Ji = 18.8 Hz, J 2 = 18.8 Hz), 1.23-1.12 (m, 2H), 0.95-0.93 (m, 4H), 0.61 (dd, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz). Example 24
12'-(1-羟基) -丙基长春氟宁 12'-(1-hydroxy)-propyl vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-甲酰基长春氟宁 2(0.169 g，0.20 mmol) 搅拌下溶于 10 ml无水四氢呋喃中， 滴加乙基溴化镁的甲苯-四氢呋喃溶液 (1.0 mol/L, 0.42 ml, 0.42 mmol), 室温搅拌 1小时后， 加入饱和碳酸氢钠溶液 (60 ml) 淬灭反应，用乙酸乙酯 (60 mlx3)萃取反应液。合并有机相，用饱和氯化钠溶液 (50
ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱 法纯化所得残余物， 得到标题产物 12'-(1-羟基) -丙基长春氟宁 24(82 mg， 白色固 体)， 产率 47%。 Under a argon atmosphere, in a dry round bottom flask, 12'-formyl vinflunine 2 (0.169 g, 0.20 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran with stirring, and ethyl bromide toluene was added dropwise. A solution of tetrahydrofuran (1.0 mol/L, 0.42 ml, 0.42 mmol), EtOAc (EtOAc) Combine the organic phase with a saturated sodium chloride solution (50 The title compound 12'-(1-hydroxy)-propyl vinflunine 24 was obtained by chromatography. (82 mg, white solid), yield 47%.
ESI:[M+1]=875。 实施例 25 ESI: [M+1] = 875. Example 25
12'-丙酰基长春氟宁 12'-propionyl vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 将 12'-(1-羟基) -丙基长舂氟宁 24(82 mg， 0.094 mmol)搅拌下溶于 10 ml无水二氯甲烷中， 缓慢滴加 DESS-MARTIN Under a argon atmosphere, 12'-(1-hydroxy)-propyl guanidine fluin 24 (82 mg, 0.094 mmol) was dissolved in 10 ml of anhydrous dichloromethane with stirring in a dry round bottom flask. Add DESS-MARTIN
Periodinane的二氯甲烷溶液 (0.03 mol/L， 10 ml, 0.3 mmol),室温搅拌 20小时后， 点板跟踪反应基本完全，加入饱和碳酸氢钠溶液 (50 ml)淬灭反应，用乙酸乙酯 (50 mlx4)萃取反应液。 合并有机相， 用饱和氯化钠溶液 (50 mlxl)洗涤， 乙酸乙酯层 用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得 到标题产物 12'-丙酰基长春氟宁 25(65 mg， 白色固体)， 产率 79%。 After the periodinane solution (0.03 mol/L, 10 ml, 0.3 mmol) was stirred at room temperature for 20 hours, the reaction was almost complete, and the reaction was quenched with saturated sodium bicarbonate (50 ml). (50 ml x 4) extract the reaction solution. The organic phase was combined, washed with EtOAc EtOAc (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Propionyl vinflunine 25 (65 mg, white solid), yield 79%.
ESI:[M+1]=873。 ESI: [M+1] = 873.
1H NMR (CDC13, 400MHz)59.69(brs, IH), 8.53(s, IH), 8.30(s, 1H)， 7.82(d, IH, J=8.4Hz), 7.10(d, IH, J=8.4Hz), 6.19(s, IH), 6.02(s, IH), 5.79-5.78(dd5 IH), 5.33(s, IH), 5.21(d, IH, J=10.0Hz), 4.46(m, 2H), 3.76(s, 3H), 3.71(s, 3H), 3.67(s, 4H), 3.30-3.25(m, 3H), 3.21-3.18(m, IH), 3.04(m, 2H), 2.98-2.86(m, 2H)， 2.75-2.70(m, IH), 2.65(s, 3H), 2.59-2.56(m, 2H), 2.4 l(m, IH), 2.30-2.20(m, 2H)， 2.01-1.97(m, 1H): 2.03(s, 3H), 1.80-1.60(m, 4H), 1.56(dd, 3H, J =18.8Hz， J2=18.8Hz), 1.19-1.13(m, 5H): 0.61 (dd, 3H, J!=7.6Hz, J2=7.2Hz)。 实施例 26 1H NMR (CDC1 3 , 400MHz) 59.69 (brs, IH), 8.53 (s, IH), 8.30 (s, 1H), 7.82 (d, IH, J = 8.4 Hz), 7.10 (d, IH, J = 8.4 Hz), 6.19(s, IH), 6.02(s, IH), 5.79-5.78(dd 5 IH), 5.33(s, IH), 5.21(d, IH, J=10.0Hz), 4.46(m, 2H ), 3.76(s, 3H), 3.71(s, 3H), 3.67(s, 4H), 3.30-3.25(m, 3H), 3.21-3.18(m, IH), 3.04(m, 2H), 2.98- 2.86(m, 2H), 2.75-2.70(m, IH), 2.65(s, 3H), 2.59-2.56(m, 2H), 2.4 l(m, IH), 2.30-2.20(m, 2H), 2.01 -1.97(m, 1H) : 2.03(s, 3H), 1.80-1.60(m, 4H), 1.56(dd, 3H, J = 18.8Hz, J 2 = 18.8Hz), 1.19-1.13(m, 5H) : 0.61 (dd, 3H, J!=7.6Hz, J 2 =7.2Hz). Example 26
4-脱乙酰基 -12'-甲氧基长春氟宁
4-deacetyl-12'-methoxy vinflunine
氩气氛下， 将 12'-碘代长春氟宁 1(0.168 g， 0.187 mmol)搅拌下溶于 6 ml甲 醇中， 加入碘化亚铜 (17.8 mg， 0.093 mmol), 碳酸铯 (60 mg， 0.187 mmol)及菲洛 林 (33.7 mg， 0.187 mmol), 110°C微波反应 1小时后， 反应液 200 ml乙酸乙酯稀 释，依次用饱和碳酸氢钠溶液 (50 ml)和饱和食盐水 (50 ml)洗涤，有机层用无水硫 酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产 物 4-脱乙酰基 -12，-甲氧基长春氟宁 26(27 mg， 白色固体)， 产率 17%。 Under an argon atmosphere, 12'-iodovinfluramine 1 (0.168 g, 0.187 mmol) was dissolved in 6 ml of methanol with stirring, and cuprous iodide (17.8 mg, 0.093 mmol), cesium carbonate (60 mg, 0.187) was added. Ment) and phenylin (33.7 mg, 0.187 mmol), after 1 hour of microwave reaction at 110 ° C, the reaction solution was diluted with 200 ml of ethyl acetate, followed by saturated sodium bicarbonate solution (50 ml) and saturated brine (50 ml) The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated. Mg, white solid), yield 17%.
ESI:[M+1]=805。 ESI: [M+1] = 805.
1H NMR (CDC13, 400MHz)59.30(brs, 1H), 8.23(s, 1H), 7.05(s, 1H), 6.98(d, 1H, J=8.4Hz), 6.76(dd, 1H, J!=8.8Hz, J2=2.0Hz), 6.26(s, 1H), 6.01(s, 1H), 5.77(dd, 1H, J!=10.4Hz, J2=4.4Hz), 5.62(d, 1H, J=10.4Hz), 4.44(d, 1H， J=12.8Hz), 4.24(d, 1H), 3.94(d, 1H， J=5.6Hz), 3.79(s, 3H), 3.77(s， 3H), 3.73(s, 3H), 3.62(s, 3H), 3.61(s, 1H), 3.29-3.14(m, 4H), 3.01(dd, 1H, =l2AHz, J2=13.2Hz), 2.88(dd, 1H, J^H.OHz, J2=14.4Hz), 2.75-2.74(m, 1H), 2.68(s, 3H), 2.64(m, 1H), 2.56-2.52(m, 2H), 2.39(s, 1H)， 2.31-2.28(m, 1H), 2.24-2.19(m, 1H)， 1.78-1.58(m, 4H), 1.54(dd, 3H, J尸 18.8Hz, J2=18.8Hz)， 1.18(m, 1H), 1.09-1.04(m, 1H), 0.73(dd, 3H, J尸 7.2Hz, J2=7.6Hz)。 实施例 27 1H NMR (CDC1 3 , 400MHz) 59.30 (brs, 1H), 8.23 (s, 1H), 7.05 (s, 1H), 6.98 (d, 1H, J = 8.4 Hz), 6.76 (dd, 1H, J! 8.8 Hz, J 2 = 2.0 Hz), 6.26 (s, 1H), 6.01 (s, 1H), 5.77 (dd, 1H, J! = 10.4 Hz, J 2 = 4.4 Hz), 5.62 (d, 1H, J = 10.4 Hz), 4.44 (d, 1H, J = 12.8 Hz), 4.24 (d, 1H), 3.94 (d, 1H, J = 5.6 Hz), 3.79 (s, 3H), 3.77 (s, 3H), 3.73(s, 3H), 3.62(s, 3H), 3.61(s, 1H), 3.29-3.14(m, 4H), 3.01(dd, 1H, =l2AHz, J 2 = 13.2Hz), 2.88(dd, 1H, J^H.OHz, J 2 = 14.4Hz), 2.75-2.74(m, 1H), 2.68(s, 3H), 2.64(m, 1H), 2.56-2.52(m, 2H), 2.39(s , 1H), 2.31-2.28 (m, 1H), 2.24-2.19 (m, 1H), 1.78-1.58 (m, 4H), 1.54 (dd, 3H, J corp. 18.8 Hz, J 2 = 18.8 Hz), 1.18 (m, 1H), 1.09-1.04 (m, 1H), 0.73 (dd, 3H, J 7.2 Hz, J 2 = 7.6 Hz). Example 27
12'-叠氮长春氟宁 12'-azide vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12，-碘代长春氟宁 1(0.189 g， 0.20 mmol), 叠氮化钠 (32 mg， 0.48 mmol)、碘化亚铜 (19 mg' 0.10 mmol)、脯氨酸 (23 mg， 0.20 mmol), 氢氧化钠粉末 (8 mg， 0.20 mmol), 搅拌下溶解于 10 ml二甲亚 砜中。 油浴 60°C-70°C加热搅拌 24小时后， 加入饱和碳酸氢钠溶液 (110 ml)淬灭 反应，用乙酸乙酯 (100 mlx3)萃取反应液。合并有机相，用饱和氯化钠溶液 (100 ml) i, 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯
化所得残余物，得到标题产物 12'-叠氮长春氟宁 27(0.117 g， 白色固体)， 产率 68Under a argon atmosphere, 12,-iodovinfluramine 1 (0.189 g, 0.20 mmol), sodium azide (32 mg, 0.48 mmol), cuprous iodide (19 mg') was added to a dry round bottom flask. 0.10 mmol), valine (23 mg, 0.20 mmol), sodium hydroxide powder (8 mg, 0.20 mmol), dissolved in 10 ml of dimethyl sulfoxide with stirring. After the oil bath was heated and stirred at 60 ° C to 70 ° C for 24 hours, the reaction was quenched with saturated aqueous sodium hydrogen carbonate (110 ml), and the mixture was extracted with ethyl acetate (100 ml×3). The organic phase was combined and dried with EtOAc EtOAc EtOAcjjj The residue obtained was purified to give the title product 12'- az.
%。 %.
ESI:[M+1]=858。 ESI: [M+1]=858.
1H NMR (CDC13, 400MHz)59.59(brs, 1H)， 8.37(s, IH), 7.26(s, IH), 7.02(d, IH, J=8.4Hz), 6.76(dd, IH, J!=8.8Hz, J2=2.0Hz), 6.22(s, IH), 6.01 (s, IH), 5.77(dd, 1H， J尸 10.5Hz, J2=4.4Hz), 5.33(s, IH), 5.21(d, IH, J=10.4Hz), 4.44(d, IH, J=12.8Hz), 4.22(d, 1H， J-12.8Hz), 3.74(s, 3H), 3.71(s, 3H), 3.66(s, 3H), 3.65(s, IH), 3.31-3.21(m, 3H), 3.21-3.14(m, IH), 2.98(dd, IH, J尸 12.8Hz, J2=12.8Hz), 2.90(dd, 1H， J尸 14.8Hz, J2=l 4.8Hz), 2.77-2.67(m, 1H)， 2.64(s, 3H), 2.59(s, IH), 2.56-2.50(m, IH), 2.40(s, IH), 2.30-2.18(m, 2H), 2.09-2.02(m, IH), 2.02(s, 3H), 1.80-1.71(m, 2H), 1.71-1.60(m, IH), 1.60-1.56(m, IH), 1.54(dd, 3H, J^lS.SHz, J2=18.8Hz), 1.25-1.12(m， 1H)， 1.12-1.05(m, IH), 0.60(dd, 3H, J!=7.2Hz, J2=7.6Hz)。 实施例 28 1H NMR (CDC1 3 , 400MHz) 59.59 (brs, 1H), 8.37 (s, IH), 7.26 (s, IH), 7.02 (d, IH, J = 8.4 Hz), 6.76 (dd, IH, J! 8.8 Hz, J 2 =2.0 Hz), 6.22 (s, IH), 6.01 (s, IH), 5.77 (dd, 1H, J corp. 10.5 Hz, J 2 = 4.4 Hz), 5.33 (s, IH), 5.21 (d, IH, J = 10.4 Hz), 4.44 (d, IH, J = 12.8 Hz), 4.22 (d, 1H, J-12.8 Hz), 3.74 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H), 3.65(s, IH), 3.31-3.21(m, 3H), 3.21-3.14(m, IH), 2.98(dd, IH, J corp. 12.8Hz, J 2 = 12.8Hz), 2.90 (dd, 1H, J corpse 14.8 Hz, J 2 = l 4.8 Hz), 2.77-2.67 (m, 1H), 2.64 (s, 3H), 2.59 (s, IH), 2.56-2.50 (m, IH), 2.40(s, IH), 2.30-2.18(m, 2H), 2.09-2.02(m, IH), 2.02(s, 3H), 1.80-1.71(m, 2H), 1.71-1.60(m, IH), 1.60-1.56(m, IH), 1.54(dd, 3H, J^lS.SHz, J 2 = 18.8Hz), 1.25-1.12(m, 1H), 1.12-1.05(m, IH), 0.60(dd, 3H, J!=7.2 Hz, J 2 = 7.6 Hz). Example 28
12'-氨基长春氟宁 12'-amino vinflunine
在干燥的圆底烧瓶中， 将 12'-叠氮长春氟宁 27(0.289 g， 0.337 mmol)搅拌下 溶解于 20 ml无水甲醇中， 加入钯碳 (36 mg， 10%), 氢化过夜。减压抽滤， 滤液 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-氨基长春氟宁 28(0.208 g, 白色固体)， 产率 74%。 In a dry round bottom flask, 12'-azide vinflunine 27 (0.289 g, 0.337 mmol) was dissolved in 20 ml of anhydrous methanol with stirring, and palladium carbon (36 mg, 10%) was added and hydrogenated overnight. The filtrate was filtered under reduced pressure. EtOAcjjjjjjjjjjjjj
ESI:[M+l]=832 o ESI: [M+l]=832 o
1H NMR (CDC13, 400MHz) 9.70(brs, IH), 6.92(s, IH), 6.87(d, IH, J=8.4Hz), 6.56(d, IH J=7.2Hz), 6.27(s, IH), 6.02(s, IH), 5.77(dd, IH,
J2=4.0Hz), 5.46(brs, 2H), 5.32(s, IH), 5.21(d, IH, J=13.2Hz), 4.39-4.36(m, 2H), 3.74(s, 3H), 3.71(s, 3H), 3.65(s, IH), 3.63(s, 3H), 3.31-3.27(m, 3H), 3.19(m, IH), 3.02(dd, IH, J尸 12.4Hz, J2=12.8Hz), 2.88(dd, IH, J^l 4.0Hz, J2=14.0Hz), 2.73 (m, 2H), 2.64(s, 3H), 2.50(s, IH), 2.38(m, IH), 2.28(d, IH, J=15.0Hz), 2.02(m, IH), 1.94(s, 3H), 1.91(m, IH), 1.78-1.75(m, 2H), 1.65-1.60(m, IH), 1.60-1.52(m, 1H)， 1.55(dd， 3H,
J2=18.8Hz), 1.45-1.19(m, 2H), 0.62(dd, 3H, J2=7.2Hz)。 实施例 29
12，-(2,2,2-三氟乙酰胺)长舂氟宁 1H NMR (CDC1 3 , 400MHz) 9.70 (brs, IH), 6.92 (s, IH), 6.87 (d, IH, J = 8.4 Hz), 6.56 (d, IH J = 7.2 Hz), 6.27 (s, IH) ), 6.02(s, IH), 5.77(dd, IH, J 2 =4.0 Hz), 5.46 (brs, 2H), 5.32 (s, IH), 5.21 (d, IH, J = 13.2 Hz), 4.39-4.36 (m, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 3.65(s, IH), 3.63(s, 3H), 3.31-3.27(m, 3H), 3.19(m, IH), 3.02(dd, IH, J corp. 12.4Hz, J 2 = 12.8Hz), 2.88(dd, IH, J^l 4.0Hz, J 2 = 14.0Hz), 2.73 (m, 2H), 2.64(s, 3H), 2.50(s, IH), 2.38(m, IH) , 2.28(d, IH, J=15.0Hz), 2.02(m, IH), 1.94(s, 3H), 1.91(m, IH), 1.78-1.75(m, 2H), 1.65-1.60(m, IH ), 1.60-1.52 (m, 1H), 1.55 (dd, 3H, J 2 = 18.8 Hz), 1.45-1.19 (m, 2H), 0.62 (dd, 3H, J 2 = 7.2 Hz). Example 29 12,-(2,2,2-trifluoroacetamide)
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-氨基长春氟宁 28(0.1 g， 0.12 mmol), 三氟乙酸酐 (22.3 ul, 0.16 mmol)、 三乙胺 (22 ul， 0.16 mmol), 搅拌下溶 解于 10 ml二氯甲烷中。室温搅拌 1小时后， 点板跟踪反应， 原料消失， 加入饱 和碳酸氢钠溶液 (40 ml)淬灭反应，用乙酸乙酯 (40 mlx3)萃取反应液。合并有机相， 用饱和氯化钠溶液 (50 mlx2)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤，滤液减 压浓缩， 用硅胶柱色谱法纯化所得残佘物， 得到标题产物 12，-(2，2，2-三氟乙酰胺) 长春氟宁 29(53 mg， 白色固体)， 产率 50%。 Under a argon atmosphere, 12'-amino vinflurine 28 (0.1 g, 0.12 mmol), trifluoroacetic anhydride (22.3 ul, 0.16 mmol), triethylamine (22 ul, 0.16 mmol) was added to a dry round bottom flask. ), dissolved in 10 ml of dichloromethane with stirring. After stirring at room temperature for 1 hour, the reaction was followed by a paddle, and the material was evaporated. The mixture was stirred and evaporated to ethyl acetate (40 ml). The organic layer was combined, washed with EtOAc EtOAc (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -(2,2,2-trifluoroacetamide) vinflunine 29 (53 mg, white solid), yield 50%.
ESI:[M+1]=928。 ESI: [M+1] = 928.
