CN103772463A - 2-methoxy-estradiol analogue and preparation method and application thereof - Google Patents
2-methoxy-estradiol analogue and preparation method and application thereof Download PDFInfo
- Publication number
- CN103772463A CN103772463A CN201310753425.5A CN201310753425A CN103772463A CN 103772463 A CN103772463 A CN 103772463A CN 201310753425 A CN201310753425 A CN 201310753425A CN 103772463 A CN103772463 A CN 103772463A
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- China
- Prior art keywords
- methoxyl group
- female steroid
- benzyloxy
- reaction
- triolefins
- Prior art date
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- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical class C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000005917 acylation reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- -1 aromatic alkyl Chemical group 0.000 claims description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 44
- 238000003756 stirring Methods 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 22
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 15
- 230000006837 decompression Effects 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 14
- 229960004756 ethanol Drugs 0.000 claims description 14
- 235000019441 ethanol Nutrition 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- 239000012153 distilled water Substances 0.000 claims description 13
- 239000010410 layer Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 235000002639 sodium chloride Nutrition 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims description 7
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Chemical group C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- NNQDMQVWOWCVEM-UHFFFAOYSA-N 1-bromoprop-1-ene Chemical group CC=CBr NNQDMQVWOWCVEM-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 125000000539 amino acid group Chemical group 0.000 claims description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- KMOUUZVZFBCRAM-OLQVQODUSA-N (3as,7ar)-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione Chemical compound C1C=CC[C@@H]2C(=O)OC(=O)[C@@H]21 KMOUUZVZFBCRAM-OLQVQODUSA-N 0.000 claims description 2
- OWXJKYNZGFSVRC-NSCUHMNNSA-N (e)-1-chloroprop-1-ene Chemical compound C\C=C\Cl OWXJKYNZGFSVRC-NSCUHMNNSA-N 0.000 claims description 2
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- WCFJUSRQHZPVKY-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NCCC(O)=O WCFJUSRQHZPVKY-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 2
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- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
The invention relates to a 2-methoxy-estradiol analogue and a preparation method and application thereof, aiming to solve the problem of preparation of the 2-methoxy-estradiol analogue and realize the application of the 2-methoxy-estradiol analogue to preparation of anti-tumor medicaments. The method comprises the following steps: dissolving 2-methoxy-3-benzyloxy-estradiol-1,3,5-(10)-triene-17beta-alcohol or 17beta-amine serving as a raw material into an organic solvent; in the presence of Lewis alkali, carrying out an acylation reaction on the raw materials and a compound (1) to obtain a 2-methoxy-3-benzyloxy-estradiol-1,3,5-(10)-triene-17beta-ester or 17beta-amide compound (2); carrying out a catalytic hydrogenation to obtain a compound (3); carrying out an acylation reaction or a hydrocarbylation reaction to obtain a compound, namely, the 2-methoxy-estradiol analogue (4), wherein a reaction formula is shown in the specifications. The preparation method of the 2-methoxy-estradiol analogue has the advantages of easiness, mild conditions and high yield, and can be effectively applied to development of anti-tumor medicaments.
Description
Technical field
The present invention relates to medicine, particularly a kind of 2ME2 analogue and preparation method thereof and purposes.
Background technology
20 century 70s, in research estrogen metabolism process, find the endogenous metabolism product 2ME2 (2-methoxyestradiol of estradiol, 2-ME), it is Cytochrome P450s oxydase in vivo and the effect of catechol-O-methyltransferase (COMT), and estradiol carries out orderly hydroxylation and methylate producing.2ME2 is present in normal people's urine, blood, it is reported 2ME2 content is lower in the male sex and conceived women's blood plasma (to be respectively 10～35pgml
-1with 18～138pgml
-1), (can reach 216～10690pgml and content is higher in pregnant woman blood plasma
-1) (Dubey R.K.et al.Trends Endocrinol Metab.2009,20 (80): 374-379).Research finds that 2ME has the antitumor action of wide spectrum, and the tolerance for the treatment of is better.The report 2-ME such as Cushman M. can have restraining effect (Cushman M.et al.J Med Chem.1995 to reaching 55 kinds of different tumour cells, 38 (12): 2041-2049), 2-ME alone or in combination other chemotherapeutics can be used for treating mammary cancer, cancer of the stomach, lung cancer, liver cancer, prostate cancer, multiple myeloma and leukemia etc.The researchs such as Susan find that 2ME only acts on the cancer cells that enlivens proliferation period, and there is a relatively high specificity, and to the cell of stationary phase without effect, thereby the less (Susan of untoward reaction, et al.Drug Resist Updates.2003,6 (6): 355-361), have high-efficiency low-toxicity, targeting strong, be difficult for the advantages such as resistance.In addition, 2ME to the avidity of estrogen receptor a little less than, and there is no some estrogen activitys (Pribluda V.S.et al.Cancer Metast Rev.2000 that estradiol or other estradiol metabolites are relevant, 19:173-200), therefore 2ME likely becomes a kind of PTS of high-efficiency low-toxicity.At present, methoxyestradiol is by EntreMed register of company, with trade(brand)name, Panzem develops, as monotherapy for multiple myeloma stable or recurrence and prostate cancer therapy, with docetaxel (docetaxel, Taxotere) combine clinical study stage II phase for hormone-refractory prostate cancer, new indication resisting rheumatoid arthritis was studied in the I clinical trial phase stage.Sanofi-aventis(Sanofi-Aventis) company, Allergan(Allergan) the acquisition part indication mandate such as company enter respectively I, II or III clinical trial phase.
But 2-ME will be widely used in clinical some urgent problems that also exist: (1) 2-ME is a kind of antitumor drug of concentration time-dependent manner, in water, solubleness is extremely low (is about 1.669 μ gml in 37 ℃ of water
-1the about 2.86(Guo Xin of lipid is red etc., Zhengzhou University's journal (medicine), 2010,45 (1): 141-143)) between (2) oral absorption and dosage, lack dependency, the biological variation of easy hydroxylation, dehydrogenation etc. fast produces inactive meta-bolites again in vivo, causes the transformation period shorter (about 20min), bioavailability is lower, and oral blood medicine and Tissue are extremely low (is less than 100ngml
-1), can not meet the dependent pharmacotoxicological effect feature of time-dose (James J, et al.Invest New Drugs, 2007,25:41-48) of medicine itself.In addition, in the structure activity relationship to 2-ME derivative (SAR) research, find, the subject matter that 2-ME exists is not that its anti-tumor activity is lower, but its first pass metabolism (Agoston G.E.et al.Bioorg Med Chem Lett faster in vivo, 2009,19:6241-6244).This points out us in the time that the structure of 2-ME is modified, should slow down emphatically the metabolism in vivo of 2-ME derivative, improves its external interference microtubule polymerization or suppresses proliferation function and be not only.The clinical application that the drawbacks limit such as water-soluble low, the oral dosage of 2-ME is large, it is irregular to absorb, the transformation period is shorter, have first pass effect and bioavailability is low 2-ME.Therefore, take 2-ME as lead compound, it being carried out structural modification and is transformed is a feasible and valuable approach.
