CN1096297A - The method of synthetic camptothecine and Mai Pi star and their analogue and allied compound - Google Patents
The method of synthetic camptothecine and Mai Pi star and their analogue and allied compound Download PDFInfo
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- CN1096297A CN1096297A CN93119287A CN93119287A CN1096297A CN 1096297 A CN1096297 A CN 1096297A CN 93119287 A CN93119287 A CN 93119287A CN 93119287 A CN93119287 A CN 93119287A CN 1096297 A CN1096297 A CN 1096297A
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- Prior art keywords
- quinoline
- indolizino
- ketone
- ester
- group
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 89
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 79
- 150000001875 compounds Chemical class 0.000 title claims abstract description 71
- QHTFEANXLNNBOX-UHFFFAOYSA-N 8-methyl-7-propanoyl-11h-indolizino[1,2-b]quinolin-9-one Chemical compound C1=CC=C2C=C(CN3C4=CC(=C(C3=O)C)C(=O)CC)C4=NC2=C1 QHTFEANXLNNBOX-UHFFFAOYSA-N 0.000 claims abstract description 26
- WAZSVCKLDOMJJX-UHFFFAOYSA-N 2h-pyrrolo[3,4-b]quinoline Chemical compound C1=CC=CC2=CC3=CNC=C3N=C21 WAZSVCKLDOMJJX-UHFFFAOYSA-N 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 52
- -1 cyclic lactone Chemical class 0.000 claims description 43
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 239000003153 chemical reaction reagent Substances 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 20
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 20
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 19
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
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- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 14
- 238000007115 1,4-cycloaddition reaction Methods 0.000 claims description 13
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 13
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 12
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- KLFJSYOEEYWQMR-NRFANRHFSA-N 10-methoxycamptothecin Chemical compound C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-NRFANRHFSA-N 0.000 claims description 10
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- 125000000524 functional group Chemical group 0.000 claims description 8
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- BJAARRARQJZURR-UHFFFAOYSA-N trimethylazanium;hydroxide Chemical compound O.CN(C)C BJAARRARQJZURR-UHFFFAOYSA-N 0.000 claims description 8
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 7
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- 230000018044 dehydration Effects 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- VDDXQSUSMHZCLS-UHFFFAOYSA-N ethenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC=C VDDXQSUSMHZCLS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 150000003949 imides Chemical class 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- MWFNDFNHIBULHZ-UHFFFAOYSA-N oxoaluminum;hydrochloride Chemical compound Cl.[Al]=O MWFNDFNHIBULHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 5
- IEEHKTFVUIVORU-UHFFFAOYSA-N 2-methylpropanedioyl dichloride Chemical compound ClC(=O)C(C)C(Cl)=O IEEHKTFVUIVORU-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
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- 239000001257 hydrogen Substances 0.000 claims description 4
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- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 claims description 4
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- 150000003509 tertiary alcohols Chemical class 0.000 claims description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 3
- 238000005852 acetolysis reaction Methods 0.000 claims description 3
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- 238000005804 alkylation reaction Methods 0.000 claims description 3
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- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
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- DAOUVKSHEHYOEW-UHFFFAOYSA-N C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.S(O)(O)(=O)=O Chemical compound C(C=1C(C(=O)OCCCCCCCC)=CC=CC1)(=O)OCCCCCCCC.S(O)(O)(=O)=O DAOUVKSHEHYOEW-UHFFFAOYSA-N 0.000 claims 1
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- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000295 fuel oil Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000003808 methanol extraction Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- HWLDNSXPUQTBOD-UHFFFAOYSA-N platinum-iridium alloy Chemical compound [Ir].[Pt] HWLDNSXPUQTBOD-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000010916 retrosynthetic analysis Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of method that is prepared as follows compound, these compounds are some pyrrolo-[3,4-b] quinoline, some 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14 (4H, 12H)-diketone, particularly camptothecine and analogue and some 8-methyl-7-(oxopropyl)-indolizino [1,2-b] quinoline-9 (11H)-ketone, particularly Nothapodytine B and Mai Pi star.
Description
The present invention relates to prepare some pyrrolo-[3,4-b] quinoline, some 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H) particularly camptothecine and its analogue of diketone, with some 8-methyl-7-(oxopropyl)-indolizino [1,2-b] quinoline-9(11H)-ketone particularly Nothapodytine B (mappicineketones) and wheat skin star (mappicines).
Known some 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H) diketone pharmaceutically is being useful.The several important example of such compound is shown in formula I a-I e.With reference to these formulas, notice R
3Replace R in the 7-position
2Replace R in the 9-position
1Replace in the 10-position, or the like.Specify each ring to represent with word A-E.4-ethyl-4-hydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H) diketone is called camptothecine usually (following formula I a), known its some approaching same compounds of group suppresses the growth of external and intravital oncocyte.
Formula number (compound name)
I a(camptothecine): R
1=R
2=R
3=H
I b(Top safe willing (Topotecan)): R
1=OH, R
2=CH
2N(CH
3)
2,
R
3＝H
Her Reno of I c(safe willing (irinotecan/CPT-11)): R
1=OC(O)-and (the 4-piperidines is also)-piperidyl, R
2=H, R
3=C
2H
5
I d(9-amino camptothecin): R
1=H, R
2=NH
2, R
3=H
I e(10,11-methylene-dioxy camptothecine): Y, R
1=-OCH
2O-, R
2=R
3=H
Though this is cytotoxic in the level that it suppresses the knurl growth for known camptothecine,
It is effective going out very little or not having the solid shape knurl of the refractory that the camptothecin analogues antagonism of Cytotoxic some water soluble knows usually.For example, the people's such as Boehm that issue at 1991.4.2. U.S.P.5 opens in 004,758, usually be called that Top is safe to agree (formula I b), (S)-the 10-[(dimethylamino) methyl]-4-ethyl-4,9-dihydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H) diketone is useful especially in the various carcinous knurls of treatment.As the U.S. series number 07/658 of applying for by R.K.Johnson at 1991.2.21,948,07/658,936 and 07/658, in 937 and in the U.S. series number 07/804 of 1991.12.10 by the R.K.Johnson application, further disclosed in 570, such knurl comprises (but being not limited thereto) ovarian cancer, esophagus cancer, nonsmall-cell lung cancer and colorectal carcinoma.As further disclosed in the U.S. series number 07/793,041 of 1991.11.15 by R.K.Johnson application, Top is safe agree also to be used to prepare also contain iridium-platinum complex preferably suitable-pharmaceutical composition of the mixed chemical treatment of platinum.Showing that also be called safe (or CPT-11) (the formula I c) of agreeing of Yi Linuo usually, the 4-(piperidines of 7-ethyl-10-hydroxycamptothecine is also) piperidyl amino manthanoate analogue anti-some knurl is effective.These two kinds of compounds carry out the human clinical trial to refractory type knurl at present.In addition, shown the 9-amino and 10 of camptothecine, 11-methylene-dioxy analogue (formula I d) has anti-tumor activity in the test of preclinical phase.
Other change of some of camptothecin molecule has antiviral activity with regard to generation and presents very little or do not have the toxic compound of born of the same parents' poison.The example of such compound comprises that wherein the E cyclic lactone promptly is respectively the two big compounds that are commonly referred to as Nothapodytine B and Mai Pi star of formula II a and II b by some displaced derivative of other functional groups.These compounds that can be used for the infection of the humans and animals that treatment causes by various viruses (for example: herpes simplex virus 1 and 2 types, cytomegalovirus and varicella zoster virus) are disclosed in the U.S. series number 07/606 of 1990.10.31 by people such as S.Petteway application, 216,1991.10.25 is by the U.S. series number 07/783 of H.S.Alaudeen application, 063,1992.4.17 U.S. series number 07/870 by people such as D.Berges application, 649 and the U.S. series number 07/868,824 of 1992.4.14 by people such as D.Berges application in.