1H NMR (CDC13, 400 Hz)59.69(brs, IH), 8.40(s, IH), 8.29(s, IH), 7.81 (s3 1H)， 7.25(d, IH, J=8.8Hz), 7.03(d, IH, J=8.8Hz), 6.27(s, IH), 6.00(s, IH), 5.76(dd, IH, Ji=9.6Hz3 J2=4.0Hz), 5.32(s, IH), 5.19(d, IH, J=10.0Hz), 4.40(d, IH, J=12.8Hz), 4.21(d, IH, J=13.2Hz), 3.73(s, 3H), 3.70(s, 3H), 3.65(s, 3H), 3.62(s, IH), 3.27-3.16(m: 4H), 2.84-2.78(m, 2H), 2.69(m, 1H)， 2.65(m, IH), 2.63(s, 3H), 2.51(dd, IH, J!=15.2Hz, J2=6.0Hz), 2.41(s， IH), 2.28(m, IH), 2.22(d, IH, J=13.6Hz), 2.04(m, IH) , 2.00(s, 3H), 1.76-1.73(m, 2H), 1.69-1.62(m, IH), 1.62-1.54(m, IH), 1.52(dd, 3H, J!=18.8Hz, J2=18.8Hz), 1.22-1.15(m， IH), 1.07(m, IH), 0.59(dd， 3H， J尸 7.2Hz， J2=7.6Hz)0 实施例 30 1H NMR (CDC1 3 , 400 Hz) 59.69 (brs, IH), 8.40 (s, IH), 8.29 (s, IH), 7.81 (s 3 1H), 7.25 (d, IH, J = 8.8 Hz), 7.03 (d, IH, J=8.8Hz), 6.27(s, IH), 6.00(s, IH), 5.76(dd, IH, Ji=9.6Hz 3 J 2 =4.0Hz), 5.32(s, IH), 5.19(d, IH, J=10.0Hz), 4.40(d, IH, J=12.8Hz), 4.21(d, IH, J=13.2Hz), 3.73(s, 3H), 3.70(s, 3H), 3.65(s, 3H), 3.62(s, IH), 3.27-3.16(m: 4H), 2.84-2.78(m, 2H), 2.69(m, 1H), 2.65(m, IH), 2.63(s, 3H), 2.51 (dd, IH, J! = 15.2 Hz, J 2 = 6.0 Hz), 2.41 (s, IH), 2.28 (m, IH), 2.22 (d, IH, J = 13.6 Hz), 2.04 ( m, IH), 2.00(s, 3H), 1.76-1.73(m, 2H), 1.69-1.62(m, IH), 1.62-1.54(m, IH), 1.52(dd, 3H, J!=18.8Hz , J 2 = 18.8 Hz), 1.22-1.15 (m, IH), 1.07 (m, IH), 0.59 (dd, 3H, J 7.2 Hz, J 2 = 7.6 Hz) 0 Example 30
12，-(2,2-二氯乙酰胺基)长春氟宁 12,-(2,2-dichloroacetamido) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-氨基长春氟宁 28(0.1 g， 0.12 mmol), 二氯甲酰氯 (16 ul， 0.16 mmol), 三乙胺 (22.2 ul， 0.16 mmol), 搅拌下溶 解于 10 ml二氯甲垸中。 室温反应 1小时后， 点板跟踪反应， 原料消失， 加入饱
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J=12.8Hz), 3.74(s, 3H), 3.71(s, 3H), 3.69((s, 3H) 3.65(s, IH), 3.64(s, 3H)， 3.30-3.16(m, 4H), 2.97(dd, IH, J^H.fflz, J2=13.2Hz), 2.88(dd, 1H， J尸 14.4Hz, J2=13.6Hz), 2.74(m,lH), 2.68(d, IH, J=16.4Hz), 2.64(s, 3H), 2.49(dd， IH, J尸 15.2Hz, J2=6.0Hz), 2.45(s, IH), 2.32(m, IH), 2.19(d, IH, J-14.4Hz), 2.04(m, IH), 2.02(s, 3H); 1.78-1.72(m, 2H), 1.68-1.63(m, 1H)， 1.60-1.55(m, IH), 1.53(dd, 3H， J!=18.8Hz, J2=18.8Hz), 1.20-1.16(m, IH), 1.06(m, IH), 0.62(dd, 3H, Ji=7.2Uz, J2=7.6Hz)。 实施例 32 .TZ00/.00ZN3/X3d S08H0/800Z OAV J=12.8Hz), 3.74(s, 3H), 3.71(s, 3H), 3.69((s, 3H) 3.65(s, IH), 3.64(s, 3H), 3.30-3.16(m, 4H), 2.97 (dd, IH, J^H.fflz, J 2 = 13.2 Hz), 2.88 (dd, 1H, J corp. 14.4 Hz, J 2 = 13.6 Hz), 2.74 (m, lH), 2.68 (d, IH, J=16.4Hz), 2.64(s, 3H), 2.49(dd, IH, J corp. 15.2Hz, J 2 =6.0Hz), 2.45(s, IH), 2.32(m, IH), 2.19(d, IH , J-14.4Hz), 2.04(m, IH), 2.02(s, 3H) ; 1.78-1.72(m, 2H), 1.68-1.63(m, 1H), 1.60-1.55(m, IH), 1.53( Dd, 3H, J!=18.8Hz, J 2 = 18.8Hz), 1.20-1.16(m, IH), 1.06(m, IH), 0.62(dd, 3H, Ji=7.2Uz, J 2 =7.6Hz) Example 32
12'- (甲磺酰氨基:)长春氟宁 12'- (Methanesulfonylamino:) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-氨基长春氟宁 28(0.09 g， 0.11 mmol) 和 4-Ν,Ν-二甲氨基吡啶 (3 mg， 0.024 mmol)溶于四氢呋喃 (10 ml)，加入三乙胺 (20 ul, 0.14 mmol)和甲基磺酰氯的四氢呋喃溶液 (1.4 ml, 0.14 mmol, 0.1 mol/L)。室 温搅拌过夜， 点板跟踪反应，原料消失，浓缩反应液，加入饱和碳酸氢钠溶液 (30 ml),用乙酸乙酯 (40 mlx3)萃取反应液。合并有机相，用饱和氯化钠溶液 (30 mlx2) 洗涤， 乙酸乙酯层用无水硫酸镁千燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯 化所得残余物， 得到标题产物 12'- (甲磺酰氨基)长舂氟宁 32(26 mg， 白色固体)， 产率 26 %。 12'-Amino-vinflurine 28 (0.09 g, 0.11 mmol) and 4-indole-indole-dimethylaminopyridine (3 mg, 0.024 mmol) were dissolved in tetrahydrofuran under a argon atmosphere in a dry round bottom flask. 10 ml), a solution of triethylamine (20 ul, 0.14 mmol) and methanesulfonyl chloride in tetrahydrofuran (1.4 ml, 0.14 mmol, 0.1 mol/L). The mixture was stirred at room temperature overnight, and the mixture was applied to the mixture. The mixture was evaporated. The mixture was concentrated. The mixture was concentrated and evaporated to ethyl acetate (30 ml). The organic phase was combined, washed with EtOAc EtOAc (EtOAcjjjjjjjjjj - (Methanesulfonylamino) guanidine flunin 32 (26 mg, white solid), yield 26%.
ESI:[M+1]=910。 ESI: [M+1] = 910.
!H NMR (CDC13, 400MHz)59.72(s, IH), 8.42(s, IH), 7.52(s, 1H)， 7.05(m, 2H), 6.34(s, IH), 6.02(s, IH), 5.79(dd, IH, Ji=10.4Hz, J2=4.2Hz), 5.33(s, IH), 5.22(d, IH, J=10.4Hz), 4.47(d, IH, J=13.2Hz), 4.32(d, IH, J=13.2Hz), 3.75(s, 3H), 3.71 (s, 3H)， 3.66(s, IH), 3.65(s, 3H), 3.33-3.25(m5 3H), 3.21-3.19(m, IH), 2.98(dd, IH, J尸 12.4Hz， J2=12.8Hz), 2.90(dd, IH, Ji=14.0Hz, J2=14.4Hz), 2.76(s, 3H), 2.73-2.71(m, 2H), 2.65(s, 3H), 2.56-2.48(m, 2H)， 2.38-2.35(m, IH), 2.26(d, IH, J=12.8Hz), 2.07(m, 1H)， 2.03(s, 3H), 1.80-1.76(m, 2H), 1.68-1.58(m, 2H), 1.54(dd, 3H， J^l S.SHz, J2=l 8.8Hz), 1.19-1.13(m, 2H), 0.62(dd; 3H， J尸 7.2Hz, J2=7.2Hz)。 实施例 33 ! H NMR (CDC1 3, 400MHz ) 59.72 (s, IH), 8.42 (s, IH), 7.52 (s, 1H), 7.05 (m, 2H), 6.34 (s, IH), 6.02 (s, IH) , 5.79 (dd, IH, Ji = 10.4 Hz, J 2 = 4.2 Hz), 5.33 (s, IH), 5.22 (d, IH, J = 10.4 Hz), 4.47 (d, IH, J = 13.2 Hz), 4.32 (d, IH, J = 13.2 Hz), 3.75 (s, 3H), 3.71 (s, 3H), 3.66 (s, IH), 3.65 (s, 3H), 3.33-3.25 (m 5 3H), 3.21 -3.19(m, IH), 2.98(dd, IH, J corp. 12.4 Hz, J 2 = 12.8 Hz), 2.90 (dd, IH, Ji = 14.0 Hz, J 2 = 14.4 Hz), 2.76 (s, 3H) , 2.73-2.71(m, 2H), 2.65(s, 3H), 2.56-2.48(m, 2H), 2.38-2.35(m, IH), 2.26(d, IH, J=12.8Hz), 2.07(m , 1H), 2.03(s, 3H), 1.80-1.76(m, 2H), 1.68-1.58(m, 2H), 1.54(dd, 3H, J^l S.SHz, J 2 =l 8.8Hz), 1.19-1.13 (m, 2H), 0.62 (dd ; 3H, J 7.2 Hz, J 2 = 7.2 Hz). Example 33
12'-( ,N-二甲氨基)长春氟宁
If 12'-( ,N-dimethylamino) vinflunine If
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ESI:[M+1]=846。 ESI: [M+1] = 846.
1H NMR (CDC13, 400MHz)59.70(brs, 1H), 8.11(s, 1H), 6.88(d, 1H, J=8.4Hz), 6.79(s, 1H)， 6.52(m, 1H, J尸 8.8Hz, J2=1.8Hz), 6.29(s, 1H), 6.01(s, 1H), 5.78(dd, 1H, Ji=10.0Hz, J2=4.0Hz), 5.33(s, 1H), 5.20(d, 1H, J=10.4Hz), 4.43(d, 1H, J=12.8Hz), 4.25(m, 1H), 3.74(s, 3H), 3.71(s, 3H), 3.65(s, 1H), 3.63(s, 3H), 3.33-3.25(m, 3H), 3.19(m, 1H), 3.04(m, 1H), 2.89(m, 1H), 2.82(s, 3H), 2.74-2.70(m, 2H)， 2.64(s, 3H), 2.53-2.49(m, 1H), 2.47(s, 1H), 2.34(m, 1H), 2.28(m, 1H), 2.02(s, 3H)， 2.00(m, 1H), 1.81-1.75(m, 2H)， 1.67(m, 1H), 1.57(m, 1H), 1.54(dd, 3H, J!=18.8Hz, J2=18.8Hz), 1.18(m, 1H), 1.05(m, 1H), 0.62(dd, 3H, J^.SHz, J2=7.2Hz)。 1H NMR (CDC1 3 , 400MHz) 59.70 (brs, 1H), 8.11 (s, 1H), 6.88 (d, 1H, J = 8.4 Hz), 6.79 (s, 1H), 6.52 (m, 1H, J 8.8 Hz, J 2 =1.8Hz), 6.29(s, 1H), 6.01(s, 1H), 5.78(dd, 1H, Ji=10.0Hz, J 2 =4.0Hz), 5.33(s, 1H), 5.20( d, 1H, J = 10.4 Hz), 4.43 (d, 1H, J = 12.8 Hz), 4.25 (m, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.65 (s, 1H), 3.63(s, 3H), 3.33-3.25(m, 3H), 3.19(m, 1H), 3.04(m, 1H), 2.89(m, 1H), 2.82(s, 3H), 2.74-2.70(m, 2H), 2.64(s, 3H), 2.53-2.49(m, 1H), 2.47(s, 1H), 2.34(m, 1H), 2.28(m, 1H), 2.02(s, 3H), 2.00(m , 1H), 1.81-1.75 (m, 2H), 1.67 (m, 1H), 1.57 (m, 1H), 1.54 (dd, 3H, J! = 18.8 Hz, J 2 = 18.8 Hz), 1.18 (m, 1H), 1.05 (m, 1H), 0.62 (dd, 3H, J^.SHz, J 2 = 7.2 Hz).
实施例 35 Example 35
12，- (乙酰氨基)长春氟宁 12,-(acetylamino) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-氨基长春氟宁 28(0.108 g，0.13 mmol) 溶于 10 ml二氯甲烷中， 加入乙酸酐 (16 ul, 0.17 mmol)和三乙胺 (24 ul, 0.17 mmol)。 室温搅拌 1小时后， 点板跟踪反应， 原料消失， 加入饱和碳酸氢钠溶液 (50 ml)淬灭反应，用乙酸乙酯 (100 mlx3)萃取反应液。合并有机相，依次用水 (100 ml)和饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12，- (乙酰氨基)长春 氟宁 35(67 mg， 白色固体)， 产率 59%。 12'-Amino-vinflurine 28 (0.108 g, 0.13 mmol) was dissolved in 10 ml of dichloromethane in a dry round bottom flask under argon, and acetic anhydride (16 ul, 0.17 mmol) and triethyl Amine (24 ul, 0.17 mmol). After stirring at room temperature for 1 hour, the reaction was taken up with a paddle, and the material was evaporated, and the mixture was evaporated to ethyl acetate (50 ml). The combined organic layers were washed with EtOAc EtOAc EtOAc. The title product 12, -(acetylamino) vinflunine 35 (67 mg, white solid) was obtained, yield 59%.
ESI:[M+1]=874。 ESI: [M+1] = 874.
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氩气氛下，在干燥的三口烧瓶中，将 12，-碘代长春氟宁 1(0.1 g， 0.106 mmol) 搅拌下溶解于无水乙醇 20 ml中， 充入一氧化碳， 加入三乙胺 (0.149 ml, 0.106 mmol)及醋酸钯 (2.4 mg， 0.0106 mmol)和 Ι,Γ-双- (二苯基膦)二茂铁 (5.9 mg, 0.0106 mmol)的乙醇溶液 (5 ml)。 油浴 50°C下搅拌过夜， 点板跟踪反应， 原料基本消失。 加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 乙酸乙酯萃取 (100 mlx3)，合并有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减 压浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-乙氧基羰基长春氟 宁 37(71 mg， 浅棕色固体)， 产率 76%。 Under a argon atmosphere, in a dry three-necked flask, 12,-iodo-vinflurine 1 (0.1 g, 0.106 mmol) was dissolved in 20 ml of absolute ethanol with stirring, charged with carbon monoxide, and added with triethylamine (0.149 ml). , 0.106 mmol) and palladium acetate (2.4 mg, 0.0106 mmol) and hydrazine, bis-bis-(diphenylphosphino)ferrocene (5.9 mg, 0.0106 mmol) in ethanol (5 ml). The oil bath was stirred at 50 ° C overnight, and the reaction was tracked by a plate to completely disappear. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Filtration, the filtrate was concentrated under reduced vacuo. mjjjjjjjj
ESI:[M+1]=889。 ESI: [M+1] = 889.
1H NMR (CDCls, 400MHz)58.52(s, 1H), 8.39(s, 1H), 7.83(dd, 1H， J尸 8.4Hz, J2=1.2Hz), 7.07(d, 1H, J=8.4Hz), 6.2 l(s, 1H), 6.02(s, 1H)， 5.78(dd, 1H， J!=10.4Hz, J2=4.0Hz), 5.30(s, 1H), 5.20(d, 1H, J=10.4Hz), 4.49(d, 1H, J=13.2Hz), 4.43(d, 1H, J=13.2Hz), 4.32(m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.67(s, 3H), 3.65(s, 1H), 3.4-3.22(m, 3H), 3.22-3.14(m, 1H), 2.99(dd, 1H, Ji=12.8Hz, J2=13.2Hz), 2.89(dd, 1H, J!=14.4Hz, J2=13.6Hz), 2.80-2.70(m, 1H)， 2.70-2.60(m, 1H), 2.64(s, 3H), 2.55(dd, 1H: J!=l 5.2Hz, J2=6.4Hz), 2.43(s, 1H), 2.34-2.22(m, 2H), 2.07-2.00(m， 1H), 2.02(s, 3H), 1.80-1.72(m, 2H)， 1.72-1.63(m, 1H), 1.63-1.55(m, 1H), 1.55(dd, 3H， 1尸18.81¾， J2=18.8Hz), 1.34(dd, 3H, J尸 7.2Hz, J2=7.2Hz), 1.30-1.20(m, 1H)， 1.20-1.10(m, 1H), 0.61(dd, 3H, J尸 7.2Hz, J2=7.2Hz)。 实施例 38 1H NMR (CDCls, 400MHz) 58.52 (s, 1H), 8.39 (s, 1H), 7.83 (dd, 1H, J 8.4 Hz, J 2 = 1.2 Hz), 7.07 (d, 1H, J = 8.4 Hz) , 6.2 l(s, 1H), 6.02(s, 1H), 5.78(dd, 1H, J!=10.4Hz, J 2 =4.0Hz), 5.30(s, 1H), 5.20(d, 1H, J= 10.4Hz), 4.49(d, 1H, J=13.2Hz), 4.43(d, 1H, J=13.2Hz), 4.32(m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.67 (s, 3H), 3.65(s, 1H), 3.4-3.22(m, 3H), 3.22-3.14(m, 1H), 2.99(dd, 1H, Ji=12.8Hz, J 2 = 13.2Hz), 2.89 (dd, 1H, J!=14.4Hz, J 2 =13.6Hz), 2.80-2.70(m, 1H), 2.70-2.60(m, 1H), 2.64(s, 3H), 2.55(dd, 1H : J !=l 5.2Hz, J 2 =6.4Hz), 2.43(s, 1H), 2.34-2.22(m, 2H), 2.07-2.00(m, 1H), 2.02(s, 3H), 1.80-1.72(m , 2H), 1.72-1.63 (m, 1H), 1.63-1.55 (m, 1H), 1.55 (dd, 3H, 1 corpse 18.81⁄4, J 2 = 18.8 Hz), 1.34 (dd, 3H, J 7.2 Hz , J 2 = 7.2 Hz), 1.30-1.20 (m, 1H), 1.20-1.10 (m, 1H), 0.61 (dd, 3H, J 7.2 Hz, J 2 = 7.2 Hz). Example 38
12，-异丙氧基讓基长春氟宁 12,-isopropoxy thiophene vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长舂氟宁 1(0.15 g, 0.159 mmol) 搅拌下溶解于无水异丙醇 (20 ml)中， 充入一氧化碳， 加入三乙胺 (0.22 ml, 1.59
mmol),醋酸钯 (3.5 mg， 0.0159 mmol)和 Ι,Γ-双- (二苯基膦)二茂铁 (8.8 mg， 0.0159 mmol)的异丙醇溶液 (5 ml)。 油浴 60Ό下搅拌 20小时， 点板跟踪反应， 原料基本 消失。 加入饱和碳酸氢钠溶液 (30 ml)淬灭反应， 乙酸乙酯萃取 (100 mlx3)， 合并 有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-异丙氧基羰 基长春氟宁 38(92 mg， 淡黄色固体)， 产率 64.3 %。 Under an argon atmosphere, in a dry round bottom flask, 12'-iodolong fluflurin 1 (0.15 g, 0.159 mmol) was dissolved in anhydrous isopropanol (20 ml) with stirring, and charged with carbon monoxide. Triethylamine (0.22 ml, 1.59 Methyl) palladium acetate (3.5 mg, 0.0159 mmol) and hydrazine, bis-bis-(diphenylphosphino)ferrocene (8.8 mg, 0.0159 mmol) in isopropanol (5 ml). The oil bath was stirred at 60 Torr for 20 hours, and the reaction was followed by a spotting, and the raw materials were almost disappeared. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Filtration, the filtrate was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
ESI:[M+1]=903。 ESI: [M+1] = 903.