Just there is the report about the research of 2ME2 derivative as far back as the eighties in 20th century abroad, about the research of its derivative was mainly carried out in nearly 20 years.Investigator carries out structural modification research for its 2-position, 3-position, 16-position and 17-position etc.In these achievements in research, representational is ENMD-1198(Zhou Q.et al.Invest New Drugs.2011,29:340-346) with STX140(Newman S.P.et al.Cell Clin Cancer Res.2008,14:597-606), enter at present clinical experiment stage I phase, have good tolerance, toxic side effect is little.Also have in addition part 2-ME derivative also to show good anti-tumor activity.Therefore 2ME2 being carried out structural modification and transformed is a kind of effective way that obtains new type antineoplastic medicine, has realistic meaning and researching value.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the present invention's object is just to provide a kind of 2ME2 analogue and preparation method thereof and purposes, can effectively solve the preparation of 2ME2 analogue and realize 2ME2 analogue in the application of preparing in antitumor drug.
The technical scheme that the present invention solves is that its general structure of 2ME2 analogue of the present invention is:
Wherein, X can be Sauerstoffatom, nitrogen-atoms or sulphur atom; Y can be carbonyl (carbonic acyl radical) or sulfonyl;
R
1can be hydrogen, one (R containing saturated or undersaturated alkyl, aromatic alkyl, fatty acyl group, aralkanoyl, heterocyclic acyl and the amino-sulfonyl of the replacement of 1～8 carbon atom
1on substituting group, can contain alkyl, alkoxyl group, halogen F, Cl, Br, the I of 1～4 carbon atom);
R
2can be the one (R of saturated or unsaturated alkyl, aromatic base, aromatic alkyl, heterocyclic aryl and the heterocycle aralkyl of the replacement that contains 1～12 carbon atom
2on monosubstituted or polysubstituted substituting group, can contain the one of alkyl or the alkoxyl group of 1～4 carbon atom, or the one of F, Cl, Br and I, or the one of hydroxyl, carboxyl, amino and sulfydryl);
2ME2 analogue its preparation method of the present invention is:
With 2-methoxyl group-3-benzyloxy-female steroid-1; 3; 5 (10)-triolefin-17 β-ol or 17 β-amine are raw material; be dissolved in organic solvent; under Lewis alkali exists, carry out acylation reaction with compound (1) and obtain 2-methoxyl group-3-benzyloxy-female steroid-1; 3; 5 (10)-triolefin-17 β-ester or 17 β-amide compound (2); then obtain compound (3) through catalytic hydrogenation reaction; finally obtain compound 2ME2 analogue (4) through acylation reaction or alkylation reaction again, reaction formula is:
Described Lewis alkali is one or both of sodium carbonate, sodium-acetate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, hydrolith, sodium hydride, triethylamine, pyridine, DMAP, picoline;
Described organic solvent is N, one or both of dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetone, chloroform, trichloromethane, methylene dichloride, toluene, ethyl acetate, methyl alcohol, ethanol, Virahol, acetonitrile, sherwood oil, tetrahydrofuran (THF), dioxane, pyridine;
Described acylation reaction raw material is the one of acyl chlorides, acid anhydrides or carboxylic acid, wherein, acyl chlorides is to contain the saturated of 1～12 carbon atom or unsaturated hydrocarbons acyl chlorides, aroyl chloride, fragrant alkane acyl chlorides, fragrant alkene acyl chlorides, heterocycle aroyl chloride, heterocycle aralkyl acyl chlorides, heterocycle virtue alkene acyl chlorides, such as Acetyl Chloride 98Min., 3-propionyl chloride, parachlorobenzoyl chloride, 2,3, the one of 4,5-phenyl tetrafluoride formyl chloride and nicotinoyl chlorine, acid anhydrides is the one of diacetyl oxide, propionic anhydride, butyryl oxide, MALEIC ANHYDRIDE, benzoyl oxide and Tetra hydro Phthalic anhydride, carboxylic acid is butyric acid, butene dioic acid (for example fumaric acid, toxilic acid), hydroxy-propionic acid (for example tartrate, oxysuccinic acid), natural and non-natural amino acid (for example glycine, L-Ala, Serine, Threonine, α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine, tyrosine, halfcystine, methionine(Met), aspartic acid, l-asparagine, L-glutamic acid, glutamine, Histidine, Methionin, arginine, proline(Pro), oxyproline, tryptophane, Beta-alanine, γ-aminobutyric acid, epsilon-amino caproic acid, ornithine, citrulline, Styptopur, tranamic acid, taurine, tosic acid and Sulphanilic Acid) one,
Its catalyzer of described catalytic hydrogenation reaction is the one of palladium carbon, skeleton nickel; Reaction solvent is one or both of methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), ethyl acetate, DMF; .
Described alkylation reaction raw material is the one of the saturated or unsaturated alkane of the halo that contains 1～8 carbon atom, halo naphthenic hydrocarbon, halogenated aryl hydrocarbon, halo aralkyl hydrocarbon, such as the one of methyl iodide, monobromethane, monobromethane, monochloroethane, N-PROPYLE BROMIDE, chloropropane, bromopropylene, propenyl chloride, bromocyclohexane, benzyl bromine, benzyl chlorine.Also can be the one of methyl-sulfate, ethyl sulfate, methylcarbonate, diethyl carbonate.Catalyzer is the one of quaternary ammonium salt benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride.Required Lewis alkali and reaction solvent are with above-mentioned acylation reaction.
2ME2 analogue prepared by the inventive method, is effective to prepare antitumor drug.