Recently, shown that also camptothecine has degeneration-resistant virus activity, the ability of duplicating that particularly has inhibition HIV (human immunodeficiency virus) (HIV-1) at the dosage that mammalian cell is not had born of the same parents' poison, therefore can be used for the treatment of and suffer from posteriori immunodeficiency syndromes (AIDS, see AIDS Res.Hum.Retr., 1991,7,65) patient.
The basis of the mode of action of these compounds is to suppress eucaryon shape cellular enzymes topoisomerase I and II, sees Cancer Res.1988,48,1722; Molec.Pharmacol.1988,34,755.The template of transcribing and duplicating as DNA for the raw information of utilizing it, some local feature of the DNA of cell must temporarily be changed, particularly, transcribe can carry out with reproduction process before, that the DNA volution that should super spiral must be carried out is loose/do not spiral, and its spirane structure does not twine thereafter.
The topoisomerase I is that a kind of molecular weight is about 100,000 monomeric enzyme.Make this enzyme be covalently bound on the DNA and introduce a cambic sub-thread and fracture, do not twine this duplex (or allowing it not twine), before separating, heavily seal this place that fractures then with the DNA line.A kind of like this evidence is arranged, and the promptly this mechanism of action is preferential important for duplicating of DNA in tumorigenic cell.People know that camptothecine is to bring into play its anti-tumor activity by topoisomerase I-DNA title complex of stablizing covalent bonding.As a result, the development of dna replication dna sequence only proceeds to the degree that sub-thread fractures of introducing.This DNA transcribes/and the net result of the inhibition of reproduction process is necrocytosis.Camptothecine and minority it approaching same compounds of group be only medicament in the clinical medicine exploitation that suppresses the topoisomerase I.
The topoisomerase II is to be made up of the subunit of two kinds of identical molecular weight 170,000.Two strands transitionality of topoisomerase II induce dna spiral fractures, and passes other bifilar fragment by this place of fractureing.Several commercially important oncolytic preparations (for example Zuyeyidal (etoposide), Zorubicin and mitoxantrone) are the inhibitor of topoisomerase II.Though camptothecine does not suppress the topoisomerase II, the derivative (being wheat skin star and Nothapodytine B) that known relevant wherein E cyclic lactone has been replaced by another functionality suppresses the topoisomerase II.Compound as these as possible anti-knurl with antiviral agent be significant.
Many methods of preparation camptothecine and its analogue are known.These comprise that several semisynthetic methods come camptothecine is changed into various relevant analogues, and for example Top is safe agree, and it is that camptothecine with natural generation is as raw material.For example, 1990.9.28 application and allow by authorization notification numbers 1992,6, the award a certificate U.S. series number 07/589 of book that 17 pay dues, disclose a kind of semisynthesis in 848 and prepared some 8-methyl-7-(oxopropyl from camptothecine or deutero-camptothecine) ketone of indolizino [1,2-b] quinoline-9(11H).1990.9.28 disclose a kind of semisynthetic method for preparing the camptothecin analogues of some water soluble from camptothecine in the U.S. series number 07/589,643 by people such as P.Burk application.At present, the only practical method that obtains that prepare and the camptothecine technical scale amount is the camplotheca acuminata of People's Republic of China's growth or at the tissue of the shrub Nothapodytes-foetida of India's growth by extraction.But, just as known in the art, some inherent shortcoming is arranged according to such natural resource, (about ＄ 28 000/kg) originates with lacking reliably to comprise very high expense of raw materials.
By different total synthetic methods, also prepare camptothecine from the material that is easy to get.Recently, at J.Am.Chem.Soc.1992,114, the cyclisation of 4+1 base is disclosed among the 5863-5864, the intermediate of wherein basic N-propargylization is formed B and C ring by intramolecular cyclization, and it is the camptothecine precursor in form.But, usually disclosed total synthetic 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone and the particularly route of camptothecine are two big retrosynthesis routes that the back is shown in Fig. 1.
Among the figure route A, with known method preparation three ring CDE ring systems, and by Friedl and neighbour-aminobenzaldehyde coupling.Like this, represent the route that crucial key disconnects with the dotted line of mark A.In route B,, and, form D ring pyridone with the standard method coupling of two steps respectively with known method preparation three ring ABC and dicyclo DE ring component.Represent the route that crucial key disconnects with the dotted line of mark B.Under many circumstances, three of route B ring ABC ring plate sections are mainly synthesized by the blue moral quinoline of the Fred that needs several steps and are prepared.Therefore, expense Rui Delande quinoline is synthetic is the element of a lot of currently known methodss.But so total synthetic value is limited, because they are subjected to the very influence of unfavorable factor: o-Aminobenzaldehyde is difficult to preparation, is easy to polymerization, and is prepared by commercial commercially available raw material for the A of camptothecine and B ring analogues and to need multistep synthetic.Therefore, much synthetic being difficult to of this class carries out, and the chemical yield of the required analogue that obtains is very low.Depend on that other routes of the commercial commercially available quinoline that multistep prepares meticulously also are subjected to the influence of similar unfavorable factor.
The invention provides a kind of synthetic pyrrolo-[3 of accomplishing of effectively being easy to, 4-b] quinoline, 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-total approach of diketone, the preferably method of camptothecin analogues.
First aspect, the invention provides a kind of method that is prepared as follows compound, pyrrolo-[3,4-b] quinoline, 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues, more preferably water-soluble camptothecin analogues, also more preferably Top is safe agree that (topotecan) and Yi Linuo are safe to agree (irinotecan), and most preferably Top is safe agree, and the N-virtue imidization thing (N-arylimidate) that said method comprises formula IV compound partly and the step of intramolecularly [4+2] cycloaddition of the non-activated acetylene moiety of described compound, the compound of formula IV is to be produced by the compound of formula III (Fig. 2 shown in following and the substituting group identical with the compound of formula IV arranged), and the compound of formula III is by general commercially available compound deriving.
Wherein: X=OH, OAlCl
2, Cl, Br, I, F, OR, OSO
2CF
3Or any good leavings group or H;
R
1=H, OH, or OR, wherein R is an ester protecting group;
R
2=H, NO
2, or protected amine functions base;
R
3=H, C
2H
5Or trialkylsilkl;
R
4=H, or CH
2COOEt;
R
5=COOMe or tosyl group; Or
R
4And R
5Connect together and form the pyridone II a of a replacement:
Y=H or Y, R
1=-OCH
2O-,
Wherein: A=H, COOR, or methylol (C-17) functional group partly in order to prepare the E cyclic lactone;
B=H, OH, the suitable leavings group as halogenide, or O(trifluoromethayl sulfonic acid ester) functional group of or the E cyclic lactone partial C of preparation camptothecine-(18-21).
Second aspect, the present invention also provides the method that is prepared as follows compound: 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone, 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues, more preferably water-soluble camptothecin analogues, also more preferably Top is safe agree agree with Yi Linuo is safe, most preferably Top is safe agree, said method comprises by 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-the vinyl trifluoromethayl sulfonic acid ester (vinyl triflate) that ketone obtains and the step of uncle's propanedioic acid negatively charged ion coupling, with preparation 7-(1,1-bis-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone.As what introduce in the application's other places, the 7-(1 of this generation, 1-is two-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone can be processed into very easily the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone or 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone.
The third aspect, the present invention also provides a kind of method that is prepared as follows compound: pyrrolo-[3,4-b] quinoline, 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues, more preferably water-soluble camptothecin analogues, also more preferably Top is safe agree agree with Yi Linuo is safe, and most preferably Top is safe agree, and said method comprises the steps:
(a) intramolecularly [4+2] cycloaddition of the N-aryl imidization thing (N-arylimidate) of formula IV compound part and the non-activated acetylene moiety of described compound obtains pyrrolo-[3, the 4-b] quinoline that is replaced by acetic ester at C-2;
(b) this 2-(acetic ester of cyclisation)-and pyrrolo-[3, the 4-b] quinoline that replaces, form 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(c) 7-hydroxyl-5, the 7-trifluoromethayl sulfonic acid ester derivative and the coupling of uncle's propanedioic acid negatively charged ion of 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone, be created on C-7 by (alkyl) diester malonate replace 5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(d) 7-(1,1-is two-alkoxy carbonyl) propyl group-5, the 1H-pyrans that 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone changes into propyl ester E ring also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues.