1H NMR (CDC13, 400MHz)58.53(s, IH), 8.36(s, IH), 7.82(dd, IH, J!=8.4Hz, J2=1.2Hz), 7.07(d, IH, J=8.8Hz), 6.2 l(s, IH), 6.02(s, IH), 5.78(dd, IH, J尸 10.0Hz, J2=4.0Hz), 5.32(s, 1H)， 5.24-5.17(m, 3H)， 4.44 (m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.66(s, 3H), 3.65(s, IH), 3.33-3.19(m, 4H), 3.00(dd, IH, J!=12.4Hz, J2=13.2Hz), 2.89(dd, IH, Ji=14.0Hz, J2=14.0Hz), 2.74-2.70(m, IH), 2.64(s, 3H), 2.61 (m, IH), 2.55(dd, IH, Ji=15.6Hz, J2=6.0Hz), 2.4 l(s, IH), 2.30-2.22(m, 2H)， 2.04-1.99(m, IH), 2.02(s, 3H), 1.80-1.72(m, 2H), 1.70-1.63(m, IH), 1.63-1.58(m, IH), 1.55(dd, 3H, Ji-18.8Hz, J2=18.8Hz), 1.31(dd, 6H,
J2=6.0Hz), 1.23-l.ll(m, 2H), 0.61(dd, 3H, J2=7.6Hz)。 实施例 39 1H NMR (CDC1 3 , 400MHz) 58.53 (s, IH), 8.36 (s, IH), 7.82 (dd, IH, J! = 8.4 Hz, J 2 = 1.2 Hz), 7.07 (d, IH, J = 8.8 Hz), 6.2 l(s, IH), 6.02(s, IH), 5.78(dd, IH, J corpse 10.0Hz, J 2 =4.0Hz), 5.32(s, 1H), 5.24-5.17(m, 3H ), 4.44 (m, 2H), 3.75(s, 3H), 3.71(s, 3H), 3.66(s, 3H), 3.65(s, IH), 3.33-3.19(m, 4H), 3.00(dd, IH, J! = 12.4 Hz, J 2 = 13.2 Hz), 2.89 (dd, IH, Ji = 14.0 Hz, J 2 = 14.0 Hz), 2.74-2.70 (m, IH), 2.64 (s, 3H), 2.61 (m, IH), 2.55 (dd, IH, Ji = 15.6 Hz, J 2 = 6.0 Hz), 2.4 l(s, IH), 2.30-2.22 (m, 2H), 2.04-1.99 (m, IH), 2.02(s, 3H), 1.80-1.72(m, 2H), 1.70-1.63(m, IH), 1.63-1.58(m, IH), 1.55(dd, 3H, Ji-18.8Hz, J 2 = 18.8Hz ), 1.31 (dd, 6H, J 2 = 6.0 Hz), 1.23-l.ll (m, 2H), 0.61 (dd, 3H, J 2 = 7.6 Hz). Example 39
12，-(N-乙基-硫脲)长春氟宁 12,-(N-ethyl-thiourea) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-氨基长春氟宁 28(0.1 g， 0.12 mmol) 搅拌下溶于 2 ml乙醇中， 加入异硫氰酸乙酯 (15.8 ul， 0.18 mmol) 0 油浴 70°C搅 拌 2小时后，点板跟踪反应，原料消失，加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 用乙酸乙酯 (50 mlx3)萃取反应液。 合并有机相， 依次用水 (100 ml)和饱和氯化钠 溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅 胶柱色谱法纯化所得残余物， 得到标题产物 12，-(N-乙基-硫脲)长春氟宁 39(65 mg, 白色固体)， 产率 60%。 Under an argon atmosphere, 12'-amino vinflurine 28 (0.1 g, 0.12 mmol) was dissolved in 2 ml of ethanol with stirring, and ethyl isothiocyanate (15.8 ul, 0.18 mmol) was added. ) 0 oil bath 70 ° C after stirring for 2 hours, the reaction is tracked, the raw material disappeared, a saturated sodium bicarbonate solution (50 ml) to quench the reaction, the reaction solution was extracted with ethyl acetate (50 mlx3). The combined organic layers were washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title product 12, -(N-ethyl-thiourea) vinflunine 39 (65 mg, white solid).
ESI:[M+1]=919。 ESI: [M+1] = 919.
1H NMR (CDC13, 400MHz)69.52(s, IH), 8.50(s, IH), 7.55(s, IH), 7.43(s, 1H)， 7.10(d， IH, J=8.8Hz), 6.93(dd， IH, J尸 8.4Hz, J2=1.4Hz), 6.26(s, IH), 6.02(s, 1H)， 5.81-5.77(m, 2H), 5.33(s, IH), 5.22(d, IH, J=9.2Hz)， 4.45(d， IH, J=12.8Hz), 4.15(d,
IH, J=12.4Hz), 3.75(s, 3H), 3.72(s, 3H), 3.66(s, 4H), 3.63-3.54(m, 2H), 3.32-3.17(m, 4H)， 2.97(dd, 1H， J^l 2.4Hz, J2=12.8Hz), 2.88(dd, 1H， J尸 14.4Hz， J2=14.0Hz), 2.72(m, IH), 2.65(s, 3H), 2.49-2.60(m, 2H), 2.40(s, IH), 2.26-2.18(m, 2H), 2.08(m, IH), 2.02(s, 3H), 1.78-1.57(m, 4H), 1.54(dd， 3H, Ι^Ι δ.δΗζ, J2=18.8Hz), 1.89(m, 1H)， 1.10-1.00(m5 IH), 1.07(dd, 3H， J尸 7.2Hz, J2=7.2Hz), 0.60(dd, 3H, J尸 7.2Hz, J2=7.2Hz)。 实施例 40 1H NMR (CDC1 3 , 400MHz) 69.52 (s, IH), 8.50 (s, IH), 7.55 (s, IH), 7.43 (s, 1H), 7.10 (d, IH, J = 8.8 Hz), 6.93 ( Dd, IH, J 8.4 Hz, J 2 = 1.4 Hz), 6.26 (s, IH), 6.02 (s, 1H), 5.81-5.77 (m, 2H), 5.33 (s, IH), 5.22 (d, IH, J=9.2Hz), 4.45(d, IH, J=12.8Hz), 4.15(d, IH, J = 12.4 Hz), 3.75 (s, 3H), 3.72 (s, 3H), 3.66 (s, 4H), 3.63-3.54 (m, 2H), 3.32-3.17 (m, 4H), 2.97 (dd , 1H, J^l 2.4Hz, J 2 = 12.8Hz), 2.88 (dd, 1H, J corp. 14.4Hz, J 2 = 14.0Hz), 2.72(m, IH), 2.65(s, 3H), 2.49- 2.60(m, 2H), 2.40(s, IH), 2.26-2.18(m, 2H), 2.08(m, IH), 2.02(s, 3H), 1.78-1.57(m, 4H), 1.54(dd, 3H, Ι^Ι δ.δΗζ, J 2 = 18.8Hz), 1.89(m, 1H), 1.10-1.00(m 5 IH), 1.07(dd, 3H, J 7.2Hz, J 2 =7.2Hz), 0.60 (dd, 3H, J 7.2 Hz, J 2 = 7.2 Hz). Example 40
12，-(N-环丙基-硫脲)长春氟宁 12,-(N-cyclopropyl-thiourea) vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-氨基长春氟宁 28(0.1 g， 0.12 mmol) 搅拌下溶于 2 ml乙醇中， 加入异硫氰酸环丙酯 (24 ul， 0.24 mmol)。 油浴 70°C搅 拌 2小时后，点板跟踪反应，原料消失，加入饱和碳酸氢钠溶液 (50 ml)淬灭反应， 用乙酸乙酯 (50 mlx3)萃取反应液。 合并有机相， 依次用水 (100 ml)、 饱和氯化钠 溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸缓干燥， 过滤， 滤液减压浓缩， 用硅 胶柱色谱法纯化所得残余物， 得到标题产物 12'-(N-环丙基-硫脲)长春氟宁 40(74 mg, 白色固体)， 产率 67%。 Under a argon atmosphere, in a dry round bottom flask, 12'-amino vinflurine 28 (0.1 g, 0.12 mmol) was dissolved in 2 ml of ethanol with stirring, and cyclopropyl isothiocyanate (24 ul, 0.24) was added. Mm). After the oil bath was stirred at 70 ° C for 2 hours, the reaction was traced and the material was evaporated. The mixture was evaporated and evaporated to ethyl acetate (50 ml). The combined organic phases were washed with EtOAc (EtOAc) (EtOAc). The title product 12'-(N-cyclopropyl-thiourea) vinflunine 40 (74 mg, white solid) was obtained, yield 67%.
ESI:[M+1]=931。 ESI: [M+1] = 931.
1H NMR (CDC13, 400MHz)58.45(s, IH), 7.87(brs, IH), 7.49(s, IH), 7.08(m, 2H), 6.30(m, 2H), 6.03(s, IH), 5.80(dd, IH, Ji=10.0Hz, J2=3.6Hz), 5.33(s, IH), 5.22(d, IH, J-lO.OHz), 4.44(s, IH), 3.75(s, 3H), 3.72(s, 3H), 3.67(s, IH), 3.65(s, 3H)， 3.32-3.28(m, 3H), 3.21(m, IH), 3.02(dd, IH, Ji=12.4Hz, J2=12.8Hz), 2.92(m, IH), 2.88(dd, IH, J^M.OHz, J2=l 4.0Hz), 2.74-2.72(m, 2H), 2.65(s, 3H), 2.58-2.54(m, 2H), 2.38(m, IH), 2.30(d, IH, J= 15.2Hz), 2.03(m, IH), 2.02(s, 3H), 1.80-1.77(m, 2H), 1.68-1.67(m, IH), 1.61-1.57(m, IH), 1.56(dd, 3H, Ji=18.8Hz, J2=18.8Hz), 1.26-1.18(m, 2H), 0.87-0.76(m, 4H), 0.60(dd, 3H, J产 7.2Hz, J2=7.2Hz)。 实施例 41 1H NMR (CDC1 3 , 400MHz) 58.45 (s, IH), 7.87 (brs, IH), 7.49 (s, IH), 7.08 (m, 2H), 6.30 (m, 2H), 6.03 (s, IH), 5.80(dd, IH, Ji=10.0Hz, J 2 =3.6Hz), 5.33(s, IH), 5.22(d, IH, J-lO.OHz), 4.44(s, IH), 3.75(s, 3H ), 3.72(s, 3H), 3.67(s, IH), 3.65(s, 3H), 3.32-3.28(m, 3H), 3.21(m, IH), 3.02(dd, IH, Ji=12.4Hz, J 2 = 12.8 Hz), 2.92 (m, IH), 2.88 (dd, IH, J^M.OHz, J 2 = l 4.0 Hz), 2.74-2.72 (m, 2H), 2.65 (s, 3H), 2.58-2.54(m, 2H), 2.38(m, IH), 2.30(d, IH, J= 15.2Hz), 2.03(m, IH), 2.02(s, 3H), 1.80-1.77(m, 2H) , 1.68-1.67(m, IH), 1.61-1.57(m, IH), 1.56(dd, 3H, Ji=18.8Hz, J 2 = 18.8Hz), 1.26-1.18(m, 2H), 0.87-0.76( m, 4H), 0.60 (dd, 3H, J yield 7.2 Hz, J 2 = 7.2 Hz). Example 41
12'-(N,N-二甲基脲)长春氟宁
12'-(N,N-dimethylurea) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12，-氨基长春氟宁 28(70 mg， 0.084 mmol), 4-N，N-二甲氨基吡啶 (12.3 mg， 0.11 mmol), 氯甲酸对硝基苯酯 (22.4 mg， 0.11 mmol),搅拌下溶于 10 ml四氢呋喃中，室温反应 30分钟后加入二甲胺盐酸 盐 (8.9 mg， 0.11 nraiol)和氢氧化钠 (4.4 mg， 0.11 mmol)的水溶液 (0.5 ml)。反应 10 分钟后， 点板跟踪反应结束， 加入饱和碳酸氢钠溶液 (40 ml)淬灭反应， 用乙酸乙 酯 (70 mlx3)萃取反应液。合并有机相， 依次用饱和氯化钠溶液 (70 mlx3)洗涤， 乙 酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残 余物， 得到标题产物 12'-(N，N-二甲基脲)长春氟宁 41(35 mg， 白色固体)， 产率 46%。 Under a argon atmosphere, 12,-amino vinflurine 28 (70 mg, 0.084 mmol), 4-N,N-dimethylaminopyridine (12.3 mg, 0.11 mmol), chloroformic acid was added to a dry round bottom flask. Nitrophenyl ester (22.4 mg, 0.11 mmol), dissolved in 10 ml of tetrahydrofuran with stirring, reacted at room temperature for 30 minutes, then added dimethylamine hydrochloride (8.9 mg, 0.11 nraiol) and sodium hydroxide (4.4 mg, 0.11 mmol) ) aqueous solution (0.5 ml). After 10 minutes of reaction, the reaction was completed by spotting, and the reaction was quenched with saturated sodium bicarbonate (40 ml), and the mixture was extracted with ethyl acetate (70 ml x 3). The organic phase was combined and washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - (N, N-dimethylurea) vinflunine 41 (35 mg, white solid), yield 46%.
ESI:[M+l]=903 c ESI: [M+l]=903 c
1H NMR (CDC13, 400MHz)59.80(brs, IH), 8.23(s, IH), 7.51(s, IH), 7.10(d, IH, J=7.6Hz), 6.97(d, H, J=8.4Hz), 6.26(s, IH), 6.23(s, IH), 6.01(s, IH), 5.78(dd, IH, J尸 10.4Hz, J2=4.0Hz), 5.34(s, IH), 5.20(d, IH, J=10.4Hz), 4.38(d, IH, J=12.4Hz), 4.18(d, IH, J=13.2Hz), 3.74(s, 3H), 3.71(s， 3H), 3.64(s, IH), 3.63(s, 3H), 3.30-3.16(m, 4H), 2.96(s, 6H), 2.94-2.89(m, 2H), 2.73(d, IH, J=l 6.0Hz), 2.65(m, IH), 2.64(s, 3H), 2.50(m, 2H), 2.36(m, IH), 2.14(d, IH, J=15.2Hz), 2.03(m, IH), 2.02(s, 3H), 1.76-1.73(m, 2H), 1.64(m, IH), 1.55(m, IH), 1.53(dd, 3H, 】尸18.41¾ J2=19.2Hz), 1.19(m, IH), 1.06(m, 1H)， 0.62(dd, 3H, J!=7.2Hz, J2=7.2Hz)。1H NMR (CDC1 3 , 400MHz) 59.80 (brs, IH), 8.23 (s, IH), 7.51 (s, IH), 7.10 (d, IH, J = 7.6 Hz), 6.97 (d, H, J = 8.4 Hz), 6.26(s, IH), 6.23(s, IH), 6.01(s, IH), 5.78(dd, IH, J corp. 10.4Hz, J 2 =4.0Hz), 5.34(s, IH), 5.20 (d, IH, J = 10.4 Hz), 4.38 (d, IH, J = 12.4 Hz), 4.18 (d, IH, J = 13.2 Hz), 3.74 (s, 3H), 3.71 (s, 3H), 3.64 (s, IH), 3.63(s, 3H), 3.30-3.16(m, 4H), 2.96(s, 6H), 2.94-2.89(m, 2H), 2.73(d, IH, J=l 6.0Hz) , 2.65(m, IH), 2.64(s, 3H), 2.50(m, 2H), 2.36(m, IH), 2.14(d, IH, J=15.2Hz), 2.03(m, IH), 2.02( s, 3H), 1.76-1.73(m, 2H), 1.64(m, IH), 1.55(m, IH), 1.53(dd, 3H, 】 corpse 18.413⁄4 J 2 =19.2Hz), 1.19(m, IH ), 1.06 (m, 1H), 0.62 (dd, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz).
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-氨基长春氟宁 28(50 mg， 0.06 mmol), 4-Ν,Ν-二甲氨基吡啶 (9.5 mg， 0.078 mmol), 氯甲酸对硝基苯酯 (15.7 mg，
0.078 mmol), 搅拌下溶于 10 ml四氢呋喃中， 室温反应 20分钟后， 点板跟踪反 应， 原料消失， 加入 25 %的氨水溶液 (12 ul， 0.078 mmol), 搅拌 10分钟后加入 饱和碳酸氢钠溶液 (40 ml)淬灭反应，用乙酸乙酯 (70 mlx3)萃取反应液。合并有机 相， 用饱和氯化钠溶液 (70 mlx3)洗涤， 乙酸乙酯层用无水硫酸续干燥， 过滤， 滤 液减压浓缩，用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-脲基长春氟宁 42(12 mg, 白色固体)， 产率 23 %。 Under a argon atmosphere, in a dry round bottom flask, 12'-amino vinflurine 28 (50 mg, 0.06 mmol), 4-indole, hydrazine-dimethylaminopyridine (9.5 mg, 0.078 mmol), chloroformic acid Nitrophenyl ester (15.7 mg, 0.078 mmol), dissolved in 10 ml of tetrahydrofuran with stirring, reacted at room temperature for 20 minutes, the reaction was stopped by spotting, the starting material disappeared, 25% aqueous ammonia solution (12 ul, 0.078 mmol) was added, stirred for 10 minutes, then saturated sodium bicarbonate was added. The solution (40 ml) was quenched and the mixture was extracted with ethyl acetate (EtOAc). The organic phase was combined, washed with aq. EtOAc (EtOAc (EtOAc) Urea-based vinflunine 42 (12 mg, white solid), yield 23%.
ESI:[M+1]=875。 ESI: [M+1] = 875.
1H NMR (CDC13, 400MHz)59.64(brs, 1H), 8.43(s, 1H)， 7.49(s, 1H), 7.02(m, 2H): 6.53(s, 1H), 6.26(s, 1H), 6.02(s, 1H), 5.78(dd, 1H, J!=10.2Hz, J2=4.2Hz), 5.33(s， 1H), 5.21(d, 1H, J=10.4Hz), 4.68(s, 2H), 4.44(d, 1H, J=12.8Hz), 4.22(d, 1H, J=12.8Hz), 3.74(s, 3H), 3.71(s, 3H), 3.65(s， 4H)， 3.30-3.18(m, 4H), 2.98(dd, 1H, J尸 12.4Hz, J2=13.2Hz), 2.98(dd, 1H, J尸 14.4Hz, J2=13.6Hz), 2.74(m, 1H), 2.64(s, 3H), 2.62(m, 1H), 2.55(m, 1H), 2.44(s, 1H), 2.29(m, 1H), 2.2 l(d, 1H, J=l 4.0Hz), 2.05(m, 1H), 2.03(s, 3H), 1.90-1.70(m, 2H), 1.70-1.60(m, 1H), 1.60-1.56(m, 1H)， 1.54(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.28-1.05(m, 2H), 0.61(dd, 3H, Ji=7.2Hz, J2=7.2Hz)。 实施例 43 1H NMR (CDC1 3 , 400MHz) 59.64 (brs, 1H), 8.43 (s, 1H), 7.49 (s, 1H), 7.02 (m, 2H): 6.53 (s, 1H), 6.26 (s, 1H), 6.02(s, 1H), 5.78(dd, 1H, J!=10.2Hz, J 2 =4.2Hz), 5.33(s, 1H), 5.21(d, 1H, J=10.4Hz), 4.68(s, 2H ), 4.44 (d, 1H, J = 12.8 Hz), 4.22 (d, 1H, J = 12.8 Hz), 3.74 (s, 3H), 3.71 (s, 3H), 3.65 (s, 4H), 3.30-3.18 (m, 4H), 2.98 (dd, 1H, J corp. 12.4 Hz, J 2 = 13.2 Hz), 2.98 (dd, 1H, J corp. 14.4 Hz, J 2 = 13.6 Hz), 2.74 (m, 1H), 2.64 (s, 3H), 2.62(m, 1H), 2.55(m, 1H), 2.44(s, 1H), 2.29(m, 1H), 2.2 l(d, 1H, J=l 4.0Hz), 2.05( m, 1H), 2.03(s, 3H), 1.90-1.70(m, 2H), 1.70-1.60(m, 1H), 1.60-1.56(m, 1H), 1.54(dd, 3H, J corpse 18.8Hz, J 2 = 18.8 Hz), 1.28-1.05 (m, 2H), 0.61 (dd, 3H, Ji = 7.2 Hz, J 2 = 7.2 Hz). Example 43
12'-(N-甲基 -脲)长春氟宁 12'-(N-methyl-urea) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-氨基长春氟宁 28(50 mg, 0.06 mmol), 4-Ν,Ν-二甲氨基吡啶 (9.5 mg， 0.078 mmol), 氯甲酸对硝基苯酉旨 (15.7 mg， 0.078 mmol), 搅拌下溶于 10 ml四氢呋喃中， 室温反应 20分钟后， 点板跟踪反 应， 原料消失， 加入 40%的甲胺水溶液 (5.3 ul， 0.078 mmol), 搅拌 10分钟后加 入饱和碳酸氢钠溶液 (40 ml)淬灭反应，用乙酸乙酯 (70 mlx3)萃取反应液。合并有 机相， 用饱和氯化钠溶液 (70 mlx3)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓縮，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'-(N-甲基 -脲) 长春氟宁 43(26 mg， 白色固体)， 产率 48.7%。 Under a argon atmosphere, in a dry round bottom flask, 12'-amino vinflurine 28 (50 mg, 0.06 mmol), 4-indole, hydrazine-dimethylaminopyridine (9.5 mg, 0.078 mmol), chloroformic acid Nitrobenzoquinone (15.7 mg, 0.078 mmol), dissolved in 10 ml of tetrahydrofuran with stirring, reacted at room temperature for 20 minutes, the reaction was followed by spotting, the starting material disappeared, and 40% aqueous solution of methylamine (5.3 ul, 0.078 mmol) was added. After stirring for 10 minutes, the reaction was quenched with EtOAc EtOAc (EtOAc) The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -(N-methyl-urea) vinflunine 43 (26 mg, white solid), yield 48.7%.
ESI:[M+1]=889。 ESI: [M+1] = 889.