The preparation method of 2ME2 analogue of the present invention is simple, mild condition, yield is high, can prepare easily 2ME2 analogue, these compounds show the antiproliferative activity evaluation experimental result of tumour cell, 2ME2 analogue provided by the invention is for for example SK-N-SH human neuroblastoma cells cell of most of tumour cells, esophageal carcinoma EC-9706 cell and EC-109 cell, MCF-7 Breast Cancer Cell, Human Prostate Cancer PC-3 Cell Line, SGC-7901 cell and MGC803 cell, SMMC-7721 liver cancer cells and HepG-2 cell, s and mouse melanin tumor cell are that B16 cell etc. has certain restraining effect, can be effective to the exploitation of anti-tumor medicinal preparation.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
Embodiment 1
The present invention is in concrete enforcement, and 2ME2 analogue is the compound of following general structure (I):
Wherein, R
1for the one of hydrogen atom, methyl, ethyl and benzyl; R
2for the one of methyl, ethyl, vinyl, propyl group, sec.-propyl, propenyl, allyl group, butyl, isobutyl-, the tertiary butyl, pentamethylene base, cyclohexyl, chloromethyl, chloroethyl, chloropropyl, methyl fluoride, fluoro ethyl, butyric acid base, butylene acidic group, hydroxy-propionic acid base, phenyl, benzyl, chloro-phenyl-, fluorophenyl, tetrafluoro phenyl, pyridyl and imidazolyl;
The compound of described logical formula I can be the one in following general formula compound:
The preparation method of the compound of described logical formula I, take I-3 compound, I-7 compound as example:
The preparation of A, I-3 compound, method is, under condition of ice bath, by 0.48g(1.22mmol) 2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-ol are dissolved in 10ml methylene dichloride, are added dropwise to while stirring 0.417ml(3mmol) triethylamine; Slowly drip containing 0.14ml(1.84mmol) dichloromethane solution of chloroacetyl chloride, control and drip an approximately 1/2s of speed, in 30min, dropwise; Under room temperature, continue to stir, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merging organic phase, then distilled water, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time successively.Anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses appropriate recrystallizing methanol, obtains beta-hydroxy-female steroid-1, white needles 2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefins-chloracetate 0.52g, yield 92.98%;
Under 60 ℃ of conditions, by beta-hydroxy-female steroid-1,2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefin-chloracetates are dissolved in 50ml ethanol, and adding 0.03g mass content is 10% palladium-carbon catalyst, and maintaining hydrogen pressure is 50psi, thin layer detects to complete reaction, suction filtration is removed palladium carbon, and concentrating under reduced pressure solvent is separated out white powder 2-methoxyl group-3 through recrystallizing methanol, 17 beta-dihydroxyies-female steroid-1,3,5 (10)-triolefins-17-chloracetate 0.38g, yield 90%.
B, the preparation of I-7 compound, method is, under condition of ice bath, get 0.50g(1.28mmol) 2-methoxyl group-3-benzyloxy-female steroid-1, 3, 5 (10)-triolefin-17 β-ol and 0.17ml(1.8mmol) 3-chlorpromazine chloride is dissolved in methylene dichloride, the preparation of same I-3 of specific operation process compound, obtain yellow oil, carry out sherwood oil, ethyl acetate column chromatography purifying, in weight ratio Shi You Mi ︰ ethyl acetate=15 ︰ 1, obtain beta-hydroxy-female steroid-1,2-methoxyl group-3-benzyloxy-17, 3, 5 (10)-triolefins-acrylate 0.49g, yield 86%.
Embodiment 2
The present invention is in concrete enforcement, and 2ME2 analogue is the compound of following general structure (II):
Wherein, R
1for the one of hydrogen atom, methyl, ethyl, benzyl, allyl group, ethanoyl, propionyl, butyryl radicals, chloracetyl, chlorine propionyl, chlorobutyryl, benzoyl, chlorobenzene formacyl, fluoro benzoyl and furancarbonyl;
The compound of described logical formula II can be the one in following general formula compound:
The preparation method of the compound of described logical formula II, take II-4 compound, II-9 compound as example:
The preparation of A, II-4 compound, method is, under ice bath by anhydrous formic acid 169.8 μ l(4.5mmol) dropwise join Sulfuryl chloride isocyanate 391.8 μ l(4.5mmol) in, rapid stirring, added acetonitrile 6ml, stirring at room temperature 7 hours toward system after 15 minutes; Then under condition of ice bath, slowly add and contain 1.50g(3.8mmol) 2-methoxyl group-3-benzyloxy-female steroid-1, N,N-dimethylacetamide (DMA) the solution 8ml of 3,5 (10)-triolefin-17 β-ol, continues stirring reaction two hours; Then add distilled water 20ml, be extracted with ethyl acetate three times, organic phase adds anhydrous sodium sulfate drying to spend the night.Suction filtration, solvent evaporated, crosses post with column chromatography silica gel, moving phase is ethyl acetate: sherwood oil=1:3, obtains beta-hydroxy-female steroid-1, white powder solid 2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefins-17-sulfamate 1.56g, productive rate 87%;
With 50ml ethanol by beta-hydroxy-female steroid-1,2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefins-17-sulfamate 1.00g(2.12mmol) dissolve, be placed in steel cylinder, adding mass content is 10% palladium carbon 50mg, stir, 60 ℃ of oil baths are reacted under 50-60psi hydrogen pressure; After 4 hours, making thin-layer chromatography (TLC) by volume ratio meter Er Lv Jia Wan ︰ acetone=15 ︰ 1 detects, after reacting completely, by 200-300 object post filtered through silica gel for mixture, concentrated white powder 2-methoxyl group-3,17 beta-dihydroxyies-female steroid-1,3 of obtaining of filtrate, 5 (10)-triolefins-17-sulfamate 0.72g, yield 90%;
Under condition of ice bath, by 120mg(0.314mmol) 2-methoxyl group-3,17 beta-dihydroxyies-female steroid-1,3,5 (10)-triolefins-17-sulfamate is dissolved in methylene dichloride, is added dropwise to while stirring 65 μ l(0.466mmol) triethylamine, get 50 μ l(0.48mmol) n-butyryl chloride, with after the dilution of 5ml methylene dichloride, add in constant pressure funnel, control and drip approximately 1/2s of speed, in 30min, dropwise, reaction system is placed under room temperature, continue to stir 2h, then use respectively distilled water, 10% sodium hydrogen carbonate solution, 2 times (10ml/ time) of the each washing of saturated nacl aqueous solution, getting organic layer adds after anhydrous magnesium sulfate drying 4-5h, filter, revolve and steam except desolventizing, obtain transparent oily matter, through column chromatography (ethyl acetate: sherwood oil=1:4), obtain beta-hydroxy-female steroid-1, compound 2-methoxyl group-3-butyryl acyloxy-17, 3, 5 (10)-triolefins-17-sulfamate 116mg, yield 82%.
The preparation of B, II-9 compound, method is, under condition of ice bath, by 200mg(0.525mmol) 2-methoxyl group-3,17 beta-dihydroxyies-female steroid-1,3,5 (10)-triolefin-17 beta-amino sulphonates are dissolved in toluene, are added dropwise to while stirring 4-(dimethylamino) pyridine 200 μ l(1.65mmol); Get furoyl chloride 100 μ l(1.01mmol), with after 5ml dilution with toluene, add in constant pressure funnel, control and drip approximately 1/2s of speed, in 30min, dropwise, reaction system is placed under room temperature, continue to stir 2h; Then respectively wash 2 times (10ml/ time) with distilled water, 10% sodium hydrogen carbonate solution, saturated nacl aqueous solution respectively, getting organic layer adds after anhydrous magnesium sulfate drying 4-5h, filter, revolve and steam except desolventizing, obtain transparent oily matter, through column chromatography (ethyl acetate: sherwood oil=1:4), obtain compound 2-methoxyl group-3-furoyl Oxy-1 7 beta-hydroxies-female steroid-1,3,5 (10)-triolefins-17-sulfamate 212mg, yield 85%.