Fourth aspect, the present invention also provides a kind of camptothecin analogues that it lacks lactone E ring for preparing, preferred 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone, the method of wheat skin star and Nothapodytine B most preferably, described method comprises the steps:
(a) molecule [4+2] cycloaddition of the N-aryl imidization thing (N-arylimidate) of formula IV compound part and the non-activated acetylene moiety of described compound obtains pyrrolo-[3, the 4-b] quinoline that is replaced by acetic ester at C-2;
(b) pyrrolo-[3,4-b] the quinoline cyclisation of 2-replacement forms 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(c) 7-hydroxyl-5, the 7-trifluoromethayl sulfonic acid ester derivative and the coupling of uncle's propanedioic acid negatively charged ion of 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone, be formed on C-7 by (alkyl) diester malonate replace 5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(d) 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone change into lactone E ring the 1H-pyrrolo-[3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues;
(e) open the E ring of described camptothecin analogues with the carbonic acid gas that extrudes, according to the termination step of selecting, obtain lacking the camptothecin analogues of lactone E ring, preferred 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone, most preferably Nothapodytine B;
(f) reduce Nothapodytine B with hydride source such as sodium borohydride, obtain Mai Pixing.
The 5th aspect, the present invention is according to the termination step of selecting, and a kind of method of total synthetic following compound is provided: 4-ethyl-4-hydroxyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, more generally be called 10-Methoxycamptothecine, 4-ethyl-4,9-dihydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone, more generally be called 10-hydroxycamptothecine, and the 10-[(dimethylamino) methyl]-4-ethyl-4,9-dihydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone, more generally be called 10-hydroxycamptothecine, and the 10-[(dimethylamino) methyl]-4-ethyl-4,9-dihydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone, it is safe willing more generally to be called Top, and described method comprises the steps:
(a) in polar solvent as described below, in the following temperature, in the presence of following reagent, the compound of heating-type III (for example VII), obtain the pyrrolo-[3 that replaced by acetic ester at C-2,4-b] quinoline, the preferred methylene dichloride of described polar solvent, 1,2-ethylene dichloride, 1, the 2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone or N-Methyl pyrrolidone, most preferably acetonitrile; Described temperature is about 20 ℃-85 ℃, preferably about 60-85 ℃, most preferably at the reflux temperature of acetonitrile; The reagent of described existence is that strong alkylating agent maybe can transform acid amides and becomes its corresponding O-alkylimide ester or imide ester, the reagent of imido halogen (imidoyl halide) maybe can cause the strong acid (as aluminum chloride) of cyclodehydration, preferred Trifluoromethanesulfonic anhydride, methyl-sulfate, Tetrafluoroboric acid alkyl oxygen, aluminum chloride, 0-benzyl tribromo-acetyl imidization thing (O-benzyltrichloroacetimidate), triphenylphosphine (triphenylphosine)/tetracol phenixin, or triphenylphosphine (triphenylphosphine)/carbon tetrabromide, most preferably Tetrafluoroboric acid trimethylammonium oxygen;
(b) use the carbamate-functional of pyrrolo-[3, the 4-b] quinoline that the C-2 that generated by the saturated acetolysis step (a) of HBr replaces, obtain Tricyclic amine;
(c) described Tricyclic amine and monoalkyl malonyl chloride, preferred monomethyl malonyl chloride coupling obtains the half amide of diester malonate;
(d) in the presence of alkali, make described diester carry out the Michael Diekmann condensation, obtain the Fourth Ring enol;
(e) the vinyl trifluoromethayl sulfonic acid ester (vinyl triflate) of the described Fourth Ring of formation enol, and make described trifluoromethayl sulfonic acid ester and the coupling of uncle's propanedioic acid negatively charged ion, form (1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(f) remove 1,2 hydrogen at 5,6 keys, obtain 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-indolizino [1,2-b] quinoline-9(11H)-ketone;
(g) 8-methoxycarbonyl group reduction, then at C-7 two ester group hydrolysis decarboxylations, and lactone forms, obtain the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone;
(h) make tertiary alcohol α to the E cyclocarbonyl of described product, obtain 10-Methoxycamptothecine;
(i) methyl ether of described 10-Methoxycamptothecine splits, and obtains 10-hydroxycamptothecine; With
(j) by with N, N, N ', N '-tetramethyl-diamino methane (BDAM) reaction, the 9-position of the described 10-hydroxycamptothecine of alkylation obtains that Top is safe to agree.
Reach in whole this application herein, term " camptothecine " comprise camptothecine and according to the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-its derivative arbitrarily of the structure of diketone member ring systems.Term " pyrrolo-[3,4-b] quinoline ", " indolizino [1,2-b] quinoline-9(11H)-ketone " and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone generally means the compound based on these ring systems.Term " camptothecin analogues " comprises camptothecine as defined above, also comprises the derivative of the camptothecine that the ring of E has wherein been replaced by other functional groups.Term " ester protecting group " is defined as and comprises C
1-C
6Alkyl and allyl group.Benzyl, phenyl and β; β; β-three chloroethyl, term " amine protecting group " are defined as and comprise alkyl and aromatic yl sulphonate; common alkyl such as methyl, ethyl, β; β; the carbamate of β-three chloroethyl, allyl group, the tertiary butyl and phenyl, acid amides such as ethanamide and propionic acid amide, and common alkyl such as methyl and benzyl.Term " trialkylsilkl " is defined as and comprises trimethylammonium, triethyl, triisopropyl and tripropyl silyl and phenyl dimetylsilyl and t-butyldimethylsilyl.
The invention provides a kind of method that is prepared as follows compound: pyrrolo-[3,4-b] quinoline, 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues, more preferably water-soluble camptothecin analogues, also more preferably Top is safe agree agree with Yi Linuo is safe, most preferably Top is safe agree, and this method comprises by N-aryl imidization thing (N-arylimidate) part of the formula IV compound of the raw material generation of formula III and intramolecular [4+2] cycloaddition of the non-activated acetylene moiety of described compound.Fig. 2 illustrates an embodiment of the inventive method, the R of its Chinese style IV compound
4And R
5Do not connect
To the pyridone that forms formula IV a together.
Fig. 2
X, R
1-R
5Described with the definition of Y suc as formula IV
Fig. 3
Representational compound and intermediate that the explanation of table I is made by method of the present invention.
The isolating productive rate product of Substrate
The table I
With the starting material of formula III in following polar solvent, under following temperature, heating, the compound of production IV thus in the presence of following reagent, it carries out [4+2] cycloaddition then, obtain pyrrolo-[3,4-b] quinoline, the preferred methylene dichloride of described polar solvent, 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone or N-Methyl pyrrolidone, most preferably acetonitrile; Described temperature is about 20-85 ℃, preferred 60-85 ℃, most preferably at the reflux temperature of acetonitrile; Described reagent is strong alkylating agent or such reagent that can produce 0-alkylimide ester or imide ester, imido halogen (imidoyl halide), or such imide derivative that can cyclodehydration, preferred Trifluoromethanesulfonic anhydride, methyl-sulfate, Tetrafluoroboric acid alkyl oxygen, aluminum chloride, 0-benzyl tribromo-acetyl imines ester, triphenylphosphine (triphenylphosine)/tetracol phenixin or triphenylphosphine (triphenylphosphine)/carbon tetrabromide, most preferably Tetrafluoroboric acid trimethylammonium oxygen.The compound of formula IV does not separate, but detects.The product of method of the present invention itself can be medicinal, and for example Top is safe agree, or intermediate 10-Methoxycamptothecine for example, is used to be processed into medicinal compound, particularly camptothecin analogues.