1H NMR (CDC13, 400MHz)59.62(brs, 1H), 8.38(s, 1H)， 7.02(m, 2H), 6.26(s, 2H); 6.02(s, 1H), 5.79(dd, 1H, J^lO.OHz, J2=4.6Hz)， 5.33(s, 1H), 5.21(d, 1H, J=10.0Hz),
69 1H NMR (CDC1 3 , 400MHz) 59.62 (brs, 1H), 8.38 (s, 1H), 7.02 (m, 2H), 6.26 (s, 2H) ; 6.02 (s, 1H), 5.79 (dd, 1H, J ^lO.OHz, J 2 =4.6Hz), 5.33(s, 1H), 5.21(d, 1H, J=10.0Hz), 69
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12'- (吗啡啉甲酰胺基)长春氟宁 12'- (morpholinecarboxamide) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-氨基长春氟宁 28(0.05 g， 0.06 mmol), 4-Ν,Ν-二甲氨基吡啶 (9.5 mg， 0.078 mmol), 氯甲酸对硝基苯酉旨 (15.7 mg， 0.078 mmol), 搅拌下溶于 10 ml四氢呋喃中， 室温反应 20分钟后， 点板跟踪反 应， 原料消失， 加入吗啡啉 (6.8 ul， 0.078 mmol), 搅拌 10分钟后加入饱和碳酸 氢钠溶液 (40 ml)淬灭反应，用乙酸乙酯 (70 mlx3)萃取反应液。合并有机相， 用饱 和氯化钠溶液 (70 mlx3)洗涤， 乙酸乙酯层用无水硫酸镁干燥，过滤， 滤液减压浓 缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'- (吗啡啉甲酰胺基)长春 氟宁 45(29 mg， 白色固体)， 产率 51.1 %。 Under a argon atmosphere, in a dry round bottom flask, 12'-amino vinflurine 28 (0.05 g, 0.06 mmol), 4-indole, hydrazine-dimethylaminopyridine (9.5 mg, 0.078 mmol), chloroformic acid Nitrobenzoquinone (15.7 mg, 0.078 mmol), dissolved in 10 ml of tetrahydrofuran with stirring, reacted at room temperature for 20 minutes, the reaction was followed by spotting, the starting material disappeared, morpholine (6.8 ul, 0.078 mmol) was added, and stirred for 10 minutes. After the reaction was quenched with saturated aqueous sodium hydrogen sulfate (40 ml), ethyl acetate The organic phase was combined, washed with EtOAc EtOAc EtOAc (EtOAcjjjjjjj (morpholinecarboxamide) vinflunine 45 (29 mg, white solid), yield 51.%.
ESI:[M+1]=945。 ESI: [M+1] = 945.
1H NMR (CDC13, 400MHz) 9.75(brs, IH), 8.26(s, IH), 7.49(s， IH), 7.06(dd, IH, J尸 8.8Hz, J2=1.6Hz), 6.98(d, IH, J=8.4Hz), 6.28(s, IH), 6.26(s, IH), 6.01(s, 1H)， 5.78(dd, IH, J尸 10.2Hz, J2=4.2Hz), 5.34(s, IH), 5.20(d, 1H， J=10.0Hz), 4.39(d, IH, J=12.8Hz), 4.17(d, IH, J=12.8Hz), 3.74(s, 3H), 3.71(s, 3H), 3.67(s, 4H, J尸 4.8Hz, J2=5.2Hz), 3.65(s, IH), 3.64(s, 3H), 3.41(s, 4H, J!=5.2Hz, J2=4.4Hz), 3.30-3.16(m, 4H), 2.94(dd, IH, J!=12.4Hz, J2=13.2Hz), 2.89(dd, IH, Κ4.4Ηζ, J2=13.6Hz), 2.72(d, IH, J=l 6.0Hz), 2.70(m, IH), 2.64(s, 3H), 2.55(m, IH), 2.48(s, IH), 2.35(m, IH), 2.14(d, IH, J=13.2Hz), 2.03(m, IH), 2.02(s, 3H), 1.81-1.74(m, 2H), 1.74-1.63(m; IH), 1.58-1.53(m, IH), 1.53(dd, 3H,
1.19(m, IH), 1.05(m, IH), 0.62(dd, 3H, J!=7.2Hz, J2=7.2Hz)。 实施例 46 1H NMR (CDC1 3 , 400MHz) 9.75 (brs, IH), 8.26 (s, IH), 7.49 (s, IH), 7.06 (dd, IH, J 8.8 Hz, J 2 =1.6 Hz), 6.98 (d , IH, J=8.4Hz), 6.28(s, IH), 6.26(s, IH), 6.01(s, 1H), 5.78(dd, IH, J corp. 10.2Hz, J 2 =4.2Hz), 5.34( s, IH), 5.20(d, 1H, J=10.0Hz), 4.39(d, IH, J=12.8Hz), 4.17(d, IH, J=12.8Hz), 3.74(s, 3H), 3.71( s, 3H), 3.67 (s, 4H, J 4.8 Hz, J 2 = 5.2 Hz), 3.65 (s, IH), 3.64 (s, 3H), 3.41 (s, 4H, J! = 5.2 Hz, J 2 = 4.4 Hz), 3.30-3.16 (m, 4H), 2.94 (dd, IH, J! = 12.4 Hz, J 2 = 13.2 Hz), 2.89 (dd, IH, Κ 4.4 Ηζ, J 2 = 13.6 Hz) , 2.72(d, IH, J=l 6.0Hz), 2.70(m, IH), 2.64(s, 3H), 2.55(m, IH), 2.48(s, IH), 2.35(m, IH), 2.14 (d, IH, J = 13.2 Hz), 2.03 (m, IH), 2.02 (s, 3H), 1.81-1.74 (m, 2H), 1.74-1.63 (m ; IH), 1.58-1.53 (m, IH) ), 1.53 (dd, 3H, 1.19 (m, IH), 1.05 (m, IH), 0.62 (dd, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz). Example 46
12'-甲酸节酯长春氟宁 12'-formic acid ester vinflunine
ESI:[M+1]=951。 ESI: [M+1] = 951.
1H NMR (CDC13, 400MHz)59.60(brs, IH), 8.52(s, IH), 8.41(s, IH), 7.85(dd, IH, J=8.8Hz), 7.40(d, 2H, J=7.2Hz), 7.34-7.24(m, 3H), 7.07(d, 1H， J=8.4Hz), 6.20(s, IH), 6.01(s, IH), 5.77(dd, IH, J!=10.4Hz, J2=4.4Hz), 5.33(s, 2H), 5.29 (s, 1H)， 5.20(d, IH, J=l 0.4Hz), 4.44(d, IH, J=13.2Hz), 4.30(m, IH), 3.74 (s， 3H)， 3.71 (s, 3H)， 3.66(s, 3H), 3.64(s, IH), 3.28-3.20(m, 3H), 3.20-3.15(m， IH), 3.01(dd, IH, J!=12.4Hz, J2-13.2Hz), 2.88(dd, IH, J尸 14.0Hz, J2=14.4Hz), 2.64(s, 3H), 2.62(m, IH), 2.56-2.5 l(m, IH), 2.37(s, IH), 2.24-2.18(m, 2H), 2.03(m, IH), 2.02(s, 3H), 1.80-1.71 (m, 2H), 1.71-1.57(m, 2H), 1.54(dd, 3H, Ji=18.8Hz, J2=18.8Hz), 1.28-1.15(m, IH), 1.15-1.06(m, IH), 0.60(dd, 3H， J!=7.2Hz, J2=7.2Hz)。 实施例 47 1H NMR (CDC1 3 , 400MHz) 59.60 (brs, IH), 8.52 (s, IH), 8.41 (s, IH), 7.85 (dd, IH, J = 8.8 Hz), 7.40 (d, 2H, J = 7.2 Hz), 7.34-7.24(m, 3H), 7.07(d, 1H, J=8.4Hz), 6.20(s, IH), 6.01(s, IH), 5.77(dd, IH, J!=10.4Hz, J 2 = 4.4 Hz), 5.33 (s, 2H), 5.29 (s, 1H), 5.20 (d, IH, J = l 0.4 Hz), 4.44 (d, IH, J = 13.2 Hz), 4.30 (m, IH), 3.74 (s, 3H), 3.71 (s, 3H), 3.66(s, 3H), 3.64(s, IH), 3.28-3.20(m, 3H), 3.20-3.15(m, IH), 3.01 (dd, IH, J! = 12.4 Hz, J 2 -13.2 Hz), 2.88 (dd, IH, J corp. 14.0 Hz, J 2 = 14.4 Hz), 2.64 (s, 3H), 2.62 (m, IH), 2.56-2.5 l(m, IH), 2.37(s, IH), 2.24-2.18(m, 2H), 2.03(m, IH), 2.02(s, 3H), 1.80-1.71 (m, 2H), 1.71 -1.57(m, 2H), 1.54(dd, 3H, Ji=18.8Hz, J 2 = 18.8Hz), 1.28-1.15(m, IH), 1.15-1.06(m, IH), 0.60(dd, 3H, J!=7.2 Hz, J 2 = 7.2 Hz). Example 47
12'-环丙基长春氟宁 12'-cyclopropyl vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.189 g， 0.2 mmol) 搅拌下溶解于 10 ml四氢呋喃，加入 13 ml环丙基溴化镁 (8 ml, lmol/L)和氯化锌 (0.54 g, 4 mmol)的甲苯—四氢呋喃溶液及醋酸钯 (4.5 mg， 0.02 mmol)和三苯基膦 (10.5 mg, 0.04 mmol)的四氢呋喃溶液 (l ml)， 室温下反应 1小时后， 点板跟踪反 应， 原料消失，加入饱和碳酸氢钠溶液 (100 ml)淬灭反应， 用乙酸乙酯 (100 mlx4) 萃取反应液， 合并有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水 硫酸镁干燥， 抽滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题 产物 12'-环丙基长春氟宁 47(53 mg, 白色固体)， 收率： 31 %。 Under a argon atmosphere, 12'-iodovinflurine 1 (0.189 g, 0.2 mmol) was dissolved in 10 ml of tetrahydrofuran in a dry round bottom flask, and 13 ml of cyclopropylmagnesium bromide (8 ml, Lmol/L) and zinc chloride (0.54 g, 4 mmol) in toluene-tetrahydrofuran solution and palladium acetate (4.5 mg, 0.02 mmol) and triphenylphosphine (10.5 mg, 0.04 mmol) in tetrahydrofuran (1 ml), After reacting for 1 hour at room temperature, the reaction was followed by spotting, the starting material disappeared, and the reaction was quenched with saturated sodium bicarbonate (100 ml). The mixture was extracted with ethyl acetate (100 ml×4), and the organic phase was combined with saturated sodium chloride. The solution (100 ml) was washed with EtOAc EtOAc (EtOAcjjjjjjjj 53 mg, white solid), Yield: 31%.
ESI:[M+1]=857。
Z9 ESI: [M+1] = 857. Z9
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S08110/8003 OAV
实施例 49 S08110/8003 OAV Example 49
12'-甲基长春氟宁 12'-methyl vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.63 g， 0.668 mmol) 搅拌下溶于 20 ml无水四氢呋喃中，分批逐滴加入 27 ml甲基溴化镁 (9.45 ml, 1.4 mol/L)和氯化锌 (1.84 g， 13.5 mmol)的甲苯-四氢呋喃溶液 (0.5 mol/L)及 7.5 ml醋 酸钯 (22.5 mg， 0.1 mmol)和三苯基膦 (52.5 mg， 0.2 mmol)的四氢呋喃溶液 (0.013 mol/L), 室温搅拌 2.5小时后， 点板跟踪反应至原料基本消失， 加入饱和碳酸氢 钠溶液 (200 ml)淬灭反应，用乙酸乙酯 (200 mlx3)萃取反应液。合并有机相， 依次 用水 (100 ml)及饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无水硫酸续千燥，过 滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-甲基长 春氟宁 49(0.247 mg， 白色固体)， 产率 44%。 Under a argon atmosphere, 12'-iodovinfluramine 1 (0.63 g, 0.668 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran under stirring in a round bottom flask, and 27 ml of methyl bromide was added dropwise in portions. Magnesium (9.45 ml, 1.4 mol/L) and zinc chloride (1.84 g, 13.5 mmol) in toluene-tetrahydrofuran (0.5 mol/L) and 7.5 ml palladium acetate (22.5 mg, 0.1 mmol) and triphenylphosphine (52.5 mg, 0.2 mmol) in tetrahydrofuran (0.013 mol/L). After stirring at room temperature for 2.5 hours, the reaction was traced until the starting material disappeared. The reaction was quenched with saturated sodium bicarbonate (200 ml). (200 ml x 3) extraction reaction solution. The organic phase was combined, washed with water (100 ml) and brine (100 ml). The title product 12'-methyl vinflunine 49 (0.247 mg, white solid) was obtained.
ESI:[M+1]=831。 ESI: [M+1] = 831.
1H NMR (CDC13, 400MHz)59.75(brs, IH), 8.29(s, IH), 7.44(s, IH), 7.02(d, IH, J=8.4Hz), 6.98(d, IH, J=8.4Hz), 6.39(s, IH), 6.08(s, IH), 5.83(dd， IH, J!=10.4Hz, J2=4.0Hz), 5.41(s, IH), 5.27(d, IH, J=10.4Hz), 4.49(d, IH, J=12.8Hz), 4.3 l(d, IH, J-12.4Hz), 3.81(s, 3H), 3.78(s, 3H), 3.71(s, IH), 3.69(s, 3H), 3.40-3.27(m, 3H), 3.27-3.20(m, IH), 3.08(dd, IH, J尸 13.2Hz, J2=12.4Hz), 2.97(dd, IH, Jj-H.fflz, J2=14.0Hz), 2.80-2.70(m, IH), 2.71 (s, 3H), 2.70-2.65(m, IH), 2.56(dd, 1H，】尸14.81¾ J2=6.0Hz), 2.5 l(s, 1H)， 2.44(s, 3H), 2.38-2.32(m, IH), 2.24(d, IH, J=14.4Hz), 2.14-2.09(m, IH), 2.09(s, 3H), 1.87-1.80(m, 2H), 1.70-1.68(m, IH), 1.68-1.61(m, 1H): 1.61(dd, 3H, J尸 18.8Hz, J2=18.8Hz), 1.22-1.20(m, IH), 1.17-1.08(brs, IH), 0.70(dd, 3H, J尸 7.6Hz, J2=7.2Hz)。 实施例 50 1H NMR (CDC1 3 , 400MHz) 59.75 (brs, IH), 8.29 (s, IH), 7.44 (s, IH), 7.02 (d, IH, J = 8.4 Hz), 6.98 (d, IH, J = 8.4 Hz), 6.39(s, IH), 6.08(s, IH), 5.83(dd, IH, J!=10.4Hz, J 2 =4.0Hz), 5.41(s, IH), 5.27(d, IH, J = 10.4 Hz), 4.49 (d, IH, J = 12.8 Hz), 4.3 l (d, IH, J-12.4 Hz), 3.81 (s, 3H), 3.78 (s, 3H), 3.71 (s, IH) , 3.69(s, 3H), 3.40-3.27(m, 3H), 3.27-3.20(m, IH), 3.08(dd, IH, J corp. 13.2Hz, J 2 = 12.4Hz), 2.97(dd, IH, Jj-H.fflz, J 2 =14.0Hz), 2.80-2.70(m, IH), 2.71 (s, 3H), 2.70-2.65(m, IH), 2.56(dd, 1H, 】 corpse 14.813⁄4 J 2 =6.0Hz), 2.5 l(s, 1H), 2.44(s, 3H), 2.38-2.32(m, IH), 2.24(d, IH, J=14.4Hz), 2.14-2.09(m, IH), 2.09(s, 3H), 1.87-1.80(m, 2H), 1.70-1.68(m, IH), 1.68-1.61(m, 1H) : 1.61(dd, 3H, J corp. 18.8Hz, J 2 =18.8Hz ), 1.22-1.20 (m, IH), 1.17-1.08 (brs, IH), 0.70 (dd, 3H, J 7.6 Hz, J 2 = 7.2 Hz). Example 50
3-三乙基硅氧 -12，-碘代长春氟宁
3-triethylsiloxy-12,-iodovinflurine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(1.78 g， 1.89 mmol) 搅拌下溶解于 30 ml二氯甲垸中， 加入二异丙基乙胺 (3.3 ml, 18.9 mmol)和三氟 甲磺酸三乙基硅烷基酯 (0.94 ml， 4.154 mmol)。 油浴 25°C下搅拌 2小时， 点板跟 踪反应， 原料消失， 加入饱和碳酸氢钠溶液 (100 ml)淬灭反应。 用乙酸乙酯 (100mlx3)萃取， 合并有机相， 用饱和氯化钠溶液 (100 ml)洗涤， 乙酸乙酯层用无 水硫酸镁干燥，过滤，滤液减压浓缩蒸干得到标题产物 3-三乙基硅氧 -12'-碘代长 春氟宁 50(2.36 g， 黄色固体)的粗产品， 直接用于下一步反应。 Under an argon atmosphere, 12'-iodovinflurine 1 (1.78 g, 1.89 mmol) was dissolved in 30 ml of dichloromethane in a dry round bottom flask, and diisopropylethylamine (3.3) was added. Ml, 18.9 mmol) and triethylsilyl triflate (0.94 ml, 4.154 mmol). The oil bath was stirred at 25 ° C for 2 hours, the reaction was followed by a spotting, the starting material disappeared, and the reaction was quenched with saturated sodium hydrogen carbonate (100 ml). The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The crude product of ethylsiloxy-12'-iodovinflurion 50 (2.36 g, yellow solid) was used directly in the next step.
3-三乙基硅氧 -12，- (吡咯垸基 -1-基)长春氟宁 3-triethylsiloxy-12,-(pyrrole-1-yl)vinflurine
氩气氛下，在干燥的圆底烧瓶中，加入带保护基的 3-三乙基硅氧 -12'-碘代长 春氟宁 50(0.338 g, 0.32 mmol)和叔丁醇钠 (0.101 mg， 1.056 mmol), 搅拌下溶解 于 10 ml甲苯中，加入吡咯烷 (0.64 ul， 0.8 mmol),室温下搅拌 3分钟，加入三 (二 亚苄基丙酮)二钯 (0)(29.2 mg， 0.032 mmol)和 2-二环己基膦 -2，,4',6，-三异丙基 -1,1，-联苯 (30.4 mg， 0.064 mmol)的甲苯溶液 (5 ml)。 油浴 80°C下搅拌 2小时， 点 板跟踪反应至原料消失。 加入乙酸乙酯 (100 ml)淬灭反应， 减压抽滤， 蒸干溶剂 得到标题产物 3-三乙基硅氧 -12'- (吡咯院基 -1-基)长春氟宁 51(0.4 g， 黄色固体) 的粗产品， 直接用于下一步反应。 Under a argon atmosphere, in a dry round bottom flask, 3-triethylsiloxy-12'-iodovinfluramine 50 (0.338 g, 0.32 mmol) and sodium tert-butoxide (0.101 mg, 1.056 mmol), dissolved in 10 ml of toluene with stirring, added pyrrolidine (0.64 ul, 0.8 mmol), stirred at room temperature for 3 minutes, and added tris(dibenzylideneacetone)dipalladium(0) (29.2 mg, 0.032 mmol) And a solution of 2-dicyclohexylphosphine-2,,4',6,-triisopropyl-1,1,-biphenyl (30.4 mg, 0.064 mmol) in toluene (5 ml). The oil bath was stirred at 80 ° C for 2 hours, and the reaction was tracked by a plate to disappear. The reaction was quenched with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjj , yellow solid) crude product, used directly in the next reaction.
ESI:[M+1]=1000。 实施例 52 ESI: [M+1] = 1000. Example 52
12，- (吡咯烷基 -1-基)长春氟宁
12,-(pyrrolidin-1-yl)vinflurine
氩气氛下， 在干燥的圆底烧瓶中， 将上述实施例 51中所得的 3-三乙基硅氧 -12'- (吡咯烷基 -1-基)长春氟宁 (0.4 g)搅拌下溶解于 10 ml 四氢呋喃中， 加入 3 ml三水合四丁基氟化铵 (0.40 g, 1.28 mmol)的四氢呋喃溶液， 冰水浴下搅拌 1小 时。 点板跟踪反应， 原料消失。加入饱和氯化钠溶液 (50 ml)淬灭反应。用乙酸乙 酯 (100 mlx3)萃取反应液， 合并有机相， 乙酸乙酯层用无水硫酸镁千燥， 过滤， 滤液减压浓缩，用硅胶柱色谱法纯化所得残余物，得到标题产物 12'- (吡咯烷基 -1- 基)长春氟宁 (21 mg， 浅灰色固体)， 产率 7.4%。 The 3-triethylsiloxy-12'-(pyrrolidin-1-yl)vinflurine (0.4 g) obtained in the above Example 51 was dissolved in a dry round bottom flask under stirring under an argon atmosphere. To 10 ml of tetrahydrofuran, a solution of 3 ml of tetrabutylammonium fluoride trihydrate (0.40 g, 1.28 mmol) in tetrahydrofuran was added, and the mixture was stirred for 1 hour under ice water. The spot plate tracks the reaction and the raw materials disappear. The reaction was quenched by the addition of a saturated sodium chloride solution (50 ml). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. - (Pyrrolidin-1-yl) vinflunine (21 mg, light gray solid), yield 7.4%.