Embodiment 3
The present invention is in concrete enforcement, and 2ME2 analogue is the compound of following general structure (III):
Wherein, R
1for the one of hydrogen atom, methyl, ethyl, propyl group, allyl group, benzyl and amino-sulfonyl, R
2for methyl, ethyl, vinyl, propyl group, sec.-propyl, propenyl, allyl group, butyl, isobutyl-, the tertiary butyl, pentamethylene base, cyclohexyl, chloromethyl, chloroethyl, chloropropyl, methyl fluoride, fluoro ethyl, butyric acid base, butylene acidic group (for example fumaric acid, toxilic acid), hydroxy-propionic acid base (for example tartrate, oxysuccinic acid), phenyl, benzyl, chloro-phenyl-, fluorophenyl, tetrafluoro phenyl, pyridyl, imidazolyl, natural and non-natural amino-acid residue (for example glycine, L-Ala, Serine, Threonine, α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine, tyrosine, halfcystine, methionine(Met), aspartic acid, l-asparagine, L-glutamic acid, glutamine, Histidine, Methionin, arginine, proline(Pro), oxyproline, tryptophane, Beta-alanine, γ-aminobutyric acid, epsilon-amino caproic acid, ornithine, citrulline, Styptopur, tranamic acid amino-acid residue) one,
The compound of described logical formula III can be the one in following general formula compound:
The preparation method of the compound of described logical formula III, take III-6 compound, III-8 compound, III-11 compound, III-12 compound, III-13 compound, III-16 compound as example:
The preparation of A, III-6 compound, method is, under condition of ice bath, by 0.300g(0.76mmol) 2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-amine are dissolved in 10ml methylene dichloride, are added dropwise to while stirring 0.213ml(1.53mmol) triethylamine; Slowly drip 0.203ml(1.53mmol) dichloromethane solution of phenyllacetyl chloride, control and drip an approximately 1/2s of speed, in 30min, dropwise; Under room temperature, continue to stir, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merge organic phase, then washing successively, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time, anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses recrystallizing methanol, obtain β-N-phenylacetyl amido-female steroid-1,2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefin 0.295g, yield 75.6%.
The preparation of B, III-8 compound, method is, under condition of ice bath, by 0.300g(0.76mmol) 2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-amine are dissolved in 10ml ethyl acetate, are added dropwise to while stirring 0.10ml(1.24mmol) pyridine; Then slowly drip 0.159ml(1.53mmol) ethyl acetate solution of n-butyryl chloride, control and drip an approximately 1/2s of speed, in 30min, dropwise; Stirring at room temperature, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merge organic phase, then washing successively, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time, anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses recrystallizing methanol, obtain positive amide-based small-female steroid-1 of 2-methoxyl group-3-benzyloxy-17 β-N-, 3,5 (10)-triolefin 0.253g, yield 71.5%;
At 60 ℃, by positive amide-based small-female steroid-1 of 0.200g2-methoxyl group-3-benzyloxy-17 β-N-, 3,5 (10)-triolefins are dissolved in 50ml ethanol, add 0.02g10% palladium-carbon catalyst, and react under the effect that is 50psi at hydrogen pressure, thin layer detects to complete reaction, suction filtration is removed palladium carbon, concentrating under reduced pressure solvent, through volume ratio meter ethyl acetate: sherwood oil=1:2 column chromatography obtains positive amide-based small-female steroid-1 of β-N-, 2-methoxyl group-17,3,5 (10)-triolefins-3-alcohol 0.138g, yield 85.7%.
The preparation of C, III-11 compound, method is, under condition of ice bath, by 0.300g(0.76mmol) 2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-amine are dissolved in 10ml tetrahydrofuran (THF), are added dropwise to while stirring 0.10ml(1.24mmol) DMAP; Then slowly drip 76mg(0.76mmol) tetrahydrofuran solution of Succinic anhydried, control and drip an approximately 1/2s of speed, in 30min, dropwise; Stirring at room temperature, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merge organic phase, then washing successively, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time, anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses ethyl alcohol recrystallization, obtain 2-methoxyl group-3-benzyloxy-17 β-N-3 '-carboxyl propionamido--female steroid-1,3,5 (10)-triolefin 0.30g, yield 80.3%;
At 60 ℃, by 0.30g2-methoxyl group-3-benzyloxy-17 β-N-3 '-carboxyl propionamido--female steroid-1,3,5 (10)-triolefins are dissolved in 50ml ethanol, add 0.03g10% palladium-carbon catalyst, and react under the effect that is 50psi at hydrogen pressure, thin layer detects to complete reaction, suction filtration is removed palladium carbon, concentrating under reduced pressure solvent, through volume ratio meter ethyl acetate: sherwood oil=1:2 column chromatography obtains β-N-3 '-carboxyl propionamido--female steroid-1,2-methoxyl group-17,3,5 (10)-triolefins-3-alcohol 0.214g, yield 87.5%.
The preparation of D, III-12 compound, method is, at ambient temperature, by 1.2g(4.0mmol) N-carbobenzoxy-(Cbz)-L-Phe and 0.05g(0.4mmol) DMAP, N-hydroxy-succinamide 0.52g(4.5mmol) be dissolved in 20ml ethyl acetate, then add 0.86g(4.5mmol) condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), stir 12～18 hours, filter, filtrate is concentrated, sherwood oil recrystallization, obtain the about 1.48g of active ester, yield 93%;
By 1.16g(3.0mmol) 2-methoxyl group-3-benzyloxy-female steroid-1, 3, 5 (10)-triolefin-17 β-amine are dissolved in 20ml dichloromethane solution, add triethylamine 0.83ml(6mmol), after stirring at room temperature 20min, add the dichloromethane solution of above-mentioned active ester, continue to stir 6 hours, after reacting completely, filter, filtrate decompression is concentrated, obtain faint yellow oily matter, through column chromatography purifying, obtain 2-methoxyl group-3-benzyloxy-17 β-N-2 '-(N-carbobenzoxy-(Cbz)) amino-L-hydrocinnamamide base-female steroid-1, 3, 5 (10)-triolefin white solid 1.78g, yield is 88%,
At ambient temperature, by 1.7g(2.53mmol) 2-methoxyl group-3-benzyloxy-17 β-N-2 '-(N-carbobenzoxy-(Cbz)) amino-L-hydrocinnamamide base-female steroid-1, 3, 5 (10)-triolefins are dissolved in dehydrated alcohol, after dissolving, add mass content 10% palladium carbon (Pd/C) catalyzer of 0.8g, hydrogenation to pressure is 60Psi, react 4 hours, filter, filtrate decompression is concentrated, obtain pale solid, by re-crystallizing in ethyl acetate, obtain β-N-2 '-amino-L-hydrocinnamamide base-female steroid-1,2-methoxyl group-17, 3, 5 (10)-triolefins-3-alcohol white solid 1.02g, yield 90.3%.