The present invention also provides a kind of method for preparing following compound: 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone, 8-methyl-7-(oxygen propyl group) indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues, more preferably water-soluble camptothecin analogues, also more preferably Top is safe agree agree with Yi Linuo is safe, and most preferably Top is safe agree, described method, mean Fig. 3, comprise making 6-dihydro indolizino [1 by 7-hydroxyl-5,2-b] vinyl trifluoro sulphonate (vinyltriflate) and the coupling of uncle's propanedioic acid negatively charged ion that quinoline-9(11M)-ketone (V) obtains prepare 7-(1,1-is two-alkoxy carbonyl) and propyl group-8-methoxycarbonyl-5, the step of 6-dihydro indolizino [1,2-b] quinoline-9(11M)-ketone (VI).As what introduce at the application's elsewhere, the 7-(1 of this generation, 1-is two-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone can be processed into very easily the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone or 8-methyl-7-(oxopropyl) indolizino [1,2-b] quinoline-9(11H)-ketone.
In an embodiment preferred of the present invention, the explanation of its illustrative is shown in Fig. 4, and raw material (VII) has such structure (referring to the formula III among Fig. 2), wherein R
4=H or CH
2COOEt; R
5=COOMe, tosyl group, benzyl, COCH
3Or COCH
2CH
3; Y=M.This professional those of ordinary skill can be easy to geography and be situated between and arrive, this embodiment of the inventive method can be used for easily by selecting suitable raw material that substitutes and suitable termination step that various useful as intermediates (pyrrolo-[3 is provided, 4-b] quinoline, indolizino [1,2-b] quinoline-9(11H)-ketone and 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone) and product, preferred camptothecin analogues.This method comprises the steps:
(a) the formula IV is (among Fig. 2, shown in the formula IV) non-activated acetylene moiety intramolecularly [4+2] cycloaddition of N-aryl imidization thing (N-arylimidate) part and described compound of compound, obtain the pyrrolo-[3 that replaced by acetic ester at C-2,4-b] quinoline, (shown in Fig. 4 Chinese style VIII);
(b) pyrrolo-of Qu Daiing [3,4-b] quinoline cyclisation 2-(acetic ester) forms 7-hydroxyl-5, the XII in 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone (for example Fig. 7));
(c) 7-hydroxyl-5,6-dihydro indolizino [1,2-b] the 7-trifluoromethayl sulfonic acid ester derivative and the coupling of uncle's propanedioic acid negatively charged ion of quinoline-9(11H)-ketone, be formed on C-7 by 5 of (alkyl) diester malonate replacement, 6-dihydro indolizino [1,2-b] and quinoline-9(11H)-ketone (X III for example, Fig. 7);
(d) 7-(1,1-pair-alkoxy carbonyl) propyl group-5, the 1H-pyrans that 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone is converted into lactone E ring also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues (X VI for example, Fig. 7).
Fig. 4
Fig. 5
With reference to above-mentioned embodiment, can be easy to the compound of preparation formula IV with currently known methods, for example shown in the 1-3 step of Fig. 5 and following Fig. 7, as the example in example (step 1-3).In step (a), in following polar solvent, under following temperature, in the presence of following reagent, the acid amides raw material of formula IV reacts, thus the compound of production IV, it carries out [4+2] cycloaddition then, the pyrrolo-that obtains replacing [3,4-b] quinoline, described polar solvent such as methylene dichloride, 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone or N-Methyl pyrrolidone, but preferred acetonitrile; Described temperature is about 20-85 ℃, preferred 60-85 ℃, most preferably at the reflux temperature of acetonitrile; Described reagent is that strong alkylating agent maybe can transform acid amides and becomes its corresponding O-alkylimide ester or the reagent of imide ester or imido halogen (imidoyl halide), for example trifluoromethyl sulfonic acid anhydride, methyl-sulfate, Tetrafluoroboric acid alkyl oxygen, aluminum chloride, O-benzyl tribromo-acetyl imines ester, triphenylphosphine (triphenylphosine)/tetracol phenixin or triphenylphosphine (triphenylphosphine)/carbon tetrabromide, preferred Tetrafluoroboric acid trimethylammonium oxygen.The solvent of this selection, temperature range and alkylating agent are used for the disclosed all embodiments of the application.
In step (b), pyrrolo-[3, the 4-b] quinoline of the replacement that is obtained by step (a) is cyclized into 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-and ketone, as described below.The most handy carbamate functional that will protect this C-to encircle nitrogen by the saturated acetate of HBr is rolled into a ball hydrolytic cleavage, the Tricyclic amine that obtains forming.Then, this amine is at C-ring nitrogen and monoalkyl malonyl chloride, preferably monomethyl malonyl chloride coupling, the half amide of malonic acid that obtains generating.When at alkali, under the existence of particular methanol salt, when this half amide of malonic acid carries out the Michael Diekmann condensation, form the D ring, obtain 7-hydroxyl-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone.
When synthetic indolizino [1, the 2-b] quinoline of needs-9(11H)-ketone, 7-hydroxyl-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-the following further reaction of ketone.In step (c), 7-hydroxyl-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] the vinyl trifluoromethayl sulfonic acid ester (vinyltriflate) and the coupling of uncle's propanedioic acid negatively charged ion of quinoline-9(11H)-ketone, form 7-(1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone.In step (d), this diester cyclisation forms indolizino [1, the 2-b] quinoline that lactone E encircles, preferred camptothecin analogues.Especially, at Sodium Nitrite or other oxygenants as 2,3-two chloro-5; 6-dicyano-1,4-benzoquinones (DDQ) exist down, by oxidation; 1,2 of tertiary hydrogen α is cut on the quino-nitrogen, obtains similar indolizino [1; 2-b] quinoline-9(11H)-ketone; then become the methylol functional group at C-8 reduction methoxycarbonyl base, and hydrolysis/go carboxylation diester malonate, the 4-that obtains generating ethyl-1H-pyrans also [3 '; 4 ': 6; 7] indolizino [1,2-b] quinoline-3,14(4H; 12H)-diketone; by atmospheric oxidation, this 4-ethyl-1H-pyrans also [3 ', 4 ': 6; 7] indolizino [1; 2-b] quinoline-3,14(4H, 12H)-diketone can further react and form tertiary alcohol α to the E cyclocarbonyl; thus, obtain camptothecine.
Camptothecine can further be processed, and obtains various camptothecin analogues.For example, with HBr make 4-ethyl-4-hydroxyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and the methoxyl group of diketone (10-Methoxycamptothecine) splits, and produces 10-hydroxycamptothecine, and itself is just pharmaceutically acceptable.By with N, N, N ', N '-tetramethyl-diamino methane (BDAM) reaction, 10-hydroxycamptothecine can change into easily that Top is safe to agree.For example, by the U.S. series number 07/589 of nearest approval at us, the method of being introduced in 848, the camptothecine product of the inventive method can further transform into wherein the E hexamethylene by some displaced camptothecin analogues of other functional groups, for example wheat skin star and Nothapodytine B, 07/589,848 document discloses from camptothecine or deutero-camptothecine and has prepared some 8-methyl-7-(oxygen propyl group) semisynthesis of indolizino [1,2-b] quinoline-9(11H)-ketone.
In another embodiment preferred of the present invention, it is the explanation of retrosynthesis in Fig. 6, and raw material is R wherein
4And R
5The compound of the formula III of the pyridone that the formation that connects together replaces.