ESI:[M+l ESI: [M+l
1H NMR (CDC13, 400MHz)89.72(brs, 1H), 8.06(s, 1H), 6.93 (d, 1H, J=8.8Hz), 6.74(brs, 1H), 6.57(d, 1H, J=8.8Hz), 6.30(s, 1H), 6.01(s, 1H), 5.78(dd, 1H, Ji=9.2Hz, J2=3.6Hz), 5.33(s, 1H), 5.2 l(d, 1H, J=10.0Hz), 4.42(m, 2H), 3.74(s, 3H), 3.71(s, 3H), 3.65(s, 1H), 3.63(s, 3H), 3.29-3.18(m, 8H)， 3.00(m, 1H)， 2.89(dd, 1H, =^.SB.z, J2=14.0Hz), 2.75(m, 2H), 2.64(s, 3H), 2.52(m, 2H), 2.38(m, 1H), 2.25(m, 1H), 2.02(s, 3H), 2.00(m, 1H), 1.93(m, 4H), 1.80-1.70(m, 2H), 1.71-1.60(m, 1H), 1.60-1.55(m, 1H), 1.55(dd, 3H, J尸 18.8Hz, J2=19.2Hz), 1.19(m, 2H), 0.64(dd, 3H， J!=7.2Hz, J2=7.2Hz 实施例 53 1H NMR (CDC1 3 , 400MHz) 89.72 (brs, 1H), 8.06 (s, 1H), 6.93 (d, 1H, J = 8.8 Hz), 6.74 (brs, 1H), 6.57 (d, 1H, J = 8.8 Hz), 6.30(s, 1H), 6.01(s, 1H), 5.78(dd, 1H, Ji=9.2Hz, J 2 =3.6Hz), 5.33(s, 1H), 5.2 l(d, 1H, J =10.0Hz), 4.42(m, 2H), 3.74(s, 3H), 3.71(s, 3H), 3.65(s, 1H), 3.63(s, 3H), 3.29-3.18(m, 8H), 3.00 (m, 1H), 2.89 (dd, 1H, =^.SB.z, J 2 = 14.0 Hz), 2.75 (m, 2H), 2.64 (s, 3H), 2.52 (m, 2H), 2.38 (m , 1H), 2.25(m, 1H), 2.02(s, 3H), 2.00(m, 1H), 1.93(m, 4H), 1.80-1.70(m, 2H), 1.71-1.60(m, 1H), 1.60-1.55 (m, 1H), 1.55 (dd, 3H, J corp. 18.8 Hz, J 2 = 19.2 Hz), 1.19 (m, 2H), 0.64 (dd, 3H, J! = 7.2 Hz, J 2 = 7.2 Hz Example 53
3-三乙基硅氧基 -12，-苯胺基长春氟宁 3-triethylsilyloxy-12,-anilinyl vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 3-三乙基硅氧 -12，-碘代长春氟宁 (0.5 g， 0.47 mmol)和叔丁醇钠 (0.162 mg， 1.692 mmol),搅拌下溶解于 10 ml 甲 苯， 加入苯胺 (118 ul， 1.269 mmol), 室温下搅拌 3分钟， 加入三 (二亚苄基丙酮) 二钯 (0)(43 mg, 0.047 mmol)和 2-二环己基膦 -2，，4，,6，-三异丙基- Ι,Γ-联苯 (44.8 mg， 0.094 mmol)的甲苯溶液 (5 ml)。 油浴 80°C下搅拌 2小时， 点板跟踪反应，
P T/CN2007/002176 原料消失。 加入乙酸乙酯 (100 ml)淬灭反应。 减压抽滤， 蒸干溶剂得到标题产物 3-三乙基硅氧基 -12'-苯胺基长春氟宁 53的粗产品， 直接用于下一步反应。 Under a argon atmosphere, in a dry round bottom flask, 3-triethylsiloxy-12,-iodovinfluramine (0.5 g, 0.47 mmol) and sodium tert-butoxide (0.162 mg, 1.692 mmol) were added and stirred. Dissolved in 10 ml of toluene, added aniline (118 ul, 1.269 mmol), stirred at room temperature for 3 minutes, added tris(dibenzylideneacetone) dipalladium (0) (43 mg, 0.047 mmol) and 2-dicyclohexyl A solution of phosphine-2,4,6,-triisopropyl-hydrazine, hydrazine-biphenyl (44.8 mg, 0.094 mmol) in toluene (5 ml). The oil bath was stirred at 80 ° C for 2 hours, and the reaction was tracked by a plate. PT/CN2007/002176 The raw materials disappeared. The reaction was quenched by the addition of ethyl acetate (100 mL). The mixture was filtered under reduced pressure and evaporated to dryness crystals crystals crystals
ESI:[M+1]=1022。 实施例 54 ESI: [M+1] = 1022. Example 54
12'-苯氨基长春氟宁 12'-phenylamino vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 将 3-三乙基硅氧基 -12'-苯胺基长春氟宁 3-Triethylsiloxy-12'-anilinyl vinflunine in a dry round bottom flask under argon
53搅拌下溶解于 10 ml四氢呋喃， 加入 3 ml三水合四丁基氟化铵 (0.593 g， 1.88 mmol)的四氢呋喃溶液， 冰水浴下搅拌 1小时。 点板跟踪反应， 原料消失。 加入 饱和氯化钠溶液 (50 ml)淬灭反应。 用乙酸乙酯 (100 mlx3)萃取反应液， 合并有机 相， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化 所得残余物， 得到标题产物 12'-苯氨基长春氟宁 54(57 mg， 浅灰色固体)， 产率 11 %。 The mixture was dissolved in 10 ml of tetrahydrofuran under stirring, and a solution of 3 ml of tetrabutylammonium fluoride trihydrate (0.593 g, 1.88 mmol) in tetrahydrofuran was added, and the mixture was stirred for 1 hour under ice water. The spot plate tracks the reaction and the raw materials disappear. The reaction was quenched by the addition of a saturated sodium chloride solution (50 ml). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Phenylamino vinflunine 54 (57 mg, light gray solid), yield 11%.
ESI:[M+1]=908。 ESI: [M+1] = 908.
1H NMR (CDC13, 400MHz)59.70(brs, IH), 8.27(s, IH), 7.34(s, IH), 7.13(dd, 1H; J尸 8.0Hz, J2=8.0Hz), 7.00(d, 1H， J=8.8Hz), 6.93(dd, IH, J^.SHz, J2=1.8Hz), 6.87(d: 2H, J-7.6Hz), 6.74(dd, IH, J^l.TRz, J2=7.2Hz), 6.32(s, IH), 6.02(s, 1H)， 5.78(dd, IH, J!=10.0Hz, J2=4.0Hz), 5.52(brs, IH), 5.34(s, IH), 5.21(d, IH, J=10.0Hz), 4.4 l(d, IH, J=12.8Hz), 4.20(d, IH, J=12.8Hz), 3.74(s, 3H), 3.71(s, 3H), 3.65(s， IH), 3.64(s, IH), 3.30-3.19(m, 4H), 2.96(dd, IH,
1H NMR (CDC1 3 , 400MHz) 59.70 (brs, IH), 8.27 (s, IH), 7.34 (s, IH), 7.13 (dd, 1H ; J 8.0 Hz, J 2 = 8.0 Hz), 7.00 (d , 1H, J=8.8Hz), 6.93(dd, IH, J^.SHz, J 2 =1.8Hz), 6.87(d : 2H, J-7.6Hz), 6.74(dd, IH, J^l.TRz , J 2 = 7.2 Hz), 6.32 (s, IH), 6.02 (s, 1H), 5.78 (dd, IH, J! = 10.0 Hz, J 2 = 4.0 Hz), 5.52 (brs, IH), 5.34 ( s, IH), 5.21(d, IH, J=10.0Hz), 4.4 l(d, IH, J=12.8Hz), 4.20(d, IH, J=12.8Hz), 3.74(s, 3H), 3.71 (s, 3H), 3.65(s, IH), 3.64(s, IH), 3.30-3.19(m, 4H), 2.96(dd, IH,
J2=13.6Hz), 2.75(m, IH), 2.68(m, IH), 2.64(s, 3H), 2.51(dd, IH, J!=15.2Hz, J2=5.8Hz), 2.47(s, IH), 2.32(m, IH), 2.20(d, IH, J=12.4Hz), 2.05(m, IH), 2.03(s, 3H): 1.83-1.75(m, 2H), 1.67-1.64(m, IH), 1.64-1.55(m, IH), 1.53(dd, 3H, Jfl Hz, J2=19.2Hz), 1.26-1.05(m, 2H), 0.63(dd, 3H, J!=7.6Hz, J2=7.2Hz)。 实施例 55 J 2 =13.6 Hz), 2.75 (m, IH), 2.68 (m, IH), 2.64 (s, 3H), 2.51 (dd, IH, J! = 15.2 Hz, J 2 = 5.8 Hz), 2.47 (s , IH), 2.32(m, IH), 2.20(d, IH, J=12.4Hz), 2.05(m, IH), 2.03(s, 3H): 1.83-1.75(m, 2H), 1.67-1.64( m, IH), 1.64-1.55(m, IH), 1.53(dd, 3H, Jfl Hz, J 2 = 19.2Hz), 1.26-1.05(m, 2H), 0.63(dd, 3H, J!=7.6Hz , J 2 = 7.2 Hz). Example 55
12'-乙基长春氟宁
12'-ethyl vinflunine
氩气氛下，在干燥的圆底烧瓶中，将 12'-碘代长春氟宁 1(0.189 g， 0.2 mmol) 搅拌下溶于 20 ml无水四氢呋喃中，滴加 5 ml醋酸钯 (4.5 mg, 0.02 mmol)和 1，1 '- 双- (二苯基膦)二茂铁 (11 mg, 0.02 mmol)的四氢呋喃溶液及 5 ml乙基溴化镁 (1 ml, 1.4
g， 1.0 mmol)的甲苯-四氢呋喃溶液 (0.5 mol/L)及室 温搅拌 1小时后， 点板跟踪反应， 原料消失， 加入饱和碳酸氢钠溶液 (50 ml)淬灭 反应，用乙酸乙酯 (50 mlx3)萃取反应液。合并有机相， 用饱和氯化钠溶液 (50 ml) 洗涤， 乙酸乙酯层用无水硫酸镜干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯 化所得残余物， 得到标题产物 12，-乙基长春氟宁 55(53 mg, 白色固体)， 产率 31 %。 Under a argon atmosphere, in a dry round bottom flask, 12'-iodovinfluramine 1 (0.189 g, 0.2 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran with stirring, and 5 ml of palladium acetate (4.5 mg, 0.02 mmol) and 1,1 '-bis-(diphenylphosphino)ferrocene (11 mg, 0.02 mmol) in tetrahydrofuran and 5 ml ethylmagnesium bromide (1 ml, 1.4 g, 1.0 mmol) of toluene-tetrahydrofuran solution (0.5 mol/L) and stirring at room temperature for 1 hour, the reaction was followed by spotting, the starting material disappeared, and the reaction was quenched with saturated sodium bicarbonate (50 ml). 50 ml x 3) extraction reaction solution. The organic phase was combined, washed with aq. EtOAc EtOAc (EtOAc m. Ethyl vinflunine 55 (53 mg, white solid), yield 31%.
ESI:[M+1]=845。 ESI: [M+1] = 845.
1H NMR (CDC13, 400MHz)59.69(s, IH), 8.24(s, IH), 7.41 (s, IH), 6.99-6.93(m, 2H), 6.32(s, IH), 6.02(s, 1H)， 5.77(dd, IH, J!=9.6Hz, J2=4.0Hz)， 5.34(s, IH), 5.21 (d, IH, J=10.4Hz), 4.43(d, IH, J-12.4Hz), 4.28(m, IH), 3.74(s, 3H), 3.71(s, 3H), 3.64(s, IH), 3.62(s, 3H), 3.30-3.24(m, 3H), 3.21-3.18(m, IH), 3.00(dd5 1H， J!=12.4Hz, J2=13.2Hz), 2.90(dd, IH, J^H.OHz, J2=14.4Hz), 2.74(m, IH), 2.74-2.64 (m, 3H), 2.66(s, 3H)， 2.52-2.49(m, IH), 2.46(s, IH), 2.30(m, IH), 2.18(m, IH), 2.10-2.05(m, IH), 2.02(s, 3H), 1.77-1.71(m, 2H), 1.71-1.63(m, IH), 1.57-1.56(m, IH), 1.54(dd, 3H, J!=18.8Hz, J2=18.8Hz), 1.23-1.14 (m, 4H), 1.08-1.04(m, IH), 0.63(dd, 3H, =7.2Uz, J2=7.2Hz )。 实施例 56 1H NMR (CDC1 3 , 400MHz) 59.69 (s, IH), 8.24 (s, IH), 7.41 (s, IH), 6.99-6.93 (m, 2H), 6.32 (s, IH), 6.02 (s, 1H) ), 5.77 (dd, IH, J!=9.6Hz, J 2 =4.0Hz), 5.34(s, IH), 5.21 (d, IH, J=10.4Hz), 4.43(d, IH, J-12.4Hz ), 4.28(m, IH), 3.74(s, 3H), 3.71(s, 3H), 3.64(s, IH), 3.62(s, 3H), 3.30-3.24(m, 3H), 3.21-3.18( m, IH), 3.00 (dd 5 1H, J! = 12.4 Hz, J 2 = 13.2 Hz), 2.90 (dd, IH, J^H.OHz, J 2 = 14.4 Hz), 2.74 (m, IH), 2.74-2.64 (m, 3H), 2.66(s, 3H), 2.52-2.49(m, IH), 2.46(s, IH), 2.30(m, IH), 2.18(m, IH), 2.10-2.05( m, IH), 2.02(s, 3H), 1.77-1.71(m, 2H), 1.71-1.63(m, IH), 1.57-1.56(m, IH), 1.54(dd, 3H, J!=18.8Hz , J 2 = 18.8 Hz), 1.23-1.14 (m, 4H), 1.08-1.04 (m, IH), 0.63 (dd, 3H, = 7.2 Uz, J 2 = 7.2 Hz). Example 56
12'-(3-呋喃：)长春氟宁 12'-(3-furan:) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-碘代长春氟宁 1(0.100 g, 0.106 mmol), 碳酸铯 (0.172 g， 0.53 mmol)和呋喃 -3-硼酸 (23.7 mg， 0.212 mmol), 搅拌
T/CN2007/002176 下溶解于 10 ml 1，4-二氧六环中。 另取一干燥反应瓶， 将 Ι,Γ-双- (二苯基膦)二茂 铁 (6 mg， 0.0106 mmol)和醋酸钯 (2.4 mg， 0.0106 mmol)搅拌下溶解于 3 ml的 1,4- 二氧六环中， 取此催化剂溶液加入上述反应瓶中。 油浴 60°C下搅拌 24小时后， 加入乙酸乙酯 (50 ml)淬灭反应。减压抽滤，滤液依次用饱和碳酸氢钠溶液 (30 ml) 及饱和氯化钠溶液 (30 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压 浓縮， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-(3-呋喃)长春氟宁 56(30 mg， 类白色固体)， 收率： 32%。 Under a argon atmosphere, 12'-iodovinfluramine 1 (0.100 g, 0.106 mmol), cesium carbonate (0.172 g, 0.53 mmol) and furan-3-boronic acid (23.7 mg, 0.212) were added to a dry round bottom flask. Mmmol), stirring Dissolved in 10 ml of 1,4-dioxane under T/CN2007/002176. Another dry reaction flask was taken, and hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (6 mg, 0.0106 mmol) and palladium acetate (2.4 mg, 0.0106 mmol) were dissolved in 3 ml of 1,4 with stirring. In the dioxane, the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, the reaction was quenched by ethyl acetate (50 ml). The mixture was filtered with EtOAc (EtOAc m.) The obtained residue was purified to purified crystalljjjjjjjjjj
ESI:[M+1]=883。 ESI: [M+1] = 883.
1H NMR (CDC13, 400MHz)58.35(s, IH), 7.76(s, IH), 7.67(s， IH), 7.40(dd, IH, Ji=1.6Hz, J2=1.6Hz), 7.26(dd, IH, J!=8.4Hz3 J2=1.2Hz), 7.06(d, IH, J=8.4Hz), 6.72(dd, IH, Ji=0.8Hz, J2=0.8Hz), 6.29(s, IH), 6.02(s, IH), 5.78(dd, IH, J^lO.OHz, J2=4.0Hz), 5.33(s, IH), 5.21(d, IH, J=9.6Hz), 4.55(d, IH, J=13.2Hz), 4.43(d, IH, J=13.2Hz), 3.76(s, 3H), 3.75(s, 3H), 3.66(s, IH), 3.65(s, 3H), 3.36-3.23(m, 3H，), 3.19(m, IH), 2.99(dd, IH, Ji=12.8Hz, J2-13.2Hz), 2.92(dd, IH, Ji=16.8Hz3 J2=14.4Hz), 2.78(m, IH), 2.7 l(d, IH, J=16.0Hz), 2.65(s, 3H), 2.54(dd, IH, J尸 15.2Hz: J2=5.2Hz，)， 5.10(s, 1H)， 2.36(m, IH), 2.27(d, IH, J=l 4.0Hz), 2.05-2.00(m, IH), 2.03(s, 3H), 1.77-1.74(m, 2H), 1.74-1.64(m, IH), 1.64-1.56(m, IH), 1.56(dd, 3H, J!=18.8Hz, J2=18.8Hz), 1.19 (m, 2H), 0.65(dd, 3H, J尸 7.2Hz, J2=7.2Hz)。 1H NMR (CDC1 3 , 400MHz) 58.35 (s, IH), 7.76 (s, IH), 7.67 (s, IH), 7.40 (dd, IH, Ji = 1.6 Hz, J 2 = 1.6 Hz), 7.26 (dd , IH, J!=8.4Hz 3 J 2 =1.2Hz), 7.06(d, IH, J=8.4Hz), 6.72(dd, IH, Ji=0.8Hz, J 2 =0.8Hz), 6.29(s, IH), 6.02(s, IH), 5.78(dd, IH, J^lO.OHz, J 2 =4.0Hz), 5.33(s, IH), 5.21(d, IH, J=9.6Hz), 4.55( d, IH, J = 13.2 Hz), 4.43 (d, IH, J = 13.2 Hz), 3.76 (s, 3H), 3.75 (s, 3H), 3.66 (s, IH), 3.65 (s, 3H), 3.36-3.23(m, 3H,), 3.19(m, IH), 2.99(dd, IH, Ji=12.8Hz, J 2 -13.2Hz), 2.92(dd, IH, Ji=16.8Hz 3 J 2 =14.4 Hz), 2.78(m, IH), 2.7 l(d, IH, J=16.0Hz), 2.65(s, 3H), 2.54(dd, IH, J corp. 15.2Hz: J 2 =5.2Hz,), 5.10 (s, 1H), 2.36(m, IH), 2.27(d, IH, J=l 4.0Hz), 2.05-2.00(m, IH), 2.03(s, 3H), 1.77-1.74(m, 2H) , 1.74-1.64(m, IH), 1.64-1.56(m, IH), 1.56(dd, 3H, J!=18.8Hz, J 2 = 18.8Hz), 1.19 (m, 2H), 0.65(dd, 3H , J 7.2 Hz, J 2 = 7.2 Hz).
实施例 57 Example 57
12'-(3-噻吩)长春氟宁 12'-(3-thiophene) vinflunine
氩气氛下，在干燥的圆底烧瓶中，加入 12'-碘代长春氟宁 1(0.95 g，0.1 mmol), 碳酸铯 (0.163 g， 0.5 mmol)和噻吩 -3-硼酸 (26 mg, 0.2 mmol), 搅拌下溶解于 5 ml 的 1,4-二氧六环中。另取一干燥反应瓶，将 Ι,Γ-双- (二苯基膦)二茂铁 (11 mg, 0.02 mmol)和醋酸钯 (4.5 mg, 0.02 mmol)搅拌下溶解于 3 ml的 1,4-二氧六环中， 取此 催化剂溶液加入上述反应瓶中。 油浴 70Ό下搅拌过夜， 点板跟踪反应， 原料消 失。加入乙酸乙酯 (50 ml)淬灭反应。减压抽滤，滤液依次用饱和碳酸氢钠溶液 (30 ml)及饱和氯化钠溶液 (30 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-(3-噻吩)长春氟 宁 57(75 mg， 白色固体)， 收率： 83 %。
ESI:[M+1]=899。 Under a argon atmosphere, 12'-iodovinfluramine 1 (0.95 g, 0.1 mmol), cesium carbonate (0.163 g, 0.5 mmol) and thiophene-3-boronic acid (26 mg, 0.2) were added to a dry round bottom flask. Methyl), dissolved in 5 ml of 1,4-dioxane with stirring. Another dry reaction flask was prepared by dissolving hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (11 mg, 0.02 mmol) and palladium acetate (4.5 mg, 0.02 mmol) in 3 ml of 1,4 In the dioxane, the catalyst solution was added to the above reaction flask. The oil bath was stirred at 70 Torr overnight, and the reaction was stopped by clicking on the plate, and the raw materials disappeared. The reaction was quenched by the addition of ethyl acetate (50 mL). The mixture was filtered with EtOAc (EtOAc m.) The obtained residue was purified by chromatography to give the title product 12'-(3-thiophene) vinflunine 57 (75 mg, white solid). ESI: [M+1] = 899.