E, the preparation of III-13 compound, method is, at ambient temperature, by 0.9g(3.6mmol) N-benzyloxy-oxo-L-valine and 1.16g(3.0mmol) 2-methoxyl group-3-benzyloxy-female steroid-1, 3, in the 70ml dichloromethane solution of 5(10)-triolefin-17 β-amine, add while stirring 0.93g(4.5mmol) condensing agent N, N ＇-dicyclohexylcarbodiimide, 0.01g(0.09mmol) DMAP, continue to stir 10 hours, after reacting completely, filter, filtrate decompression is concentrated, obtain faint yellow oily matter, through column chromatography purifying, obtain amino-3 '-methyl-L-amide-based small-female steroid-1 of 2-methoxyl group-3-benzyloxy-17 β-N-2 '-(N-carbobenzoxy-(Cbz)), 3, 5 (10)-triolefin white solid 1.7g, productive rate is 90.7%,
At ambient temperature, by 1.7g(2.53mmol) amino-3 '-methyl-L-amide-based small-female steroid-1 of 2-methoxyl group-3-benzyloxy-17 β-N-2 '-(N-carbobenzoxy-(Cbz)), 3, 5 (10)-triolefins are dissolved in dehydrated alcohol, after dissolving, add mass content 10% palladium carbon (Pd/C) catalyzer of 0.8g, hydrogenation to pressure is 60Psi, react 4 hours, filter, filtrate decompression is concentrated, obtain pale solid, by re-crystallizing in ethyl acetate, obtain β-N-2 '-amino-3,2-methoxyl group-17 '-methyl-L-amide-based small-female steroid-1, 3, 5 (10)-triolefins-3-alcohol white solid 1.04g, yield 92%.
F, the preparation of III-16 compound, method is, under the condition of room temperature, by 0.605g(3.2mmol) N-tert-butoxycarbonyl-β-alanine and 1.16g(3.0mmol) 2-methoxyl group-3-benzyloxy-female steroid-1, 3, 5(10)-triolefin-17 β-amine is dissolved in 75ml ethyl acetate, successively add while stirring 0.93g(4.5mmol) condensing agent 1, 3-dicyclohexylcarbodiimide and 0.010g(0.09mmol) catalyzer DMAP, stir 10 hours, after reacting completely, filter, filtrate decompression is concentrated, obtain faint yellow oily matter, through column chromatography purifying, obtain 2-methoxyl group-3-benzyloxy-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefin white solid 1.51g, yield is 89.3%,
Then by 1.51g(2.6mmol) 2-methoxyl group-3-benzyloxy-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefin white solids are dissolved in dehydrated alcohol, add mass content 10% palladium-carbon catalyst of 0.5g, hydrogenation to pressure is 60Psi, react 4 hours, filter, filtrate decompression is concentrated, obtain pale solid, with ethyl acetate-sherwood oil mixed solvent recrystallization, obtain 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins-3-alcohol white solid 1.19g, yield 94%,
By 1.0g(2.1mmol) 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins-3-alcohol white solid is dissolved in methylene dichloride, then slowly drip 1.31g(6.3mmol) methyl-phosphorous acid diisobutyl ester (DBMP), then add 15.46ml(10.5mmol) sulfamic acid chloride, at room temperature stirring reaction 20 hours of mixed solution, then respectively with ethyl acetate and distilled water extraction, organic phase saturated common salt water washing, dry, concentrated, then obtain 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1 through chromatographic column purifying, 3, 5 (10)-triolefins-3-sulfamate 1.04g, yield 90%,
Then by 1.04g(1.88mmol) 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins-3-sulfamate is dissolved in 10ml dichloromethane solution, drip 2ml85% phosphate aqueous solution, vigorous stirring reaction 8 hours under room temperature, mixture is with 25ml distilled water diluting and be cooled to 0 ℃, be extracted with ethyl acetate (3 × 30ml), organic layer dried over mgso, concentrated β-N-3 '-amino-propionamido--female steroid-1, white solid 2-methoxyl group-17 that obtains, 3, 5 (10)-triolefins-3-aminosulfonyl ester 0.75g, yield 88%.
G, the preparation of III-15 compound, method is, obtain 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1 according to the preparation method of III-16 compound, 3, 5 (10)-triolefins-3-alcohol (1.0g, 2.1mmol) be dissolved in 20ml N, in dinethylformamide solution, then add 1.2g(8.4mmol) Anhydrous potassium carbonate and 200 μ l(2.46mmol) bromopropylene, and add as required a small amount of Tetrabutyl amonium bromide in 50～60 ℃ of stirring reaction 8h, be chilled to room temperature, then pour in 50g frozen water solution, then be extracted with ethyl acetate, the organic layer merging washs with saturated aqueous common salt and distilled water respectively, use anhydrous Na
2sO
4dry, filter vacuum concentration, enriched material obtains product 2-methoxyl group-3-allyloxy-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1 through column chromatography for separation, 3,5 (10)-triolefin white solid 0.88g, yield 82%,
Then by 0.88g(1.7mmol) 2-methoxyl group-3-allyloxy-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins are dissolved in 10ml dichloromethane solution, drip 2ml85% phosphate aqueous solution, vigorous stirring reaction 8 hours under room temperature, mixture is with 25ml distilled water diluting and be cooled to 0 ℃, be extracted with ethyl acetate (3 × 30ml), organic layer dried over mgso, concentrated white solid 2-methoxyl group-3-allyloxy-17 β-N-3 '-aminopropan amide group-female steroid-1 that obtains, 3, 5 (10)-triolefin 0.60g, yield 85%.
Embodiment 4
The present invention is in concrete enforcement, and 2ME2 analogue is the compound of following general structure (IV):
Wherein, R
1for the one of hydrogen atom, benzyl, amino-sulfonyl, R
2can be the one of methyl, p-methylphenyl, beta-aminoethyl, p-aminophenyl;
The one that described logical formula IV compound is following structural compound:
Method according to I-3 compound and I-7 compound can be synthesized the compound that obtains I-1, I-2, I-4, I-5, I-6, I-8, no longer describes in detail.
Can synthesize and obtain II-1, II-2, II-3, II-5, II-6, II-7, II-8 compound according to the method for II-4 compound and II-9 compound, no longer describe in detail.
Method according to III-6 compound and III-8 compound can be synthesized the compound that obtains III-1, III-2, III-3, III-4, III-5, III-7, III-9, IV-1, IV-2, no longer describes in detail.