The total synthetic retrosynthetic analysis that carries out to camptothecine
Fig. 6
In another preferred embodiment, the invention provides a kind of method for preparing camptothecin analogues, this analogue lacks lactone E ring, preferred 8-methyl-7-(oxygen propyl group) indolizino [1,2-b] quinoline-9(11H)-ketone, most preferably (II a), said method comprises the steps: for wheat skin star (II b) and Nothapodytine B
(a) non-activated acetylene moiety intramolecularly [4+2] cycloaddition of the N-aryl imide moieties of the compound of formula IV and described compound obtains pyrrolo-[3, the 4-b] quinoline that is replaced by acetic ester at C-2;
(b) pyrrolo-[3, the 4-b] quinoline of this 2-replacement of cyclisation forms 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(c) 7-hydroxyl-5, the 7-trifluoromethayl sulfonic acid ester derivative and the coupling of uncle's propanedioic acid negatively charged ion of 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone, be formed on C-7 with (alkyl) diester malonate replace 5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(d) transform 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone be converted into lactone E ring the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone, preferred camptothecin analogues;
(e) according to selected termination step, the E that opens described camptothecin analogues with the carbonic acid gas that extrudes encircles, and obtains lacking the camptothecin analogues of lactone E ring, preferred 8-methyl-7-(oxygen propyl group) indolizino [1,2-b] quinoline-9(11H)-ketone, most preferably wheat skin star or Nothapodytine B.
Most preferably, according to the termination step of selecting, the invention provides a kind of method of total synthetic following compound, as shown in Figure 7, these compounds are: 4-ethyl-4-hydroxyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone, be called 10-Methoxycamptothecine more usually, 4-ethyl-4,9-dihydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone, more generally be called 10-hydroxycamptothecine, and the 10-[(dimethylamino) methyl]-4-ethyl-4,9-dihydroxyl-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-and diketone, it is safe willing more generally to be called Top, and said method comprises the steps:
(a) in following polar solvent, under following temperature, in the presence of following reagent, the compound of heating-type III (for example VII), the compound of production IV, this compound carry out [4+2] cycloaddition, obtain pyrrolo-[3, the 4-b] quinoline (VIII) that replaced by acetic ester at C-2; The preferred methylene dichloride of described polar solvent, 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone or N-Methyl pyrrolidone, most preferably acetonitrile; Described temperature is about 20-85 ℃, preferably about 60-85 ℃, most preferably at the reflux temperature of about acetonitrile; Described reagent is that strong alkylating agent or those can transform acid amides and become its corresponding O-alkylimide ester or imide ester, the reagent of imido halogen (imidoyl halide), perhaps can cause the strong acid (as aluminum chloride) of ring dehydration, Trifluoromethanesulfonic anhydride preferably, methyl-sulfate, the Tetrafluoroboric acid alkyl, aluminum chloride, O-benzyl tribromo-acetyl imidization thing (O-benzyltrichloroacelimidate), triphenylphosphine (triphenylphosine)/tetracol phenixin or triphenylphosphine (triphenylphosphine)/carbon tetrabromide, most preferably Tetrafluoroboric acid trimethylammonium oxygen;
(b) use the carbamate functional group of pyrrolo-[3, the 4-b] quinoline that the C-2 that obtained by (a) step by the saturated acetolysis of HBr replaces, obtain Tricyclic amine (X);
(c) said Tricyclic amine and monoalkyl malonyl chloride, preferred monomethyl malonyl chloride coupling obtains half-acid amides (XI) of diester malonate;
(d) in the presence of a kind of alkoxide, said malonic ester half-acid amides is carried out the Michael Diekmann condensation, obtains Fourth Ring enol (XII);
(e) the vinyl trifluoromethayl sulfonic acid ester (vinyl triflate) of the said Fourth Ring of formation enol, and with said trifluoromethayl sulfonic acid ester and the coupling of uncle's propanedioic acid negatively charged ion, form 7-(1, the 1-tert-butoxycarbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone (X III);
(f) at 7-(1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone 5, the 6-key is removed 1,2 hydrogen, obtains 7-(1, the 1-tert-butoxycarbonyl) propyl group-8-methoxycarbonyl-indolizino [1,2-b] quinoline-9(11H)-ketone (X IV);
(g) 7-(1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-indolizino [1,2-b] the 8-methoxycarbonyl reduction of quinoline-9(11H)-ketone, then in C-7 two ester group hydrolysis-decarboxylation and form lactone, obtain 4-ethyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone (X V);
(h) form a tertiary alcohol α to said 4-ethyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-the E cyclocarbonyl of diketone on, obtain 10-Methoxycamptothecine (X VI);
(i) methyl esters of said 10-Methoxycamptothecine fracture obtains 10-hydroxycamptothecine (X VII); With
(j) by with N, N, N ', N '-tetramethyl-diamino methane (BDAM) reaction, 9 alkylations of said 10-hydroxycamptothecine obtain that Top is safe to agree (X VII).
As in Fig. 5 and Fig. 7, seeing, can be with known method from the raw material of the various feedstock production formula III (for example VIII) that are easy to obtain.
Fig. 7
Safe agree total synthetic of Top; 13 steps, total recovery 5-6%
Fig. 7 (continuing)
Provide the safe willing total synthetic most preferred method of the present invention of Top further to be illustrated in the following embodiments.
Embodiment
Among the synthetic embodiment below, temperature be degree centigrade (℃).Except as otherwise noted, all raw materials all obtain from commercial source.Need not further describe, can think that these professional those skilled in the art can use the present invention to its wideest scope according to the introduction of front.This given embodiment only is for the present invention is described, references of the claim that do not think to limit the scope of the invention in any manner, these requires as the contriver of back.
The following examples illustrate the safe most preferred method of total synthetic of agreeing of Top of the present invention.This method generally is shown in Fig. 7.Several numbers of the step of drawing among step in an embodiment and Fig. 7 are consistent.
Embodiment 1
Step 1
To the monomethyl ester (100g in methylene dichloride (3000ml), 95% purity, 0.66mol), P-anisidine (90g, 99% purity, 1.1 equivalents) and add dimethylaminopropyl ethyl carbodiimide (WSC in the suspension of the stirring of I-hydroxybenzotriazole (89g, 1 equivalent), 125g, 1 equivalent).At 20 ℃ the mixture that generates was stirred 16 hours.Add methylene chloride in addition (2000ml), and with mixture in succession with the aqueous hydrochloric acid of dilution (10%, 1500ml) and water (2 * 1500ml) wash.The evaporation organic layer obtains thick yellow-green colour solid, with development of 500ml diethyl ether and filtering separation, obtains the yellow powder (productive rate 89%) of 147g.mp144-145℃。
IR（KBr）3400-3200，1720，1699，1687，1672，1651，1638，1613，1556，1509，1240，1163，843，830cm
-1;
1H NMR(δ, CDCl
3): 1.30(t, J=7.1Hz, 3H, CH
2CH
3), 3.77(s, 3H, OCH
3), 4.25(q, J=7.1Hz, 2H, CH
2CH
3), 6.85(d, J=8.8Hz, 2H, aromatics), 6.91,7.07(AB, q, J=15.3Hz, 4H, alkene), 7.50(d, J=8.9Hz, 2H, aromatics), 7.84(br, 1H, NH);
1H NMR(δ, MeOD): 1.23(t, J=7.0Hz, 3H, CH
2CH
3), 3.69(s, 3H, OCH
3), 4.16(q, J=7.1Hz, 2H, CH
2CH
3), 6.71,7.08(AB, q, J=15.3Hz, 4H, alkene), 6.81(d, J=9.1Hz, 2H, aromatics) and, 7.47(d, J=9.1Hz, 2H, aromatics); MS m/z250(MH
+), 204,176,127.
Step 2
Will the fumaric acid list p-methoxyphenyl acid amides mono ethyl ester in the trimethyl carbinol (700ml) (50g, 0.2mol) and the mixture of propargyl amine (40ml, 3 equivalents) under 100 ℃ of backflows, stirred 24 hours.Reaction mixture is cooled to 20 ℃, and on rotatory evaporator, removes and desolvate, ethyl acetate (1500ml) is added in the remaining sticking oil, with the hydrochloric acid (solution that 10%, 3 * 500ml) washing generates.To make the alkalescence that contains water be about 8 to PH by adding the solid sodium bicarbonate at leisure then.With the ethyl acetate (suspension that 3 * 500ml) extractions generate.With organic layer water (300ml) washing that merges, and dry, and evaporation obtains black semisolid, and it is used hexane: ethyl acetate (1: 1) is handled and is filtered.Use the rotatory evaporator concentrated filtrate, obtain brown oil, it slowly forms solid.With t-butyl methyl ether development, this solid can crystallization, obtains white crystal, mp66-67 ℃ (52.4g, yield 85.9%).