1H NMR (CDC13, 400MHz)59.64(brs, 1H)， 8.35(s, IH), 7.79(s, IH), 7.38-7.29(m: 4H), 7.08(d, IH, J=8.4Hz), 6.30(s, IH), 6.02(s, IH), 5.77(dd, IH, J^lO^Hz, J2=4.4Hz), 5.35(s, IH), 5.21(d, IH, J=10.4Hz), 4.46(d, 1H， J=12.8Hz), 4.3 l(d, 1H， J=12.4Hz), 3.75(s, 3H)， 3.72(s, 3H), 3.65(s, 4H)， 3.29-3.25(m, 3H), 3.18(ddd, 1H， J!=9.6Hz, J2=9.2Hz, J3=4.8Hz), 3.00(dd, IH, ^UARz, J2=13.2Hz), 2.91(dd, IH, Ji=14.8Hz, J2=13.6Hz), 2.74(m, IH), 2.64(s, 3H), 2.60(m, IH), 2.55-2.50(m, IH), 2.44(s, 1H)， 2.27-2.19(m, 2H), 2.05(m, IH), 2.03(s, 3H), 1.79-1.76(m, 2H), 1.73-1.58(m, 2H), 1.55(dd, 3H， J尸 18.8Hz, J2=18.8Hz), 1.19(m, IH), 1.07(m, IH), 0.64(dd, 3H, J尸 7.2Hz， J2=7.2Hz)。 实施例 58 1H NMR (CDC1 3 , 400MHz) 59.64 (brs, 1H), 8.35 (s, IH), 7.79 (s, IH), 7.38-7.29 (m : 4H), 7.08 (d, IH, J = 8.4 Hz), 6.30(s, IH), 6.02(s, IH), 5.77(dd, IH, J^lO^Hz, J 2 =4.4Hz), 5.35(s, IH), 5.21(d, IH, J=10.4Hz ), 4.46(d, 1H, J=12.8Hz), 4.3 l(d, 1H, J=12.4Hz), 3.75(s, 3H), 3.72(s, 3H), 3.65(s, 4H), 3.29- 3.25(m, 3H), 3.18(ddd, 1H, J!=9.6Hz, J 2 =9.2Hz, J 3 =4.8Hz), 3.00(dd, IH, ^UARz, J 2 = 13.2Hz), 2.91( Dd, IH, Ji=14.8Hz, J 2 =13.6Hz), 2.74(m, IH), 2.64(s, 3H), 2.60(m, IH), 2.55-2.50(m, IH), 2.44(s, 1H), 2.27-2.19(m, 2H), 2.05(m, IH), 2.03(s, 3H), 1.79-1.76(m, 2H), 1.73-1.58(m, 2H), 1.55(dd, 3H, J corpse 18.8 Hz, J 2 = 18.8 Hz), 1.19 (m, IH), 1.07 (m, IH), 0.64 (dd, 3H, J 7.2 Hz, J 2 = 7.2 Hz). Example 58
12'-(2-甲酰基噻吩 -3-基)长春氟宁 12'-(2-formylthiophen-3-yl) vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-碘代长春氟宁 1(0.189 g， 0.2 mmol), 碳酸铯 (0.326 g， 1.0 mmol)和 2-甲酰基噻吩 -3-硼酸 (32 mg， 0.4 mmol), 搅拌下溶解于 10 ml的 1,4-二氧六环中。 另取一干燥反应瓶， 将 Ι,Γ-双- (二苯基 膦)二茂铁 (22 mg， 0.04 mmol)和醋酸钯 (9 mg， 0.04 mmol)搅拌下溶解于 3 ml的 1， 4-二氧六环中，取此催化剂溶液加入上述反应瓶中。油浴 60°C下搅拌 24小时后， 加入乙酸乙酯 (50 ml)淬灭反应。减压抽滤，滤液依次用饱和碳酸氢钠溶液 (30 ml) 及饱和氯化钠溶液 (30 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压 浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'-(2-甲酰基噻吩 -3-基) 长春氟宁 58(0.03 g， 类白色固体)， 收率： 32%。 Under a argon atmosphere, 12'-iodovinfluramine 1 (0.189 g, 0.2 mmol), cesium carbonate (0.326 g, 1.0 mmol) and 2-formylthiophene-3-boronic acid were added to a dry round bottom flask. 32 mg, 0.4 mmol), dissolved in 10 ml of 1,4-dioxane with stirring. Another dry reaction flask was taken, and hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (22 mg, 0.04 mmol) and palladium acetate (9 mg, 0.04 mmol) were dissolved in 3 ml of 1, 4 with stirring. In the dioxane, the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, ethyl acetate (50 ml) was added to quench. The mixture was filtered under reduced pressure. EtOAc (EtOAc m. The obtained residue was purified to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
ESI:[M+1]=927。 ESI: [M+1] = 927.
1H NMR (CDC13, 400MHz)89.93(s, IH), 8.58(s, IH), 7.8 l(s, IH), 7.73(dd, IH, J!=5.0Hz, J2=1.0Hz), 7.32-7.28(m, 2H), 7.24(d, IH, J=9.0Hz), 6.39(s, IH), 6.12(s, 1H)， 5.88(dd, IH, Ji=10.0Hz, J2=4.0Hz), 5.43(s, IH), 5.3 l(d, IH, J=10.0Hz), 4.57(d, 1H， J=13.0Hz), 4.43(m, IH), 3.84(s, IH), 3.80(s, IH), 3.75(s, 4H), 3.39-3.33(m, 3H), 3.28(m, IK), 3.08(dd, IH, J尸 11.0Hz, J2=12.0Hz), 3.00(dd, IH, Ji=l 5.0Hz, J2=13.0Hz), 2.83(m, IH), 2.74(s, 3H), 2.71(m, IH), 2.63(dd, IH, J!=15.0Hz,
7 002176 1H NMR (CDC1 3 , 400MHz) 89.93 (s, IH), 8.58 (s, IH), 7.8 l (s, IH), 7.73 (dd, IH, J! = 5.0 Hz, J 2 = 1.0 Hz), 7.32 -7.28(m, 2H), 7.24(d, IH, J=9.0Hz), 6.39(s, IH), 6.12(s, 1H), 5.88(dd, IH, Ji=10.0Hz, J 2 =4.0Hz ), 5.43(s, IH), 5.3 l(d, IH, J=10.0Hz), 4.57(d, 1H, J=13.0Hz), 4.43(m, IH), 3.84(s, IH), 3.80( s, IH), 3.75 (s, 4H), 3.39-3.33 (m, 3H), 3.28 (m, IK), 3.08 (dd, IH, J corp. 11.0 Hz, J 2 = 12.0 Hz), 3.00 (dd, IH, Ji=l 5.0Hz, J 2 =13.0Hz), 2.83(m, IH), 2.74(s, 3H), 2.71(m, IH), 2.63(dd, IH, J!=15.0Hz, 7 002176
J2=6.0Hz), 2.54(s, IH), 2.39-2.33(m, 2H), 2.11(s, 3H), 2.10(m, IH), 1.88-1.85(m, 2H), 1.76-1.74(m, IH), 1.70-1.69(m, IH), 1.63(dd, 3H, J尸 19.0Hz, J2=l 9.0Hz), 1.27(m, IH), 1.08(m, IH), 0.73(dd, 3H， J!=7.0Hz, J2=8.0Hz)。 J 2 =6.0 Hz), 2.54 (s, IH), 2.39-2.33 (m, 2H), 2.11 (s, 3H), 2.10 (m, IH), 1.88-1.85 (m, 2H), 1.76-1.74 ( m, IH), 1.70-1.69 (m, IH), 1.63 (dd, 3H, J corp. 19.0 Hz, J 2 = l 9.0 Hz), 1.27 (m, IH), 1.08 (m, IH), 0.73 (dd , 3H, J!=7.0Hz, J 2 =8.0Hz).
实施例 59 Example 59
12'- (吡唑 -4-基)长春氟宁 12'-(pyrazol-4-yl) vinflunine
氩气氛下，在干燥的圆底烧瓶中，加入 12'-碘代长春氟宁 1(0.95 g，0.1 mmol), 碳酸铯 (0.163 g， 0.5 mmol)和 1-氯 -吡唑 -4-硼酸 (0.022 g， 0.2 mmol), 搅拌下溶解 于 10 ml的 1,4-二氧六环中。另取一干燥反应瓶，将 Ι,Γ-双- (二苯基膦)二茂铁 (Π mg， 0.02 mmol)和醋酸钯 (4.5 mg， 0.02 mmol)搅拌下溶解于 3 ml的 1， 4-二氧六 环中， 取此催化剂溶液加入上述反应瓶中。 油浴 60°C下搅拌 24小时后， 加入乙 酸乙酯 (50 ml)淬灭反应。减压抽滤，滤液依次用饱和碳酸氢钠溶液 (30 ml)及饱和 氯化钠溶液 (30 ml)洗涤， 乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 12'- (吡唑 -4-基)长春氟宁 59(34 mg, 白色固体：)， 收率： 18%。 Under a argon atmosphere, 12'-iodovinfluramine 1 (0.95 g, 0.1 mmol), cesium carbonate (0.163 g, 0.5 mmol) and 1-chloro-pyrazole-4-boronic acid were added to a dry round bottom flask. (0.022 g, 0.2 mmol), dissolved in 10 ml of 1,4-dioxane with stirring. Another dry reaction flask was prepared by dissolving hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (Π mg, 0.02 mmol) and palladium acetate (4.5 mg, 0.02 mmol) in 3 ml of 1, 4 In the dioxane, the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, ethyl acetate (50 ml) was added to quench the reaction. The mixture was filtered with EtOAc (EtOAc m.) The obtained residue was purified to purified crystalljjjjjlilililililililililililili
ESI:[M+1]=883。 实施例 60 ESI: [M+1] = 883. Example 60
12'-(3,4-二甲基-异噁唑 -4-基) -长春氟宁 12'-(3,4-dimethyl-isoxazole-4-yl)-vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-碘代长春氟宁 1(0.189 g， 0.2 mmol),碳酸铯 (0.33 g， 1.0 mmol)Sl 3， 5-二甲基噁唑 -4-硼酸 (0.056 g, 0.4 mmol), 搅拌下溶解于 10 ml的 1,4-二氧六环中。 另取一千燥反应瓶， 将 1，Γ-双- (二苯基 膦)二茂铁 (22 mg, 0.04 mmol)和醋酸钯 (9 mg, 0.04 mmol)搅拌下溶解于 3 ml的 1，
4-二氧六环中，取此催化剂溶液加入上述反应瓶中。油浴 60°C下搅拌 24小时后， 点板跟踪反应， 原料消失， 加入乙酸乙酯 (50 ml)淬灭反应。减压抽滤， 滤液依次 用饱和碳酸氢钠溶液 (30 ml)及饱和氯化钠溶液 (30 ml)洗涤，乙酸乙酯层用无水硫 酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题产 物 12，-(3,4-二甲基-异噁唑 -4-基) -长春氟宁 60(56 mg， 白色固体)， 收率： 30%。 Under a argon atmosphere, in a dry round bottom flask, 12'-iodovinflurion 1 (0.189 g, 0.2 mmol), cesium carbonate (0.33 g, 1.0 mmol), S3, 5-dimethyloxazole- 4-boronic acid (0.056 g, 0.4 mmol) was dissolved in 10 ml of 1,4-dioxane with stirring. Another thousand dry reaction flask was dissolved in 3 ml of 1, 1 - bis-bis-(diphenylphosphino)ferrocene (22 mg, 0.04 mmol) and palladium acetate (9 mg, 0.04 mmol). In the 4-dioxane, the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, the reaction was followed by spotting, the material disappeared, and ethyl acetate (50 ml) was added to quench the reaction. The mixture was filtered under reduced pressure. EtOAcjjjjjjjjjjjjjjj The obtained residue was purified to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
ESI:[M+1]=912。 ESI: [M+1] = 912.
1H NMR (CDC13, 400MHz)59.86(brs, IH), 8.51(s, IH), 7.52(s, IH), 7.20(d, IH, J=9.0Hz), 7.04(d, IH, J=8.0Hz), 6.43(s, IH), 6.11(s, IH), 5.88(dd, 1H， Ji=9.5Hz, J2=4.5Hz), 5.43(s, IH), 5.3 l(d, 1H， J=10.0Hz), 4.55(d, 1H， J=l 2.0Hz), 4.37(m, IH), 3.84(s, 3H), 3.80(s, 3H), 3.75(s， 1H)， 3.74(s, 3H)， 3.39-3.28(m, 4H), 3.08-2.97(m, 2H): 2.83(m， 1H)， 2.74(s, 3H), 2.69(m, IH), 2.63 (m, IH), 2.55(s, IH), 2.42(s, 3H), 2.38-2.25(m, 2H), 2.28(s, 3H), 2.14(m, IH), 2.11(s, 3H), 1.88-1.76(m, 3H), 1.69-1.67(m, IH), 1.63(dd, 3H， Jt=l 9.0Hz, J2=l 9.0Hz), 1.27(m, IH), 1.19(m, IH),
1H NMR (CDC1 3 , 400MHz) 59.86 (brs, IH), 8.51 (s, IH), 7.52 (s, IH), 7.20 (d, IH, J = 9.0 Hz), 7.04 (d, IH, J = 8.0 Hz), 6.43(s, IH), 6.11(s, IH), 5.88(dd, 1H, Ji=9.5Hz, J 2 =4.5Hz), 5.43(s, IH), 5.3 l(d, 1H, J =10.0Hz), 4.55(d, 1H, J=l 2.0Hz), 4.37(m, IH), 3.84(s, 3H), 3.80(s, 3H), 3.75(s, 1H), 3.74(s, (3H), 3.39-3.28 (m, 4H), 3.08-2. (s, IH), 2.42(s, 3H), 2.38-2.25(m, 2H), 2.28(s, 3H), 2.14(m, IH), 2.11(s, 3H), 1.88-1.76(m, 3H ), 1.69-1.67(m, IH), 1.63(dd, 3H, J t =l 9.0Hz, J 2 =l 9.0Hz), 1.27(m, IH), 1.19(m, IH),
实施例 61 Example 61
12，-[2-(3-甲基-丁基) -吡唑 -4-基] -长春氟宁 12,-[2-(3-methyl-butyl)-pyrazol-4-yl]-vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-碘代长春氟宁 1(0.189 g, 0.2 mmol), 碳酸铯 (0.33 g， 1.0 讓 ol)和 1-(3-甲基丁基)小氢-吡唑 -4-硼酸 (0.073 g， 0.4 mmol), 搅拌下溶解于 10 ml的 4-二氧六环中。 另取一干燥反应瓶， 将 1，Γ- 双- (二苯基膦)二茂铁 (22 mg, 0.04 mmol)和醋酸钯 (9 mg, 0.04 mmol)搅拌下溶解 于 3 ml的 1,4-二氧六环中， 取此催化剂溶液加入上述反应瓶中。 油浴 60°C下搅 拌 24小时后， 点板跟踪反应， 原料消失， 加入乙酸乙酯 (50 ml)淬灭反应。 减压 抽滤，滤液依次用饱和碳酸氢钠溶液 (30 ml)及饱和氯化钠溶液 (30 ml)洗涤， 乙酸 乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余 物， 得到标题产物 12，-[2-(3-甲基-丁基) -吡唑 -4-基] -长春氟宁 61(0.142 g， 白色固 收率： 74%。 Under a argon atmosphere, in a dry round bottom flask, 12'-iodovinfluramine 1 (0.189 g, 0.2 mmol), cesium carbonate (0.33 g, 1.0 ol) and 1-(3-methylbutyl) were added. Small hydrogen-pyrazole-4-boronic acid (0.073 g, 0.4 mmol) was dissolved in 10 ml of 4-dioxane with stirring. Another dry reaction flask was taken, and 1, Γ-bis-(diphenylphosphino)ferrocene (22 mg, 0.04 mmol) and palladium acetate (9 mg, 0.04 mmol) were dissolved in 3 ml of 1,4 with stirring. In the dioxane, the catalyst solution was added to the above reaction flask. After stirring in an oil bath at 60 ° C for 24 hours, the reaction was followed by spotting, the material disappeared, and ethyl acetate (50 ml) was added to quench the reaction. The mixture was filtered with EtOAc (EtOAc m.) The residue obtained was purified by chromatography to give the title product 12,-[2-(3-methyl-butyl)-pyrazol-4-yl]-vinflunine 61 (0.142 g, white solid: 74%.
ESI:[M+1]=953。
N2007/002176 NMR (CDC13, 400MHz)59.73(brs, IH), 8.39(s, IH), 7.79(s, IH), 7.75(s, 1H): 7.64(s, IH), 7.32(d, IH, J=8.0Hz), 7.13(d, IH, J=8.0Hz), 6.37(s, IH), 6.10(s, 1H): 5.85(dd, IH, J^lO.OHz, J2=5.0Hz), 5.42(s, IH), 5.29(d, 1H， J=9.0Hz), 4.54(d, 1H; J=13.0Hz), 4.38(m, IH), 4.17(dd, 2H, Ji=8.0Hz, J2=7.0Hz), 3.83(s, 3H), 3.81(s， 3H): 3.73(s, 4H), 3.36-3.31(m, 3H), 3.26(ddd, IH, J尸 9.0Hz, J2=9.0Hz), 3.08(dd, 1R J尸 11.0Hz, J2=l 3.0Hz), 2.99(dd, IH, Ji=14.0Hz, J2=14.0Hz), 2.82(m, IH), 2.72(s; 3H), 2.69(m, IH), 2.63 (m, IH), 2.52(s, IH), 2.35(m, IH), 2.28(d, IH, J=11.0Hz): 2.11(m， IH), 2.10(s, 3H), 1.86-1.79(m, 4H), 1.76-1.71(m, 2H), 1.70-1.64(m, 1H): 1.63(m, 3H, J^l 9.0Hz, J2=19.0Hz), 1.27(m, IH), 1.15(m, IH), 0.98(d, 6H, J=6.6Hz): 0.71(dd, 3H, J!=7.0Hz, J2=7.4Hz)。 ESI: [M+1] = 953. N2007/002176 NMR (CDC1 3 , 400MHz) 59.73 (brs, IH), 8.39 (s, IH), 7.79 (s, IH), 7.75 (s, 1H): 7.64 (s, IH), 7.32 (d, IH) , J=8.0Hz), 7.13(d, IH, J=8.0Hz), 6.37(s, IH), 6.10(s, 1H): 5.85(dd, IH, J^lO.OHz, J 2 =5.0Hz ), 5.42(s, IH), 5.29(d, 1H, J=9.0Hz), 4.54(d, 1H ; J=13.0Hz), 4.38(m, IH), 4.17(dd, 2H, Ji=8.0Hz , J 2 =7.0Hz), 3.83(s, 3H), 3.81(s, 3H): 3.73(s, 4H), 3.36-3.31(m, 3H), 3.26(ddd, IH, J 9.0Hz, J 2 = 9.0 Hz), 3.08 (dd, 1R J corpse 11.0 Hz, J 2 = l 3.0 Hz), 2.99 (dd, IH, Ji = 14.0 Hz, J 2 = 14.0 Hz), 2.82 (m, IH), 2.72 (s ; 3H), 2.69 (m, IH), 2.63 (m, IH), 2.52 (s, IH), 2.35 (m, IH), 2.28 (d, IH, J = 11.0 Hz) : 2.11 (m, IH), 2.10(s, 3H), 1.86-1.79(m, 4H), 1.76-1.71(m, 2H), 1.70-1.64(m, 1H): 1.63(m, 3H, J^l 9.0Hz, J 2 =19.0Hz), 1.27(m, IH), 1.15(m, IH), 0.98(d, 6H, J=6.6Hz) : 0.71(dd, 3H, J!=7.0Hz, J 2 =7.4Hz) .