Can synthesize the compound that obtains III-10 according to the method for III-11 compound, no longer describe in detail.
Method according to III-12 compound and III-13 compound can be synthesized the compound that obtains III-14, no longer describes in detail.
Can synthesize the compound that obtains III-17, IV-3, IV-4 according to the method for III-16 compound, no longer describe in detail.
The compound that the present invention is synthetic, empirical tests and evaluation, the few nucleotide of its structural formula is according to seeing the following form, and instrument is the DPX-400 type NMR spectrometer with superconducting magnet of Bruker company.
Upper table provides 2ME2 analogue (totally 38 kinds); can be effective to prepare antitumor drug (preparation); but 38 kinds of embodiment that are only used to performance of the present invention is described and provide that provide; the protection domain being not intended to limit the invention, 2ME2 analogue prepared by the present invention is as follows to the antiproliferative activity evaluation experimental data of tumour cell:
(1) given the test agent and cancerous cell line
2ME2 analogue of the present invention (totally 38 kinds) and 2-ME are respectively with dimethyl sulfoxide (DMSO) (DMSO, Amresco0231ACS Grade) be mixed with the former medicine stock solution of 10mmol/L, 4 ℃ of preservations, face the used time with RPMI-1640(or DMEM) substratum (10%FBS, 1% mycillin) dilution.
Testing selected cancerous cell line is that SK-N-SH human neuroblastoma cells cell, esophageal carcinoma EC-9706 cell and EC-109 cell, MCF-7 Breast Cancer Cell, Human Prostate Cancer PC-3 Cell Line, SGC-7901 cell and MGC803 cell, SMMC-7721 liver cancer cells and HepG-2 cell, s and mouse melanin tumor cell are B16 cell.Wherein SK-N-SH, B16 cell are cultivated in DMEM substratum, and other cell is cultivated in RPMI1640 substratum.
(2) experimental technique
Restraining effect with 38 kinds of 2ME2 analogues of SRB staining detection to different carcinoma cell proliferation, filters out the good compound of inhibition.The cell in vegetative period of taking the logarithm, adjusting concentration is 2.5 × 10
4individual/ml, is inoculated in 96 well culture plates, every hole 200 μ l.5%CO
2, cultivate 24h in 37 ℃ of incubators of saturated humidity.Treat cell attachment, experimental group adds RPMI-1640 substratum (10%FBS, 1% mycillin) dilution 2-ME derivative to final concentration is 1 μ mol/L, group of solvents adds the substratum containing DMSO, blank group adds RPMI-1640 substratum (10%FBS, 1% mycillin), and zeroing group is acellular substratum, every hole final volume is 200 μ l, establishes 6 multiple holes for every group.5%CO
2, hatch after 72 hours for 37 ℃, it is 10% that every hole adds the 50%TCA200 μ l(final concentration of precooling) fixing, leave standstill 10min, place 1h for 4 ℃.Sucking-off pastille substratum, the ultrapure washing of 150 μ l 5 times for every hole, dries dry air.Every hole adds the SRB solution of 100 μ l, leaves standstill and places 15min, does not wash 5 times dry air with 1% acetic acid with protein bound SRB.In conjunction with the non-buffering of 150 μ l10mmol/L Tris alkali dissolution for SRB.Measure every hole OD value by full-automatic microplate reader at 515nm wavelength place, be calculated as follows inhibiting rate.The calculation formula of inhibiting rate: inhibiting rate=1-experimental group OD value/blank group OD value × 100%, wherein experimental group and the blank group of value being after deduction zeroing group, and utilize SPSS15.0 statistical software to calculate the half-inhibition concentration (IC of derivative to different tumor cell lines
50).
(3) experimental result
Experimental result is respectively in table 1, table 2, table 3, table 4
The IC of the serial I compound of table 1 to 6 kinds of cells
50value (μ mol/L)
The IC of table 2 series II compound to 5 kinds of cells
50value (μ mol/L)
The serial III of table 3 and the IC of serial IV compound to 5 kinds of cells
50value (μ mol/L)
From the preliminary pharmacologically active data in table 1, table 2, table 3, some 2ME analogues provided by the present invention show the value-added effect of antitumor cell of wide spectrum, such as chemical compounds I-1, I-3, I-5 pair HepG-2 cell, Hela cell, SGC-7901 cell, PC-3 cell, SK-N-SH cell and EC-9706 cell all demonstrate good restraining effect.Compound ii-3, II-6, II-7, II-8, II-9 pair EC-109 cell, B16 cell, PC-3 cell and SMMC-7721 cell have good antitumor cell increment effect, compound III-2, III-8, III-12, III-13, III-14, III-15, III-16, III-17, III-16, III-16, IV-2, IV-3, IV-4 pair PC-3 cell, SK-N-SH cell, EC-9706 cell, MCF-7 cell and SGC-7901 cell all have good inhibition tumor cell increment effect, can be used for the exploitation of anti-tumor medicinal preparation, there is actual using value, it is the innovation on treatment cancer drug.
Claims (10)
1. a 2ME2 analogue, is characterized in that, its general structure is:
Wherein, X is Sauerstoffatom, nitrogen-atoms or sulphur atom; Y is carbonyl or sulfonyl;
R
1for hydrogen, containing the one of saturated or undersaturated alkyl, aromatic alkyl, fatty acyl group, aralkanoyl, heterocyclic acyl and the amino-sulfonyl of the replacement of 1～8 carbon atom, R
1it on substituting group, is the one of the alkyl that contains 1～4 carbon atom, alkoxyl group, halogen F, Cl, Br, I;
R
2for the one of saturated or unsaturated alkyl, aromatic base, aromatic alkyl, heterocyclic aryl and the heterocycle aralkyl of the replacement that contains 1～12 carbon atom, R
2the alkyl that contains 1～4 carbon atom on upper monosubstituted or polysubstituted substituting group or the one of alkoxyl group, or the one of F, Cl, Br and I, or the one of hydroxyl, carboxyl, amino and sulfydryl.