IR（KBr）3400-3200，2048，1734，1650，1605，1552，1514，1464，1272，1248，1178，1165，833cm
-1;
1H NMR(δ, CDCl
3): 1.23(t, J=7.1Hz, 3H, CH
2CH
3), 2.24(t, J=2.4Hz, 1H, alkynes), 2.81, (AB, q, J=16.6,7.3Hz, 1H, CH
2COO), 2.94(AB, q, J=16.6,4.2Hz, 1H, CH
2COO), 3.45,3.55(AB, d, d, J=17.0,2.4Hz, 2H, CH
2NH), 3.65(d, d, J=7.3,4.3Hz, 1H, OCCHNH), 3.76(s, 3H, OCH
3), 4.14(q, J=7.1Hz, 2H, CH
2CH
3), 6.84(d, J=8.9Hz, 2H, aromatics), 7.46(d, J=8.9Hz, 2H, aromatics), 9.13(br, 1H, NH);
MS m/z305（MH
+），259，217，182，154，123.
By hexane: what the ethyl acetate inceptive filtering obtained is N-propargyl aspartic acid N-p-methoxyphenyl acid amides as the by product pale solid, mp165-166 ℃.
1H NMR(δ, CDCl
3): 2.30(t, J=2.4Hz, 1H, alkynes), 2.69, (AB, q, J=17.9,5.3Hz, 1H, CH
2CO
2R), 3.09(AB, q, J=17.9,8.3Hz, 1H, CH
2CON), 3.46,3.70(AB, d, d, J=17.4,2.4Hz, 2H, CH
2NH), 3.80(s, 3H, OCH
3), 4.17(d, d, J=8.3,5.2Hz, 1H, OCCHNH), and 6.96(d, J=8.9Hz, 2H, aromatics), 7.18(d, J=8.9Hz, 2H, aromatics).
Step 3
Remain under 0 ℃ having the refrigerative internal temperature, to the raw material amine in methylene dichloride (150ml) (44.66g, 0.146mol) and drip pure methyl-chloroformate (14.9ml, 1.3 equivalents) in the solution of pyridine (15.1g, 1.3 equivalents).In 0 ℃ of mixture that stir to generate 30 minutes.Add methylene chloride (400ml) in addition in reaction mixture.With aqueous hydrochloric acid (10%, 2 * 150ml) and saturated nacl aqueous solution (2 * 150ml) wash this solution in succession.Remove organic solvent on rotatory evaporator, obtain brown oil, it makes elutriant by silica-gel plate (200g) with ether.Concentrated filtrate on rotatory evaporator obtains required product (41.46g), yield 78%, and it is as the product that obtains.With diethyl ether development, this product can recrystallization, reclaims approximately 95%, obtains white crystal, mp97-98 ℃.
IR（KBr）3300，2120，1725，1709，1687，1600，1512，1463，1247，1173，830cm
-1;
1H NMR(δ, CDCl
3): 1.25(t, J=7.1Hz, 3H, CH
2CH
3), 2.30(br, 1H, alkynes), 2.89,3.31(br, 2H, CH
2COO), 3.76(s, 3H, OCH
3), 4.06,4.22(AB, d, d, J=18,2.3Hz, 2H, CH
2NH), 4.56-4.98(br, 1H, OCCHNH), and 6.82(d, J=8.9Hz, 2H, aromatics), 7.36(d, J=8.9Hz, 2H, aromatics), 7.90-8.03(br, 1H, NH);
MS m/z363（MH
+），331，317，240，212，123.
Step 4
Under refluxing, will the carbamate in the acetonitrile (500ml) (27.7g, 0.077mol) and the mixture of Tetrafluoroboric acid trimethylammonium oxygen (40g, 3.5 equivalents) stirred 2.5 hours.Behind the cool to room temperature, under continuously stirring, add saturated nacl aqueous solution (200ml).Separate organic layer, contain water and extract with 3 * 300ml acetic ester.(3 * 300ml) and saturated nacl aqueous solution (100ml) washing, dry and evaporation obtains yellow semisolid to the organic phase that merges, and it uses recrystallizing methanol, obtains the 25.4g yellow solid, mp132-134 ℃ with saturated sodium bicarbonate solution.
IR（KBr）1728，1701，1623，1577，1504，1451，1228，1122，1029，825，769cm
-1;
1H NMR(δ, CDCl
3): 1.06,1.08(t, t, J=7.3Hz, 3H, CH
2CH
3), 3.80(br, 2H, CH
2COO), 3.78,3.80(s, s, 3H, OCH
3), 3.90(s, 3H, OCH
3), 4.78-4.95(m, 2H, CH
2NH), 5.29(d, J=14.1Hz, 1H, OCCHNH), and 7.05(s, 1H, aromatics), 7.31(d, d, J=9.2,2.8Hz, 1H, aromatics), 7.84,7.88(s, s, 1H, aromatics), 7.91(d, J=9.0Hz, 1H, aromatics);
MS m/z345（MH
+），317，299，285，271，257.
Step 5
In tricyclic compound (25.4g), add with the saturated acetic acid solution of Hydrogen bromide (129ml), in this mixture of stirring at room 24 hours.Remove on rotatory evaporator and desolvate, 300ml water is added in this resistates, mixture is with 2 * 200ml ethyl acetate extraction, and the eliminating organic extract.Contain water and be alkalescence to PH＞10 with solid sodium carbonate.The precipitated solid that filter to collect generates, (45 ℃/740mm) drying obtain the 8.98g product in stove.The water that contains that obtains after the filtration is further used 3 * 400ml dichloromethane extraction, and dry organic phase and evaporation obtain a kind of dirty oil, add ethyl acetate (100ml) in this dirty oil, with the dilute hydrochloric acid solution (mixture that 3%, 3 * 100ml) washing generates.Make aqueous phase alkalescence to PH＞8 by adding sodium bicarbonate, use dichloromethane extraction then, dry also evaporation, obtain the 2.25g product, it mixed with for the first time isolating solid the branch, obtain the yellow solid that total amount is 11.13g, mp83-86 ℃ (2 steps in the carbamate of cyclisation never, total recovery 51%).
IR（KBr）3350，1723，1622，1502，1236，1183，1026，893，842cm
-1;
1H NMR(δ, CDCl
3): 1.24(t, J=7.1Hz, 3H, CH
2CH
3), 2.63(d, d, J=16.5,9.8Hz, 1H, CH
2COO), 3.26(d, d, J=16.5,2.9Hz, 1H, CH
2COO), 3.89(s, 3H, OCH
3), 4.16(q, d, J=7.0,1.3Hz, 2H, CH
2CH
3), 4.36(s, 2H, CH
2NH), 4.84(d, d, J=9.8,2.8Hz, 1H, OCCHNH), and 7.03(d, J=2.7Hz, 1H, aromatics), 7.29(d, d, J=9.2,2.8Hz, 1H, aromatics), 7.82(s, 1H, aromatics) and, 7.91(d, J=9.2Hz, 1H, aromatics);
MS m/z287（MH
+），199.
Step 6
(6.98g adds pyridine (3.0g, eqoride(2.66ml, 95% purity, 1.3 equivalents) in solution 24.4mmol), drip purely then, and the speed of dropping will be to keep internal temperature at 0 ℃ to the Tricyclic amine in methylene dichloride (250ml).After adding, at 0 ℃ with this mixture restir 1 hour.Add methylene chloride (350ml), (10%, 2 * 100ml) washing is then with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing with hydrochloric acid for the solution of generation.Dry organic layer and evaporation obtain 10.4g heavy oil shape crude product, and it need not be purified and just be used for next step reaction.By from 1: 1 ethyl acetate: the sample that recrystallization obtains analyzing the hexane obtains white powder, mp114.5-116 ℃.