实施例 62 Example 62
12'-[2-(3-甲基-丁基) -吡唑 -4-基] -长春氟宁 12'-[2-(3-Methyl-butyl)-pyrazole-4-yl]-vinflunine
氩气氛下， 在干燥的圆底烧瓶中， 加入 12'-碘代长春氟宁 1(0.734 g， 0.78 mmol), 溶解于 20 ml无水甲苯中， 加入二 (三丁基锡)试剂 (1.57 ml)及醋酸钯 (35 mg， 0.16 mmol)和三苯基膦 (82 mg， 0.32 mmol)的甲苯溶液 (10 ml)。 油浴 102°C 下搅拌过夜， 点板跟踪反应， 原料消失。加入饱和碳酸氢钠溶液 (50 ml), 乙酸乙 酯 (100 mlx3)萃取， 合并有机相， 依次用水 (100 ml)和饱和氯化钠溶液 (100 ml)洗 涤， 乙酸乙脂层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化 所得残余物， 得到标题产物 12'- [三丁基锡] -长舂氟宁 62(0.445 g， 白色固体)， 收 率： 53 %。 Under a argon atmosphere, 12'-iodovinfluramine 1 (0.734 g, 0.78 mmol) was added to a dry round bottom flask, dissolved in 20 ml of anhydrous toluene, and bis(tributyltin) reagent (1.57 ml) was added. And a solution of palladium acetate (35 mg, 0.16 mmol) and triphenylphosphine (82 mg, 0.32 mmol) in toluene (10 ml). The oil bath was stirred at 102 ° C overnight, and the reaction was stopped by clicking on the plate, and the raw materials disappeared. Add saturated sodium bicarbonate solution (50 ml), ethyl acetate (100 ml×3), extract the organic phase, and wash with water (100 ml) and saturated sodium chloride solution (100 ml) successively. Magnesium was dried, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
测试例 Test case
长春碱类化合物抗肿瘤活性的测定 Determination of antitumor activity of vinblastine compounds
实验方法： SRB Experimental method: SRB
细 胞株: A549(人非小细胞肺癌） Cell line: A549 (human non-small cell lung cancer)
实验设计:细胞与不同浓度化合物 (分别为 100,10-0.001 M )温育 72小时， 采用 Experimental design: cells were incubated with different concentrations of compounds (100, 10-0.001 M, respectively) for 72 hours.
SRB方法评价化合物对细胞增殖的抑制程度，计算抑制率，根据抑制率采用 Logit 方法计算 IC50, 比较化合物的体外抗肿瘤活性。
抑制率计算方法： The SRB method was used to evaluate the degree of inhibition of cell proliferation by the compound, and the inhibition rate was calculated. The IC50 was calculated by Logit method according to the inhibition rate, and the in vitro antitumor activity of the compound was compared. Calculation method of inhibition rate:
抑制率（)= (对照组 OD值-用药 OD值）/对照组 OD值 xlOO Inhibition rate () = (control group OD value - medication OD value) / control group OD value xlOO
本发明分 2次平行实验对待测样品的 IC50进行考察， 测得化合物对 A549 细胞 (人非小细胞肺癌)的抑制率见表 1。 长春碱类化合物对 A549细胞 (人非小细胞肺癌)的抑制率 The IC50 of the sample to be tested is examined in two parallel experiments, and the inhibition rate of the compound on A549 cells (human non-small cell lung cancer) is shown in Table 1. Inhibition rate of vinblastine compounds on A549 cells (human non-small cell lung cancer)
IC50 IC50
实施例 R1 Example R1
(μΜ) (μΜ)
3 Ν≡→' 0.29 3 Ν≡→' 0.29
4 1.88 4 1.88
5 α 2.16 5 α 2.16
6 " k 0.56 6 " k 0.56
7 1.17 7 1.17
8 (X. 1.01 8 (X. 1.01
9 ¾; 1.02 9 3⁄4; 1.02
10 2.50 10 2.50
11 0.29 11 0.29
13 0.05 13 0.05
14 3.52 14 3.52
H
评价实施例 3及 13对人非小细胞肺癌 A549裸小鼠移植瘤的疗 效 H Evaluating the efficacy of Examples 3 and 13 on human non-small cell lung cancer A549 nude mice xenografts
实验目的： Purpose:
评价实施例 3及 13的酒石酸盐对人肺癌 A549裸小鼠移植瘤的疗效。 受试药物： The effects of the tartrates of Examples 3 and 13 on human lung cancer A549 nude mice xenografts were evaluated. Test drug:
.名称： 长春氟宁 la， 实施例 3及 13的酒石酸盐
制剂：长春氟宁 la酒石酸盐： 原料， 白色粉末；实施例 3酒石酸盐： 原料， 白色粉末； 实施例 13酒石酸盐： 原料， 为淡黄色。 Name: vinflunine la, the tartrate salts of Examples 3 and 13 Formulation: vinflunine la tartrate: starting material, white powder; Example 3 tartrate: starting material, white powder; Example 13 tartrate: starting material, pale yellow.
配制方法： 长春氟宁 la酒石酸盐， 实施例 3酒石酸盐及 13酒石酸盐均用 生理盐水配制成所需浓度。 实验动物： Preparation method: vinflunine la tartrate, Example 3 Tartrate and 13 tartrate were all formulated to the desired concentration with physiological saline. Experimental animals:
BALB/cA-nude裸小鼠， $， 5-6周龄， 购自上海斯莱克实验动物有限责任公 司。 合格证号： SCXK (沪） 2004—0005。 伺养环境： SPF级。 实验步骤： BALB/cA-nude nude mice, $5-6 weeks old, were purchased from Shanghai Slack Laboratory Animals LLC. Certificate No.: SCXK (Shanghai) 2004-0005. Serving environment: SPF level. Experimental steps:
皮下接种人肺癌 A549瘤块组织， 待肿瘤生长至 100-300mm3后， 将动物随 机分组 (d0)。给药剂量实施例 3及 13均为 40mg/kg， 60mg/kg, 80mg kg。均静脉 给药 （iv); 实施例 3及 13 40mg/kg、 60mg/kg、 80mg/kg均为 d0、 4， 共 2次。 每周测 2—3次瘤体积， 称鼠重， 记录数据。 肿瘤体积（V) 计算公式为： Human lung cancer A549 tumor tissue was inoculated subcutaneously, and after the tumor grew to 100-300 mm 3 , the animals were randomly divided into groups (d0). Dosages Examples 3 and 13 were 40 mg/kg, 60 mg/kg, and 80 mg kg. All intravenous administration (iv); Examples 3 and 13 40 mg / kg, 60 mg / kg, 80 mg / kg are d0, 4, a total of 2 times. The tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded. The tumor volume (V) is calculated as:
V= l/2xaxb2 其中 a、 b分别表示长、 宽。 表 1.静脉注射长春氟宁 la， 实施例 3及 13对人肺癌 A549裸小鼠移植瘤的疗效 组别 剂 量 动物 去瘤后体重 TV RTV T/C (%) V = l/2xaxb 2 where a and b represent length and width, respectively. Table 1. Effect of intravenous injection of vinflunine la, Examples 3 and 13 on human lung cancer A549 nude mice xenografts. Group dose animals after tumor weight TV RTV T/C (%)
(mg/kg) 数 (克） x±SD x±SD (mg/kg) number (g) x±SD x±SD
d0 dO dn dO dn D0 dO dn dO dn
dn Dn
对照 10 15.2 17.9 218±44 2592±660 12.25±3.59 Control 10 15.2 17.9 218±44 2592±660 12.25±3.59
10 10
实施例 13 40 5 17.2 20.3 218±50 2262±446 10.67±2.29 87.1 实施例 13 60 5 15.5 18.3 186±32 1577±733 8.90±4.83 72.7 Example 13 40 5 17.2 20.3 218±50 2262±446 10.67±2.29 87.1 Example 13 60 5 15.5 18.3 186±32 1577±733 8.90±4.83 72.7
J J
实施例 13 80 5 17.8 18.2 211±21 1204±515 5.82±2.80 47.5a Example 13 80 5 17.8 18.2 211±21 1204±515 5.82±2.80 47.5 a
J J
实施例 3 40 5 15.7 18.3 245±52 2128士 209 8.98±2.77 73.3 Example 3 40 5 15.7 18.3 245±52 2128士 209 8.98±2.77 73.3
5 5
实施例 3 60 5 17.5 20.9 192±50 2134±372 11.84±4.15 96.7 Example 3 60 5 17.5 20.9 192±50 2134±372 11.84±4.15 96.7
J J
实施例 3 80 5 16.4 18.2 208±39 1404±436 7.06±2.77 57.6a Example 3 80 5 16.4 18.2 208±39 1404±436 7.06±2.77 57.6 a
5
长春氟宁 17.5 5 16.1 18.0 192±49 1463±777 8.26±5.44 67.4 la 5 5 Vincent fluin 17.5 5 16.1 18.0 192±49 1463±777 8.26±5.44 67.4 la 5
长春氟宁 35 5 17.5 18.5 204±17 1139±371 5.70±2.16 46.5a la 5 Changchun Flunan 35 5 17.5 18.5 204±17 1139±371 5.70±2.16 46.5 a la 5
d0: 分笼给药时间； dn: 第 1次给药后 14天。 aP<0.01 vs对照; 结论： D0: time of administration in a cage; dn: 14 days after the first administration. a P<0.01 vs control; Conclusion:
长春氟宁 la， 实施例 3及 13 的酒石酸盐高剂量给药时， 均明显抑制肺癌 A549的生长； 其中长春氟宁 la及实施例 13有明显的剂量依赖性， 而实施例 3 剂量依赖性不明显。 3个化合物比较， 长春氟宁 la毒性较大。 总的评价， 实施 例 13与长春氟宁 la的疗效相当。 评价实施例 27， 33及 49对人肺癌 A549裸小鼠移植瘤的疗效 实验目的： The high doses of vinorelbine la, the tartaric acid salts of Examples 3 and 13 all significantly inhibited the growth of lung cancer A549; wherein vinflunine la and Example 13 were dose dependent, and Example 3 was dose dependent. Not obvious. Compared with the three compounds, vinflunine la is more toxic. Overall, Example 13 was comparable to the effect of vinflunine la. Evaluation of the efficacy of the 27, 33 and 49 on human lung cancer A549 nude mice xenografts
评价实施例 27， 33及 49的酒石酸盐对人肺癌 A549裸小鼠移植瘤的疗效。 受试药物： The efficacy of the tartrates of Examples 27, 33 and 49 on human lung cancer A549 nude mice xenografts was evaluated. Test drug:
药物名称： 长春氟宁 la， 实施例 27， 33及 49的酒石酸盐。 Drug name: vinflunine la, tartrates of Examples 27, 33 and 49.
制剂： 长春氟宁 la酒石酸盐： 原料， 白色粉末； 实施例 27酒石酸盐： 原料， 白色粉末； 实施例 33酒石酸盐： 原料， 白色粉末。 实施例 49酒石酸盐： 原料， 白 色粉末。 Formulation: vinflunine la tartrate: starting material, white powder; Example 27 tartrate: starting material, white powder; Example 33 tartrate: starting material, white powder. Example 49 Tartrate: Raw material, white powder.
配制方法： 长春氟宁 la， 实施例 17， 33及 49的酒石酸盐均用生理盐水配成所 需浓度。 实验动物： Preparation method: vinflunine la, the tartrates of Examples 17, 33 and 49 were all formulated to the desired concentration with physiological saline. Experimental animals:
BALB/cA-nude裸小鼠， $， 5-6周龄， 购自上海斯莱克实验动物有限责任公 司； 合格证号： SCXK (沪） 2004— 0005; 饲养环境： SPF级。 实验步骤： BALB/cA-nude nude mice, $5-6 weeks old, purchased from Shanghai Slack Laboratory Animals Co., Ltd.; Certificate No.: SCXK (Shanghai) 2004-0005; Feeding environment: SPF. Experimental steps:
裸小鼠皮下接种人肺癌 A549瘤块， 待肿瘤生长至 100-300mm3后， 将动物随 机分组 (d0)。 给药剂量 SHR1011、 SHR1012、 SHR1013、 SHR1014均为 10 mg/kg， 20mg/kg， 40mg/kg; 静脉注射给药， d0，7各 1次。每周测 2— 3次瘤体积， 称鼠重， 记录数据。 肿瘤体积 （V)计算公式为： Nude mice were subcutaneously inoculated with human lung cancer A549 tumor masses, and after the tumors were grown to 100-300 mm 3 , the animals were randomly divided into groups (d0). The doses of SHR1011, SHR1012, SHR1013, and SHR1014 were 10 mg/kg, 20 mg/kg, and 40 mg/kg; intravenous administration, d0, and 7 times. The tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded. The tumor volume (V) is calculated as:
V= l/2xaxb2 其中 a、 b分别表示长、 宽。
表 1.静脉注射实施例 17， 33， 49及长春氟宁 la对人肺癌 A549裸小鼠移植瘤的疗效 组别 剂 量 动物数 荷瘤小鼠体 TV RTV T/C V = l/2xaxb 2 where a and b represent length and width, respectively. Table 1. Intravenous injection of Example 17, 33, 49 and vinflunine la for human lung cancer A549 nude mice xenografts. Group dose animal number tumor-bearing mouse body TV RTV T/C
(mg kg) 重 （克） x±SD x±SD (%) dO/ dn d0 dn dO dn (mg kg) Weight (g) x±SD x±SD (%) dO/ dn d0 dn dO dn
对照 10/ 10 17.3 20.3 125±19 2096±608 17.10±5.42 Control 10/ 10 17.3 20.3 125±19 2096±608 17.10±5.42
27 10 5/ 5 17.8 21.8 132±17 1633±538 12.77±5.77 74.7 27 10 5/ 5 17.8 21.8 132±17 1633±538 12.77±5.77 74.7
27 20 5/ 5 17.5 21.1 135±21 1489±257 11.66±3.05 68.227 20 5/ 5 17.5 21.1 135±21 1489±257 11.66±3.05 68.2
27 40 5/ 5 17.6 19.8 115土 21 1196±347 10.30±1.24 60.2*27 40 5/ 5 17.6 19.8 115 soil 21 1196±347 10.30±1.24 60.2*
49 10 5/ 5 17.0 20.1 128±14 1944±675 15.57±6.99 91.149 10 5/ 5 17.0 20.1 128±14 1944±675 15.57±6.99 91.1
49 20 5/ 5 17.6 20.8 128±18 1763±339 15.26±3.08 89.249 20 5/ 5 17.6 20.8 128±18 1763±339 15.26±3.08 89.2
49 40 5/ 5 17.6 18.0 117±15 1174±267 10.07±2.18 58.9*49 40 5/ 5 17.6 18.0 117±15 1174±267 10.07±2.18 58.9*
33 10 5/ 5 17.6 21.4 130±23 2001±762 15.76±6.28 92.233 10 5/ 5 17.6 21.4 130±23 2001±762 15.76±6.28 92.2
33 20 5/ 5 16.9 20.1 116±15 1598±320 13.81±2.22 80.833 20 5/ 5 16.9 20.1 116±15 1598±320 13.81±2.22 80.8
33 40 5/ 5 17.5 20.0 108±18 1504±388 13.86±1.92 81.1 长春氟宁 la 10 5/ 5 17.2 20.1 122±14 2085±459 17.48±5.04 102 长春氧宁 la 20 5/ 5 17.7 19.1 109±19 H47±344 10.92±4.32 63.9 长春氟宁 la 40 5/2 17.4 17.9 121±18 862±444 8.32±5.37 48.7* dO: 分笼给药时间； dn: 第 1次给药后 14天。 *P<0.01 vs对照 33 40 5/ 5 17.5 20.0 108±18 1504±388 13.86±1.92 81.1 vinflunine la 10 5/ 5 17.2 20.1 122±14 2085±459 17.48±5.04 102 vinpodene la 20 5/ 5 17.7 19.1 109±19 H47±344 10.92±4.32 63.9 vinflunine la 40 5/2 17.4 17.9 121±18 862±444 8.32±5.37 48.7* dO: time of administration in a cage; dn: 14 days after the first dose. *P<0.01 vs control
结论： in conclusion:
长春氟宁 la， 实施例 27及 49的酒石酸盐均能明显抑制人肺癌 A549的生长； 实施例 33对肺癌 A549没有明显的疗效。 The vinorelbine la, the tartrates of Examples 27 and 49 all significantly inhibited the growth of human lung cancer A549; Example 33 had no significant effect on lung cancer A549.
从毒性上看， 长春氟宁 la的毒性最强， 实施例 27的毒性较弱， 实施例 49的毒 性介于他们之间。 总体上评价， 对肺癌 A549的疗效， 实施例 27>长春氟宁 la> 实施例 49>实施例 33。
From the toxicological point of view, vinflunine la is the most toxic, the toxicity of Example 27 is weak, and the toxicity of Example 49 is between them. Overall evaluation, the effect on lung cancer A549, Example 27> vinflunine la> Example 49> Example 33.
Claims
1.如下列通式 (I)所示的化合物或其盐- 1. A compound represented by the following formula (I) or a salt thereof -
其中： R 选自垸基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、 环烷基、 杂环 烷基、 卤素、 氨基、 氰基、 三氟甲基、 -N3、 -C(0)R5、 -COOR5 -NR5C(0)R6、 擺58(0)2 -NHC(S)NR5R6 , -C(OH)R5 -(CH2)nNR5R6、 -NHC(0)NR5R6 -C≡CSi(R7)3、 -C(0)NR5R6、 -C(0)NHOH -S02NR5R6、 -NHS(0)2R5 -S(0)2NR5R6、 -SR5、 -S(0)R5、 -S(0)2R5 -SSR5、 -B(OR5)2或 -Sn(R7)3； 其中垸基、 垸氧基、 烯 基、 炔基、 芳基、 杂芳基、 杂环烷基进一步被一个或多个烷基、 烷氧基、 炔基、 羟基、 羟烷基、 氨基、 胺烷基、 氰基、 卤素、 三氟甲基、 乙酰基、 环烷基或杂环 垸基所取代； Wherein: R is selected from the embankment, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, amino, cyano, trifluoromethyl, -N 3, -C(0)R 5 , -COOR 5 -NR 5 C(0)R 6 , pendulum 5 8(0) 2 -NHC(S)NR 5 R 6 , -C(OH)R 5 -(CH 2 ) n NR 5 R 6 , -NHC(0)NR 5 R 6 -C≡CSi(R 7 ) 3 , -C(0)NR 5 R 6 , -C(0)NHOH -S0 2 NR 5 R6, -NHS (0) 2 R 5 -S(0) 2 NR 5 R6, -SR 5 , -S(0)R 5 , -S(0) 2 R 5 -SSR 5 , -B(OR 5 ) 2 or -Sn (R 7 ) 3 ; wherein fluorenyl, decyloxy, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl is further substituted by one or more alkyl, alkoxy, alkynyl, hydroxy, hydroxy Substituted by an alkyl group, an amino group, an aminoalkyl group, a cyano group, a halogen, a trifluoromethyl group, an acetyl group, a cycloalkyl group or a heterocyclic fluorenyl group;
¾选自烷基或 -CH(O); 3⁄4 is selected from alkyl or -CH(O);
R3选自氢原子、 烷基或 -C(0)R5 ; R 3 is selected from a hydrogen atom, an alkyl group or -C(0)R 5 ;
选自氢原子、 -C(0)R5或 -Si(R7)3 ; Selected from a hydrogen atom, -C(0)R 5 or -Si(R 7 ) 3 ;
R5和 各自分别选自氢原子、 烷基、 烷氧基、 环烷基、 卤代烷基、 芳基、 杂芳基或杂环烷基； 其中烷基、环垸基、 芳基、杂芳基或杂环烷基进一步被一个 或多个烷基、 烷氧基、 烯基、 羟基、 环垸基、 芳基、 杂芳基、 卤素或 -NR5R6所 取代； R 5 and each are each selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a halogenated alkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group; wherein alkyl, cyclodecyl, aryl, heteroaryl Or a heterocycloalkyl group is further substituted by one or more alkyl, alkoxy, alkenyl, hydroxy, cyclodecyl, aryl, heteroaryl, halogen or -NR 5 R 6 ;
同时， 与 与 N原子一起形成一个 4 8元的杂环基； 其中 5 8元杂环 内含有一个或多个 N 0 S原子； At the same time, together with the N atom, a 4-8 membered heterocyclic group is formed; wherein the 5 8 membered heterocyclic ring contains one or more N 0 S atoms;
R7为垸基； R 7 is a sulfhydryl group;
Z选自 -OR5 -NR5Re或 -NHNHC(0)R5 Z is selected from -OR 5 -NR 5 Re or -NHNHC(0)R 5
同时， 和 Z成键与插入的原子形成一个环； At the same time, the bond with Z forms a ring with the inserted atoms;
n是。〜 4 n is. ~ 4
2. 根据权利要求 1所述的化合物或其盐， 其中 为氢原子或乙酰基。
The compound according to claim 1 or a salt thereof, which is a hydrogen atom or an acetyl group.