2. 2ME2 analogue according to claim 1, is characterized in that, the one for following general formula compound:
Wherein:
In logical formula I, R
1for the one of hydrogen atom, methyl, ethyl and benzyl; R
2for the one of methyl, ethyl, vinyl, propyl group, sec.-propyl, propenyl, allyl group, butyl, isobutyl-, the tertiary butyl, pentamethylene base, cyclohexyl, chloromethyl, chloroethyl, chloropropyl, methyl fluoride, fluoro ethyl, butyric acid base, butylene acidic group, hydroxy-propionic acid base, phenyl, benzyl, chloro-phenyl-, fluorophenyl, tetrafluoro phenyl, pyridyl and imidazolyl;
In logical formula II, R
1for the one of hydrogen atom, methyl, ethyl, benzyl, allyl group, ethanoyl, propionyl, butyryl radicals, chloracetyl, chlorine propionyl, chlorobutyryl, benzoyl, chlorobenzene formacyl, fluoro benzoyl and furancarbonyl;
In logical formula III, R
1for the one of hydrogen atom, methyl, ethyl, propyl group, allyl group, benzyl and amino-sulfonyl; R
2for the one of methyl, ethyl, vinyl, propyl group, sec.-propyl, propenyl, allyl group, butyl, isobutyl-, the tertiary butyl, pentamethylene base, cyclohexyl, chloromethyl, chloroethyl, chloropropyl, methyl fluoride, fluoro ethyl, butyric acid base, butylene acidic group, hydroxy-propionic acid base, phenyl, benzyl, chloro-phenyl-, fluorophenyl, tetrafluoro phenyl, pyridyl, imidazolyl and amino-acid residue;
In logical formula IV, R
1for the one of hydrogen atom, benzyl, amino-sulfonyl, R
2for the one of methyl, p-methylphenyl, beta-aminoethyl, p-aminophenyl.
3. 2ME2 analogue according to claim 2, is characterized in that, described logical formula I compound is the one in following:
Logical formula II compound is the one in following:
Logical formula III compound is the one in following:
Logical formula IV compound is the one in following:
4. the preparation method of 2ME2 analogue claimed in claim 1, is characterized in that, reaction formula is:
With 2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-ol or 17 β-amine are raw material (1), be dissolved in organic solvent, under Lewis alkali exists, carry out acylation reaction with raw material and obtain 2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-ester or 17 β-amide compound (2), then obtain compound (3) through catalytic hydrogenation reaction, finally obtain compound 2ME2 analogue (4) through acylation reaction or alkylation reaction again;
Described Lewis alkali is one or both of sodium carbonate, sodium-acetate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, hydrolith, sodium hydride, triethylamine, pyridine, DMAP, picoline;
Described organic solvent is N, one or both of dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetone, chloroform, trichloromethane, methylene dichloride, toluene, ethyl acetate, methyl alcohol, ethanol, Virahol, acetonitrile, sherwood oil, tetrahydrofuran (THF), dioxane, pyridine;
Described acylation reaction raw material is the one of acyl chlorides, acid anhydrides or carboxylic acid, wherein, acyl chlorides is to contain the saturated of 1～12 carbon atom or unsaturated hydrocarbons acyl chlorides, aroyl chloride, fragrant alkane acyl chlorides, fragrant alkene acyl chlorides, heterocycle aroyl chloride, heterocycle aralkyl acyl chlorides, heterocycle virtue alkene acyl chlorides, such as Acetyl Chloride 98Min., 3-propionyl chloride, parachlorobenzoyl chloride, 2,3, the one of 4,5-phenyl tetrafluoride formyl chloride and nicotinoyl chlorine; Acid anhydrides is the one of diacetyl oxide, propionic anhydride, butyryl oxide, MALEIC ANHYDRIDE, benzoyl oxide and Tetra hydro Phthalic anhydride; Carboxylic acid is butyric acid, butene dioic acid, hydroxy-propionic acid, amino acid whose one;
Its catalyzer of described catalytic hydrogenation reaction is the one of palladium carbon, skeleton nickel; Reaction solvent is one or both of methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), ethyl acetate, DMF; .
Described alkylation reaction raw material is the one of the saturated or unsaturated alkane of the halo that contains 1～8 carbon atom, halo naphthenic hydrocarbon, halogenated aryl hydrocarbon, halo aralkyl hydrocarbon, such as the one of methyl iodide, monobromethane, monobromethane, monochloroethane, N-PROPYLE BROMIDE, chloropropane, bromopropylene, propenyl chloride, bromocyclohexane, benzyl bromine, benzyl chlorine, or the one of methyl-sulfate, ethyl sulfate, methylcarbonate, diethyl carbonate; Catalyzer is the one of quaternary ammonium salt benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, and required Lewis alkali and reaction solvent are with above-mentioned acylation reaction.
5. the preparation method of 2ME2 analogue according to claim 4, it is characterized in that, under condition of ice bath, by 0.48g2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-ol are dissolved in 10ml methylene dichloride, are added dropwise to while stirring 0.417ml triethylamine; Slowly drip the dichloromethane solution containing 0.14ml chloroacetyl chloride, control and drip approximately 1/2s of speed, in 30min, dropwise; Under room temperature, continue to stir, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merge organic phase, then distilled water, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time successively, anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses appropriate recrystallizing methanol, obtain beta-hydroxy-female steroid-1, white needles 2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefins-chloracetate 0.52g, yield 92.98%;
Under 60 ℃ of conditions, by beta-hydroxy-female steroid-1,2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefin-chloracetates are dissolved in 50ml ethanol, and adding 0.03g mass content is 10% palladium-carbon catalyst, and maintaining hydrogen pressure is 50psi, thin layer detects to complete reaction, suction filtration is removed palladium carbon, and concentrating under reduced pressure solvent is separated out white powder 2-methoxyl group-3 through recrystallizing methanol, 17 beta-dihydroxyies-female steroid-1,3,5 (10)-triolefins-17-chloracetate 0.38g, yield 90%.
6. the preparation method of 2ME2 analogue according to claim 4, it is characterized in that, under ice bath, anhydrous formic acid 169.8 μ l are dropwise joined in Sulfuryl chloride isocyanate 391.8 μ l to rapid stirring, after 15 minutes, add acetonitrile 6ml, stirring at room temperature 7 hours toward system; Then under condition of ice bath, slowly add 2-methoxyl group-3-benzyloxy-female steroid-1 of containing 1.50g, the N,N-dimethylacetamide solution 8ml of 3,5 (10)-triolefin-17 β-ol, continues stirring reaction two hours; Then add distilled water 20ml, be extracted with ethyl acetate three times, organic phase adds anhydrous sodium sulfate drying to spend the night, suction filtration, solvent evaporated, cross post with column chromatography silica gel, moving phase is ethyl acetate: sherwood oil=1:3, obtains beta-hydroxy-female steroid-1, white powder solid 2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefins-17-sulfamate 1.56g, productive rate 87%;
With 50ml ethanol, by beta-hydroxy-female steroid-1,2-methoxyl group-3-benzyloxy-17,3,5 (10)-triolefins-17-sulfamate 1.00g dissolves, be placed in steel cylinder, adding mass content is 10% palladium carbon 50mg, stirs, 60 ℃ of oil baths are reacted under 50-60psi hydrogen pressure; After 4 hours, making thin-layer chromatography by volume ratio meter Er Lv Jia Wan ︰ acetone=15 ︰ 1 detects, after reacting completely, by 200-300 object post filtered through silica gel for mixture, concentrated white powder 2-methoxyl group-3,17 beta-dihydroxyies-female steroid-1,3 of obtaining of filtrate, 5 (10)-triolefins-17-sulfamate 0.72g, yield 90%;
Under condition of ice bath, by 120mg2-methoxyl group-3,17 beta-dihydroxyies-female steroid-1,3,5 (10)-triolefins-17-sulfamate is dissolved in methylene dichloride, is added dropwise to while stirring 65 μ l triethylamines, get 50 μ l n-butyryl chlorides, with after the dilution of 5ml methylene dichloride, add in constant pressure funnel, control and drip approximately 1/2s of speed, in 30min, dropwise, reaction system is placed under room temperature, continue to stir 2h, then use respectively distilled water, 10% sodium hydrogen carbonate solution, the each washing of saturated nacl aqueous solution 2 times, 10ml/ time, getting organic layer adds after anhydrous magnesium sulfate drying 4-5h, filter, revolve and steam except desolventizing, obtain transparent oily matter, through column chromatography, obtain beta-hydroxy-female steroid-1, compound 2-methoxyl group-3-butyryl acyloxy-17, 3, 5 (10)-triolefins-17-sulfamate 116mg, yield 82%.