IR（KBr）1747，1737，1654，1621，1503，1441，1135，900，846cm
-1;
1H NMR(δ, CDCl
3): 1.08(t, J=7.3Hz, 3H, CH
2CH
3), 3.24(dd, J=17.2,3.3Hz, 1H, CH
2COO), 3.55,3.57(2 * s, 2H, COCH
2COO), 3.78(s, 3H, COCCH
3), 3.93(q, J=7.2Hz, 2H, CH
2CH
3), 3.93(s, 3H, OCH
3), 4.98,5.07(AB, d, J=13.6Hz, 2H, CH
2N), 5.47(t, J=3.8Hz, 1H, CHNH), and 7.07(d, J=2.7Hz, 1H, aromatics), 7.35(dd, J=9.2,2.8Hz, 1H, aromatics), 7.88(s, 1H, aromatics) and, 7.95(d, J=9.1Hz, 1H, aromatics)
MS m/z387（MH
+），355，313，299，285，239，199，101.
Step 7
In room temperature, at blended solvent (216ml, methyl alcohol: drip sodium methoxide solution (25% solution 7.4ml in methyl alcohol, 1.2 equivalents) in the solution of the raw material toluene=1: 5) (10.4g).In 20 ℃ of mixtures that stir to generate 1 hour.Add water (250ml) under stirring, separate each layer, the extraction of organic layer water.The water that contains that merges is acidified to PH＜2 with hydrochloric acid (10%).Filter the collecting precipitation thing, wash with water up to being designated as neutrality with the PH test paper.Vacuum (60 ℃/740mm) dry this white solid obtain the 5.73g product, mp219-220 ℃ (2 step yield 69%).
IR（KBr）3429，1673，1661，1643，1623，1567，1501，1450，1238，1227，1377，1046，1026，822cm
-1;
1H NMR(δ, CDCl
3): 2.86(d, d, J=17,13.6Hz, 1H, CH
2COO), 3.31(d, d, J=17,4.4Hz, 1H, CH
2COO), 3.92(s, 3H, OCH
3), 3.93(s, 3H, OCH
3), 4.75,5.13(AB, d, J=17Hz, 2H, CH
2NH), 5.14(d, d, J=13.5,4.5Hz, 1H, OCCHNH), 7.07(d, J=2.7Hz, 1H, aromatics), 7.36(d, d, J=9.2,2.8Hz, 1H, aromatics) and, 7.94(d, J=9.3Hz, 1H, aromatics), 7.97(s, 1H, aromatics) and 13.89(s, 1H, OH);
MS m/z 341（MH
+），337，323，309，283，265.
Step 8
(1g adds triethylamine (0.5ml, 1.2 equivalents) in suspension 2.9mmol) to the Fourth Ring enol in methylene dichloride (50ml).Bathe the brown solution of cooling generation to-78 ℃ with dry ice-propanone.Drip pure Trifluoromethanesulfonic anhydride (0.6ml, 1.2 equivalents), after adding, replace dry ice-propanone to bathe,, pour into then in the frozen water (100ml) 0 ℃ of stirred reaction mixture 1 hour in addition with ice bath.With this mixture of 3 * 100ml dichloromethane extraction.Organic phase water (100m) washing that merges, dry and evaporation obtains brown solid, and it is directly used in next step reaction.
1H NMR(δ, CDCl
3): 2.75,3.12(AB, d, d, J=15.9,13.8Hz, 1H, CH
2COO), 3.25,3.48(AB, d, d, J=17.3,5.3Hz, 1H, CH
2COO), 3.82,3.92(s, s, 3H, OCH
3), 3.95,3.96(s, s, 3H, OCH
3), 4.80,5.14(AB, d, J=17.8Hz, 2H, CH
2NH), 5.39(d, d, J=15.0,4.5Hz, 1H, OCCHNH), and 7.11(d, J=2.7Hz, 1H, aromatics), 7.42(d, d, d, J=9.4,2.9,2.9Hz, 1H, aromatics), 7.99(d, J=9.2Hz, 1H, aromatics), 8.03,8.04(s, s, 1H, aromatics).
To at THF(10ml) in the suspension of sodium hydride (132mg, 80% in mineral oil, 1.3 equivalents) in drip at THF(10ml) in the solution of di-t-butyl malonic ester (1.43g, 2 equivalents).In 20 ℃ of mixtures that stir to generate 15 minutes, this mixture became transparent solution, drips at THF(50ml in this solution) in above obtain the trifluoromethayl sulfonic acid ester.In 20 ℃ of sap green mixtures that stir to form 1 hour, and pour in the 150ml icy water that contains 2ml acetate.With this mixture of 3 * 150ml dichloromethane extraction, the organic layer that merges with dried over mgso also evaporates, obtain black semisolid, it is purified with flash chromatography (2: 1 hexanes: ethyl acetate is made elutriant), obtain needed product (680mg), yield 41% separates this product, it is flying upward a property brown crystal, mp88-91 ℃.
IR（KBr）1736，1665，1623，1504，1368，1130，1158，1231，1253，832，726cm
-1;
1H NMR(δ, CDCl
3): 1.03(t, J=7.3Hz, 3H, CH
2CH
3), 1.48,1.51(s, s, 9H, CCH
3), 2.05,2.19(q, d, J=14.2,7.3Hz, 2H, CH
2CH
3), 2.65(d, d, J=14.2,14.2Hz, 1H, CH
2COO), 3.21(d, d, J=16.4,4.1Hz, 1H, CH
2COO), 3.80(s, 3H, OCH
3), 3.92(s, 3H, OCH
3), 4.76,5.14(AB, d, J=16.4Hz, 2H, CH
2NH), 5.13(d, d, J=13.9,4.0Hz, 1H, OCCHNH), and 7.07(d, J=2.5Hz, 1H, aromatics), 7.33(d, d, J=9.2,2.6Hz, 1H, aromatics), 7.94(d, J=9.2Hz, 1H, aromatics) and, 7.95(s, 1H, aromatics);
MS m/z567（MH
+），511，479，467，411，379，323.
Step 9
At 65 ℃, with raw material (1.84g, 3.25mmol) and Sodium Nitrite (1.15g, 95% purity, 5 equivalents) at 10: 3 acetate of 39ml: the mixture in the water stirred 8 hours.The reaction mixture cool to room temperature is also poured in the 300ml ice-water.With 3 * 200ml dichloromethane extraction mixture dried over mgso organic layer.Concentrate organic layer in rotatory evaporator, obtain 1.8g yellow solid (98% crude product yield), its purity is enough to directly carry out next step reaction.From methylene dichloride: the sample that recrystallization obtains analyzing the hexane, mp198-200 ℃.
IR（KBr）1742，1730，1649，1623，1605，1510，1370，1254，844，834cm
-1;
1H NMR(δ, CDCl
3): 1.00(t, J=7.4Hz, 3H, CH
2CH
3), 1.50(s, 9H, CCH
3), 2.38(q, J=7.4Hz, 2H, CH
2CH
3), 3.89(s, 3H, OCH
3), 3.98(s, 3H, OCH
3), 5.27(s, 2H, CH
2NH), 7.15(d, J=2.7Hz, 1H, aromatics), 7.25(s, 1H, aromatics) and, 7.45(d, d, J=9.3,2.8Hz, 1H, aromatics), 8.09(d, J=9.4Hz, 1H, aromatics) and, 8.24(s, 1H, aromatics);
MS m/z565（MH
+），509，493，477，465，453，409，393，377，365，333.