3. 根据权利要求 1所述的化合物或其盐， 其中 R4为氯原子。 The compound according to claim 1 or a salt thereof, wherein R4 is a chlorine atom.
4. 根据权利要求 1所述的化合物或其盐， 其中 Z为甲氧基。 The compound according to claim 1 or a salt thereof, wherein Z is a methoxy group.
5. 根据权利要求 1所述的化合物或其盐，其中 R3为氢原子或乙酰基， 为氢原 子， Z为甲氧基。 The compound according to claim 1 or a salt thereof, wherein R 3 is a hydrogen atom or an acetyl group, which is a hydrogen atom, and Z is a methoxy group.
6. 根据权利要求 1所述的化合物或其盐， 其中 为甲酰基。 The compound according to claim 1 or a salt thereof, wherein is a formyl group.
7. 根据权利要求 1所述的化合物或其盐， 其中 为烷基。 The compound according to claim 1 or a salt thereof, wherein is an alkyl group.
8. 根据权利要求 1所述的化合物或其盐，其中该化合物以药学上可接受的游离 态 The compound according to claim 1 or a salt thereof, wherein the compound is in a pharmaceutically acceptable free state
形式存在。 Form exists.
9.根据权利要求 1所述的化合物或盐， 其中所述盐为药学可接受的酸加成盐， 所述酸包括选自硫酸、 硝酸、 氢溴酸、 氢碘酸或磷酸的无机酸， 或选自酒石酸、 乙酸、 甲磺酸、 苯磺酸、 甲苯磺酸、 柠檬酸、 马来酸、 富马酸或乳酸的有机酸。 The compound or salt according to claim 1, wherein the salt is a pharmaceutically acceptable acid addition salt, and the acid includes a mineral acid selected from sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid or phosphoric acid, Or an organic acid selected from the group consisting of tartaric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, maleic acid, fumaric acid or lactic acid.
10.根据权利要求 9所述的化合物或其盐， 其中所述酸为酒石酸。 The compound according to claim 9 or a salt thereof, wherein the acid is tartaric acid.
11. 根据权利要求 1所述的化合物或其盐， 其中包括如下化学结构式 : The compound according to claim 1 or a salt thereof, which comprises the following chemical structural formula :
Z2 Z2
9LU00/L00Z l3/13d S08T10/800Z OAV
O/JS0AV Ġ9LU00/L00Z l3/13d S08T10/800Z OAV O/JS0AV Ġ
P2 P2
9LU00/L00Z l3/13d S08T10/800Z OAV
ζ 9LU00/L00Z l3/13d S08T10/800Z OAV ζ
9LU00/L00Z l3/13d S08T10/800Z OAV
98 9LU00/L00Z l3/13d S08T10/800Z OAV 98
9LU00/L00Z l3/13d S08T10/800Z OAV
9LU00/L00Z l3/13d S08T10/800Z OAV
87
87
12.一种如权利要求 1所述的通式 (I)化合物或其盐的制备方法， 包括： A process for the preparation of a compound of the formula (I) or a salt thereof according to claim 1, which comprises:
以长春氟宁 (I-la)为原料， 在 -20°C〜3(TC下， 在无水二氯甲烷及三氟乙酸的 混合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物；
Using vinflunine (I-la) as a raw material, reacting with a halogenating reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid at -20 ° C to 3 (TC) to obtain a halogen-substituted formula (I) -lb) compound;
(I-la) (I-lb) (I-la) (I-lb)
将所述的通式化合物 (I-lb)在过渡金属催化下加热 40〜150°C进行偶联反应， 最终得到通式 (I)化合物； The compound of the formula (I-lb) is subjected to a coupling reaction by heating at 40 to 150 ° C under a transition metal catalysis to finally obtain a compound of the formula (I);
其中， 各个取代基的定义与权利要求 1相同; Wherein each substituent has the same definition as in claim 1;
X为卤素。 X is a halogen.
13.一种如权利要求 1所述的通式 (I)化合物或其盐的制备方法， 包括： A method of producing a compound of the formula (I) or a salt thereof according to claim 1, comprising:
以长春氟宁 (I-la)为原料， 在三氟乙酸溶剂中与六亚甲基四胺在 20Ό · 100°C下油浴反应得到通式 (I-lc)化合物； The compound of the formula (I-lc) is obtained by reacting vinflunine (I-la) with a hexamethylenetetramine in an oil bath at 20 Ό 100 ° C in a solvent of trifluoroacetic acid;
(I-la) (I-lc) 将所述的通式 (I-lc)化合物在无水二氯甲烷中， 与R1NH2、三乙酰基硼氢化 钠在 25〜8(TC下进行还原胺化反应得到通式 (I)化合物；
(I-la) (I-lc) The compound of the formula (I-lc) is carried out in anhydrous dichloromethane with R 1 NH 2 and sodium triacetylborohydride at 25 to 8 (TC). Reductive amination reaction to give a compound of the formula (I);
其中， 各个取代基的定义与权利要求 1相同; Wherein each substituent has the same definition as in claim 1;
14.一种如权利要求 1所述的通式 (I)化合物或其盐的制备方法， 包括： A method of producing a compound of the formula (I) or a salt thereof according to claim 1, comprising:
以长春氟宁 (I-la)为原料， 在三氟乙酸溶剂中与六亚甲基四胺在 Using vinflunine (I-la) as a raw material in hexamethyltetramine in a solvent of trifluoroacetic acid
100°C下油浴进行反应得到通式 (I-lc)化合物； The reaction is carried out in an oil bath at 100 ° C to obtain a compound of the formula (I-lc);
(I-la) (I-lc) 通式 (I-lc)化合物在无水四氢呋喃溶液中与 R8MgBr格氏反应得到通式 (I-le) 化合物； (I-la) (I-lc) The compound of the formula (I-lc) is reacted with R 8 MgBr in an anhydrous tetrahydrofuran solution to obtain a compound of the formula (I-le);
将所述的通式 (I-le)化合物在室温条件下在二氯甲烷中进行戴斯一马丁氧 化， 得到通式 (I)化合物；
The compound of the formula (I-le) is subjected to oxidation of Dess-Martin in dichloromethane at room temperature to obtain a compound of the formula (I);
其中， 各个取代基的定义与权利要求 1相同； Wherein each substituent has the same definition as in claim 1;
R8选自烷基或环垸基， 其中烷基或环烷基可以进一步被一个或多个烷基、 烯基、 环烷基或卤素所取代； R 8 is selected from alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group may be further substituted by one or more alkyl, alkenyl, cycloalkyl or halogen;
15. 一种如权利要求 1所述的通式 (I)化合物或其盐的制备方法， 包括- 以长春氟宁 (I-la)为原料， 在 -20°C〜30°C下， 在无水二氯甲烷及三氟乙酸的 混合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物； 15. A process for the preparation of a compound of the formula (I) or a salt thereof according to claim 1, comprising - using vinflunine (I-la) as a starting material, at -20 ° C to 30 ° C, Reaction with a halogenating reagent in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid to obtain a halogen-substituted compound of the formula (I-lb);
(I-la) 得到的通式化合物 (I-lb)在 -20°C〜40°C下在二氯甲垸中与三氟甲磺酸垸基 硅烷基酯进行反应， 得到通式 (I-ld)化合物； (I-la) The obtained compound of the formula (I-lb) is reacted with decylsilyl triflate in chloroform at -20 ° C to 40 ° C to obtain a formula (I). -ld) compound;
如上所得的通式 (I-ld)化合物在甲苯中， 在三 (二亚苄基丙酮)二钯 (0)和 2-二 环己基膦 -2',4',6'-三异丙基 -Ι,Γ-联苯催化下与 ΝΗ2反应得到通式 (I-lf)化合物;
The compound of the formula (I-ld) obtained above is in toluene, in tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphine-2',4',6'-triisopropyl - hydrazine, hydrazine-biphenyl catalyzed reaction with hydrazine 2 to give a compound of the formula (I-lf);
将所述的通式化合物 (I-li)在四氢呋喃溶剂中与四丁基氟化铵反应脱掉垸基 硅最终得到通式 (I)化合物； The compound of the formula (I-li) is reacted with tetrabutylammonium fluoride in tetrahydrofuran solvent to remove the mercapto silicon to finally obtain a compound of the formula (I);
其中， 各个取代基的定义与权利要求 1相同； Wherein each substituent has the same definition as in claim 1;
R8选自烷基或环烷基， 其中垸基或环垸基进一步被一个或多个烷基、 烯基、 环烷基或卤素所取代； R 8 is selected from alkyl or cycloalkyl, wherein the indenyl or cyclodecyl group is further substituted by one or more alkyl, alkenyl, cycloalkyl or halogen;
X为卤素。 X is a halogen.
16.根据权利要求 12所述的制备方法， 其中所使用的过渡金属催化剂选自： 醋 酸钯、 碘化亚铜、 钯碳、 三苯基膦、 四- (三苯基膦)化钯、 二- (三苯基膦)氯化钯、 1,1'-双- (二苯基膦)二茂铁或三 (二亚苄基丙酮)二钯。 The preparation method according to claim 12, wherein the transition metal catalyst used is selected from the group consisting of palladium acetate, cuprous iodide, palladium carbon, triphenylphosphine, tetrakis-(triphenylphosphine) palladium, and - (triphenylphosphine)palladium chloride, 1,1'-bis-(diphenylphosphino)ferrocene or tris(dibenzylideneacetone)dipalladium.
17. 根据权利要求 15所述的制备方法， 其中所述的卤代试剂选自： N-溴代琥珀 酰亚胺、 N-碘代琥珀酰亚胺或一氯化碘。 The preparation method according to claim 15, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-iodosuccinimide or iodine monochloride.
18.根据权利要求 15所述的制备方法， 其中在无水二氯甲垸及三氟乙酸的混合 溶剂中二氯甲烷与三氟乙酸的比例为 10:1〜1:10。 The process according to claim 15, wherein the ratio of dichloromethane to trifluoroacetic acid in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid is from 10:1 to 1:10.
19.根据权利要求 18所述的制备方法， 其中在无水二氯甲烷及三氟乙酸的混合 溶剂中二氯甲烷与三氟乙酸的比例为 1:1。 The process according to claim 18, wherein the ratio of dichloromethane to trifluoroacetic acid in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid is 1:1.
20. 一种如下列通式 (I-lb)和 (I-lc)所示的化合物， 其作为权利要求 1所述通式 (I) 化合物合成的中间体：
20. A compound represented by the following formula (I-lb) and (I-lc) which is an intermediate for the synthesis of the compound of the formula (I) according to claim 1:
(I-lb) (I-lc) (I-lb) (I-lc)
其中， 各个取代基的定义与权利要求 1相同； Wherein each substituent has the same definition as in claim 1;
X为卤素。 X is a halogen.
21.一种制备如权利要求 20所述的通式 (I-lb)或者通式 (I-lc)化合物或其盐的方 法， 包括以下步骤- A method of producing a compound of the formula (I-lb) or the formula (I-lc) or a salt thereof according to claim 20, which comprises the following steps -
(I-lb) (I-lc) 以长春氟宁 (I-la)为原料， 在适当的温度 (-20Ό〜30Ό)下， 在无水二氯甲烷 及三氟乙酸的混合溶剂中与卤代试剂反应， 得到卤素取代通式 (I-lb)化合物； (I-lb) (I-lc) using vinflunine (I-la) as a raw material, at a suitable temperature (-20Ό~30Ό), in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid with halogen Reacting with a reagent to obtain a halogen-substituted compound of the formula (I-lb);
(I-la) (Mb) 或者将所述的长春氟宁 (I-la)在三氟乙酸溶剂中与六亚甲基四胺在 20°C〜 (I-la) (Mb) or the vinflunine (I-la) in a solvent of trifluoroacetic acid with hexamethylenetetramine at 20 ° C ~
100°C下反应得執通式 (I4P)化合物； The compound of the formula (I4P) is obtained by reaction at 100 ° C;
· '"·''' '二: .. · '"·''' 'Two: ..
22.根据权利要求 21所述的制备方法， 其中所述的卤化试剂选自： N-溴代琥珀 酰亚胺、 N-碘代琥珀酰亚胺或一氯化碘。 The production method according to claim 21, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-iodosuccinimide or iodine monochloride.
23.根据权利要求 21所述的制备方法， 其中在无水二氯甲烷及三氟乙酸的混合 溶剂中二氯甲烷与三氟乙酸的比例为 10:1〜1:10。 The process according to claim 21, wherein a ratio of dichloromethane to trifluoroacetic acid in a mixed solvent of anhydrous dichloromethane and trifluoroacetic acid is from 10:1 to 1:10.
24.根据权利要求 23所述的制备方法， 其中在所用混合溶剂中二氯甲垸与三氟 乙酸的比例为 1:1。 The process according to claim 23, wherein the ratio of methylene chloride to trifluoroacetic acid in the mixed solvent used is 1:1.
25.—种药物组合物，其中含有权利要求 1-11、18中任一项所述的化合物或其盐， 以及药学可接受的的载体或赋形剂。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, 18 or a salt thereof, and a pharmaceutically acceptable carrier or excipient.
26.一种如权利要求 1所述化合物或其盐在制备治疗哺乳动物细胞增殖相关疾病 或其它疾病的药物中的用途。 26. Use of a compound of claim 1 or a salt thereof for the manufacture of a medicament for the treatment of a cell proliferation-related disease or other disease in a mammal.
27.一种如权利要求 25所述的组合物在制备治疗哺乳动物细胞增殖相关疾病或 其它疾病的药物中的用途。 27. Use of a composition according to claim 25 for the manufacture of a medicament for the treatment of a cell proliferation-related disease or other disease in a mammal.
28.根据权利要求 26或 27所述的用途， 其中所述与哺乳动物细胞增殖相关疾病 或其它疾病包括癌症、 细菌感染疾病、 过敏症、 心脏病、 AIDS、 噬人体 T淋巴 细胞病毒 1型感染、人疱疹病毒 3型、人疱疹病毒 4型、人乳头状瘤病毒、糖尿 病、 类风湿性关节炎、 阿耳茨海默病、 发炎、 关节炎、 疟疾、 自身免 ¾性疾病、 湿疹、 红斑狼疮、 牛皮癣、 风湿性疾病、 干燥角膜结膜炎综合征或病毒感染。 The use according to claim 26 or 27, wherein the disease or other diseases associated with mammalian cell proliferation include cancer, bacterial infection disease, allergy, heart disease, AIDS, human T lymphocyte virus type 1 infection , human herpesvirus type 3, human herpesvirus type 4, human papillomavirus, diabetes, rheumatoid arthritis, Alzheimer's disease, inflammation, arthritis, malaria, self-eliminating disease, eczema, erythema Lupus, psoriasis, rheumatic diseases, dry keratoconjunctivitis syndrome or viral infections.
29.根据权利要求 28所述的用途， 其中所述癌症为肺癌、 肝癌、 胰腺癌、 食管 癌、 胃癌、 甲状腺癌、 黑色素癌、 脑癌、 膀胱癌、 非小细胞肺癌、 小细胞癌、 恶性淋巴瘤、 乳腺癌或恶性黑色素瘤。
The use according to claim 28, wherein the cancer is lung cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, thyroid cancer, melanoma, brain cancer, bladder cancer, non-small cell lung cancer, small cell carcinoma, malignant Lymphoma, breast cancer or malignant melanoma.
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2923485A1 (en) * | 2007-11-12 | 2009-05-15 | Pierre Fabre Medicament Sa | ANTIMITOTIC COMPOUNDS DERIVED FROM VINCA ALKALOIDS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| US7745619B2 (en) | 2003-12-04 | 2010-06-29 | Albany Molecular Research, Inc. | Vinca derivatives |
| US7842802B2 (en) | 2003-12-04 | 2010-11-30 | Albany Molecular Research, Inc. | Vinorelbine derivatives |
| US8618299B2 (en) | 2009-07-01 | 2013-12-31 | Albany Molecular Research, Inc. | Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof |
| US8629158B2 (en) | 2009-07-01 | 2014-01-14 | Albany Molecular Research, Inc. | Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
| US8637501B2 (en) | 2009-07-01 | 2014-01-28 | Albany Molecular Research, Inc. | Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof |
| US8697700B2 (en) | 2010-12-21 | 2014-04-15 | Albany Molecular Research, Inc. | Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof |
| US8716308B2 (en) | 2008-01-11 | 2014-05-06 | Albany Molecular Research, Inc. | (1-azinone)-substituted pyridoindoles |
| US8993765B2 (en) | 2010-12-21 | 2015-03-31 | Albany Molecular Research, Inc. | Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof |
| US9073925B2 (en) | 2009-07-01 | 2015-07-07 | Albany Molecular Research, Inc. | Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
| US10112915B2 (en) | 2015-02-02 | 2018-10-30 | Forma Therapeutics, Inc. | 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10183934B2 (en) | 2015-02-02 | 2019-01-22 | Forma Therapeutics, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10555935B2 (en) | 2016-06-17 | 2020-02-11 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105121447B (en) * | 2013-04-19 | 2018-02-02 | 暨南大学 | Vinca derivative and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5620985A (en) * | 1993-07-21 | 1997-04-15 | Pierre Fabre Medicament | Antimitotic binary alkaloid derivatives from catharanthus roseus |
| WO2005055943A2 (en) * | 2003-12-04 | 2005-06-23 | Amr Technology, Inc. | Vinorelbine derivatives |
| WO2005055939A2 (en) * | 2003-12-04 | 2005-06-23 | Amr Technology, Inc. | Vinca derivatives |
-
2006
- 2006-07-17 CN CNA2006101062829A patent/CN101108859A/en active Pending
-
2007
- 2007-07-17 WO PCT/CN2007/002176 patent/WO2008011805A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5620985A (en) * | 1993-07-21 | 1997-04-15 | Pierre Fabre Medicament | Antimitotic binary alkaloid derivatives from catharanthus roseus |
| WO2005055943A2 (en) * | 2003-12-04 | 2005-06-23 | Amr Technology, Inc. | Vinorelbine derivatives |
| WO2005055939A2 (en) * | 2003-12-04 | 2005-06-23 | Amr Technology, Inc. | Vinca derivatives |
Cited By (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7745619B2 (en) | 2003-12-04 | 2010-06-29 | Albany Molecular Research, Inc. | Vinca derivatives |
| US7842802B2 (en) | 2003-12-04 | 2010-11-30 | Albany Molecular Research, Inc. | Vinorelbine derivatives |
| US8053428B2 (en) | 2003-12-04 | 2011-11-08 | Albany Molecular Research, Inc. | Vinorelbine derivatives |
| US8895543B2 (en) | 2003-12-04 | 2014-11-25 | Albany Molecular Research, Inc. | Vinca derivatives |
| FR2923485A1 (en) * | 2007-11-12 | 2009-05-15 | Pierre Fabre Medicament Sa | ANTIMITOTIC COMPOUNDS DERIVED FROM VINCA ALKALOIDS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| WO2009098369A1 (en) * | 2007-11-12 | 2009-08-13 | Pierre Fabre Medicament | Antimitotic compounds derived from vinca alkaloids, preparation thereof and therapeutic use thereof |
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| US10457652B2 (en) | 2015-02-02 | 2019-10-29 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
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| US10464909B2 (en) | 2015-02-02 | 2019-11-05 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10472337B2 (en) | 2015-02-02 | 2019-11-12 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10479772B2 (en) | 2015-02-02 | 2019-11-19 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10183934B2 (en) | 2015-02-02 | 2019-01-22 | Forma Therapeutics, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10494353B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10494352B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10494354B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10501424B2 (en) | 2015-02-02 | 2019-12-10 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10513501B2 (en) | 2015-02-02 | 2019-12-24 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11891365B2 (en) | 2015-02-02 | 2024-02-06 | Valo Health, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10822316B2 (en) | 2015-02-02 | 2020-11-03 | Valo Early Discovery, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10829461B2 (en) | 2015-02-02 | 2020-11-10 | Valo Early Discovery, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10829462B2 (en) | 2015-02-02 | 2020-11-10 | Valo Early Discovery, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10870645B2 (en) | 2015-02-02 | 2020-12-22 | Valo Early Discovery, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US11702412B2 (en) | 2015-02-02 | 2023-07-18 | Valo Health, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10988450B2 (en) | 2015-02-02 | 2021-04-27 | Valo Early Discovery, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11274084B2 (en) | 2015-02-02 | 2022-03-15 | Valo Health, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11274085B2 (en) | 2015-02-02 | 2022-03-15 | Valo Health, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11279681B2 (en) | 2015-02-02 | 2022-03-22 | Valo Health, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10874649B2 (en) | 2016-06-17 | 2020-12-29 | Valo Early Discovery, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
| US11730721B2 (en) | 2016-06-17 | 2023-08-22 | Valo Health, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
| US10555935B2 (en) | 2016-06-17 | 2020-02-11 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
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