7. the preparation method of 2ME2 analogue according to claim 4, it is characterized in that, under condition of ice bath, by 0.300g2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-amine are dissolved in 10ml ethyl acetate, are added dropwise to while stirring 0.10ml pyridine; Then slowly drip the ethyl acetate solution of 0.159ml n-butyryl chloride, control and drip approximately 1/2s of speed, in 30min, dropwise; Stirring at room temperature, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merge organic phase, then washing successively, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time, anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses recrystallizing methanol, obtain positive amide-based small-female steroid-1 of 2-methoxyl group-3-benzyloxy-17 β-N-, 3,5 (10)-triolefin 0.253g, yield 71.5%;
At 60 ℃, by positive amide-based small-female steroid-1 of 0.200g2-methoxyl group-3-benzyloxy-17 β-N-, 3,5 (10)-triolefins are dissolved in 50ml ethanol, add 0.02g10% palladium-carbon catalyst, and react under the effect that is 50psi at hydrogen pressure, thin layer detects to complete reaction, suction filtration is removed palladium carbon, concentrating under reduced pressure solvent, through volume ratio meter ethyl acetate: sherwood oil=1:2 column chromatography obtains positive amide-based small-female steroid-1 of β-N-, 2-methoxyl group-17,3,5 (10)-triolefins-3-alcohol 0.138g, yield 85.7%.
8. the preparation method of 2ME2 analogue according to claim 4, it is characterized in that, under condition of ice bath, by 0.300g2-methoxyl group-3-benzyloxy-female steroid-1,3,5 (10)-triolefin-17 β-amine are dissolved in 10ml tetrahydrofuran (THF), are added dropwise to while stirring 0.10ml4-Dimethylamino pyridine; Then slowly drip the tetrahydrofuran solution of 76mg Succinic anhydried, control and drip approximately 1/2s of speed, in 30min, dropwise; Stirring at room temperature, thin layer detects to complete reaction, in reaction solution, adds suitable quantity of water, and with dichloromethane extraction 3 times, merge organic phase, then washing successively, saturated sodium bicarbonate, saturated aqueous common salt are respectively washed 1 time, anhydrous sodium sulfate drying, suction filtration, filtrate decompression is concentrated, then uses ethyl alcohol recrystallization, obtain 2-methoxyl group-3-benzyloxy-17 β-N-3 '-carboxyl propionamido--female steroid-1,3,5 (10)-triolefin 0.30g, yield 80.3%;
At 60 ℃, by 0.30g2-methoxyl group-3-benzyloxy-17 β-N-3 '-carboxyl propionamido--female steroid-1,3,5 (10)-triolefins are dissolved in 50ml ethanol, add 0.03g10% palladium-carbon catalyst, and react under the effect that is 50psi at hydrogen pressure, thin layer detects to complete reaction, suction filtration is removed palladium carbon, concentrating under reduced pressure solvent, through volume ratio meter ethyl acetate: sherwood oil=1:2 column chromatography obtains β-N-3 '-carboxyl propionamido--female steroid-1,2-methoxyl group-17,3,5 (10)-triolefins-3-alcohol 0.214g, yield 87.5%.
9. the preparation method of 2ME2 analogue according to claim 4, it is characterized in that, under the condition of room temperature, by the N-tert-butoxycarbonyl-β-alanine of 0.605g and 1.16g2-methoxyl group-3-benzyloxy-female steroid-1, 3, 5(10)-triolefin-17 β-amine is dissolved in 75ml ethyl acetate, successively add while stirring 0.93g condensing agent 1, 3-dicyclohexylcarbodiimide and 0.010g catalyzer DMAP, stir 10 hours, after reacting completely, filter, filtrate decompression is concentrated, obtain faint yellow oily matter, through column chromatography purifying, obtain 2-methoxyl group-3-benzyloxy-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefin white solid 1.51g, yield is 89.3%,
Then by 1.51g2-methoxyl group-3-benzyloxy-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefin white solids are dissolved in dehydrated alcohol, add mass content 10% palladium-carbon catalyst of 0.5g, hydrogenation to pressure is 60Psi, react 4 hours, filter, filtrate decompression is concentrated, obtain pale solid, with ethyl acetate-sherwood oil mixed solvent recrystallization, obtain 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins-3-alcohol white solid 1.19g, yield 94%,
By 1.0g2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins-3-alcohol white solid is dissolved in methylene dichloride, then slowly drip 1.31g methyl-phosphorous acid diisobutyl ester, then add 15.46ml sulfamic acid chloride, at room temperature stirring reaction 20 hours of mixed solution, then respectively with ethyl acetate and distilled water extraction, organic phase saturated common salt water washing, dry, concentrated, then obtain 2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1 through chromatographic column purifying, 3, 5 (10)-triolefins-3-sulfamate 1.04g, yield 90%,
Then by 1.04g2-methoxyl group-17 β-N-3 '-(N-tertbutyloxycarbonyl) amino-propionamido--female steroid-1, 3, 5 (10)-triolefins-3-sulfamate is dissolved in 10ml dichloromethane solution, drip 2ml85% phosphate aqueous solution, vigorous stirring reaction 8 hours under room temperature, mixture is with 25ml distilled water diluting and be cooled to 0 ℃, be extracted with ethyl acetate 3 times, each consumption 30ml, organic layer dried over mgso, concentrated β-N-3 '-amino-propionamido--female steroid-1, white solid 2-methoxyl group-17 that obtains, 3, 5 (10)-triolefins-3-aminosulfonyl ester 0.75g, yield 88%.
10. the 2ME2 analogue described in claim 1 or 2-4 is in the application of preparing in antitumor drug.
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