Step 10
At 0 ℃, to the raw material in glycol dimethyl ether (50ml) (1.24g drips DIBAL(11ml in solution 2.2mmol), 1.0M in hexane, 5 equivalents).Color finally becomes dun from xanthochromia Cheng Lan.After adding, stirred the mixture 1 hour at 0 ℃, and pour in the frozen water (300ml).With 3 * 250ml dichloromethane extraction mixture.Dry organic layer and evaporation obtain the 1.18g yellow solid, add 3: 2 methyl alcohol of 50ml in this solid: hydrochloric acid.In the solution of this stirring, add sodium borohydride (200mg, 3 equivalents) with a spot of form, after adding the mixture that generates was stirred 15 minutes.Except that desolvating, in resistates, add dilute hydrochloric acid (50ml, 0.4% solution) with rotatory evaporator.With this mixture of 3 * 100ml dichloromethane extraction.Organic layer with dried over mgso merges concentrates, and obtains black solid, adds trifluoroacetic acid (20ml) in this solid.In this mixture of stirring at room 1 hour.Remove trifluoroacetic acid with rotatory evaporator, in resistates, add water 50ml.With this mixture of 3 * 100ml dichloromethane extraction, the organic layer with dried over mgso merges concentrates, and obtains 774mg crude product (yield 98%), and it can be directly used in next step reaction.From methylene dichloride: the sample that the hexane recrystallization obtains analyzing, mp259-261 ℃.
IR（KBr）1735，1657，1604，1506，1243，825cm
-1;
1H NMR(δ, CDCl
3): 1.09(t, J=7.4Hz, 3H, CH
2CH
3), 2.09(m, 2H, CH
2CH
3), 3.61(t, J=6.5Hz, 1H, CHCOO), 3.98(s, 3H, OCH
3), 5.27(s, 2H, CH
2NH), 5.39,5.56(AB, d, J=16.0Hz, 2H, CH
2COO), 7.13(s, 1H, aromatics), 7.16(d, J=2.7Hz, 1H, aromatics) and, 7.47(d, d, J=19.3,2.7Hz, 1H, aromatics), 8.10(d, J=9.3Hz, 1H, aromatics) and, 8.25(s, 1H, aromatics);
MS m/z363（MH
+），333，319.
Step 11
Under agitation, at 60ml N, the raw material in the dinethylformamide (665mg adds piperidines 3.2ml in solution 1.84mmol), and with bubble oxygen by this solution 6 hours.Remove DMF with rotatory evaporator, obtain the 680mg brown solid, mp278-280 ℃ (100%).As being shown by HPLC, the total area meets required product greater than 95% crude product, and proceeds like that by desired.
IR（KBr）3400，1738，1656，1600，1512，1267，1165，1156，1105，825cm
-1;
1H NMR(δ, CDCl
3): 1.05(t, J=7.1Hz, 3H, CH
2CH
3), 1.91(q, J=7.1Hz, 2H, CH
2CH
3), 3.70(s, 1H, OH), 3.99(s, 3H, OCH
3), 5.28(s, 2H, CH
2NH), 5.32,5.76(AB, d, J=15.8Hz, 2H, CH
2COO), 7.17(s, 1H, aromatics), 7.48(d, J=10.0Hz, 1H, aromatics) and, 7.62(s, 1H, aromatics), 8.13(d, J=9.3Hz, 1H, aromatics) and, 8.27(s, 1H, aromatics);
MS m/z379（MH
+），335，333.
Step 12
At 155 ℃, (60mg, 0.16mmol) with HBr(48% solution, mixture 3ml) refluxed 2 hours with raw material.The reaction mixture cool to room temperature, add water 50ml, use methylene dichloride: the methanol extraction mixture.With dried over mgso organic layer and concentrated, obtain crude product, it is purified with chloroform by silica gel chromatography, obtain required product (42mg, yield 72%), mp269-272 ℃, with spectrum and stratographic analysis, sample by semi-synthetic preparation is identical separately with camptothecine from natural generation for it.
1H NMR(δ, DMSO-d
6): 0.87(t, J=7.3Hz, 2H, CH
2CH
3), 1.85(hept, J=7.3Hz, 2H, CH
2CH
3), 5.22(s, 2H, CH
2N), 5.40(s, 2H, CH
2OCO), 7.25(s, 1H, aromatics), 7.28(s, 1H, aromatics) and, 7.41(d, J=9.1Hz, 1H, aromatics), 8.01(d, J=9.1Hz, 1H, aromatics) and, 8.45(s, 1H, aromatics);
Step 13
To 2: 1 methylene dichloride at 3ml: the raw material in the 1-propyl alcohol (20mg adds the 0.05ml(1.5 equivalent in solution 0.05mmol)) N, N, N ', N '-tetramethyl-diamino methane (BDAM) was in this mixture of stirring at room 16 hours.Add hydrochloric acid (1ml, 37% the aqueous solution in 5ml 1-propyl alcohol) at leisure, in room temperature restir mixture 5 hours.Solvent removed in vacuo obtains the brown semisolid of moisture absorption, and it is with anti-phase HPLC(acetonitrile: water: trifluoroacetic acid=16: 84: 15) purify, obtain racemize SK ﹠amp; F 104864, the yield that obtains from 10-hydroxycamptothecine about 88%.By confirming that with its NMR of representative sample comparison of required product and MaSS spectrum and stratographic characteristic product is identical.
1H NMR(δ, DMSO-d
6): 0.87(t, J=7.2Hz, 3H, CH
2CH
3), 1.86(hept, J=7.0Hz, 2H, CH
2CH
3), 2.84(s, 6H, NCH
3), 4.72[s, 2H, CH
2N(CH
3)
2], 5.28(s, 2H, CH
2N), 5.41(s, 2H, CH
2OCO), 6.50(s, 1H, OH), and 7.28(s, 1H, aromatics), 7.64(d, J=9.2Hz, 1H, aromatics), 8.18(d, J=9.2Hz, 1H, aromatics) and, 8.91(s, 1H, aromatics);
MS m/z422（MH
+），377，307，289，220，154，136，107，77.
13 steps total synthetic in the safe willing about 5-6% of total recovery of Top.
Claims (41)
1, a kind of preparation is selected from and is mainly pyrrolo-[3,4-b] quinoline, 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] and quinoline-3,14 (4H, 12H)-diketone and 8-methyl-7 (oxygen propyl group)-indolizino [1,2-b] method of compound of quinoline-9 (11H)-ketone, described method comprises the step of N-virtue imidization thing (N-arylimidate) part and intramolecularly [4+2] cycloaddition of the last activatory acetylene moiety of described compound of the compound of formula IV:
Wherein: X=OH, OAlCl
2, Cl, Br, I, F, OR, OSO
2CF
3Or any good leavings group or H;
R
1=H, OH, or OR, wherein R is an ester protecting group;
R
2=H, NO
2, or protected amine function group;
R
3=H, C
2H
5Or trialkylsilkl;
R
4=H, or CH
2COOEt;
R
5=COOMe or tosyl group; Or
R
4And R
5Connect together and form the pyridone IV a of a replacement:
Y=H or Y, R
1=-OCH
2O-,
Wherein: A=H, COOR, or the functional group of methylol (C-17) part of preparation E cyclic lactone;
B=H, OH, suitable leavings group is halogenide for example, or the functional group of the E cyclic lactone partial C-(18-21) of O (trifluoromethayl sulfonic acid ester) or preparation camptothecine.
2,1 method as requested, wherein said step also comprises the compound that heats described formula IV, the compound of formula III, the heating corresponding conditions be in polar solvent, under about 20-85 ℃ temperature, be selected from following reagent in the presence of, described reagent mainly is selected from strong alkylating agent, picture can produce or O-alkylimide ester or imide ester, and the reagent of imido halogen (imidoyl halide) and picture can encircle the imide derivative of dehydration.
3,2 method as requested, wherein said polar solvent is selected from methylene dichloride, 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone and N-Methyl pyrrolidone.
4, according to the method for claim 3, wherein said polar solvent is an acetonitrile.
5, according to the method for claim 2, wherein said temperature is about 60-85 ℃.
6, according to the method for claim 5, wherein said temperature is the reflux temperature of about acetonitrile.
7, according to the method for claim 2, wherein said strong alkylating agent or can produce or reagent or those imide derivatives that can encircle dehydration of O-alkylimide ester or imide ester, imines halogen (imidoyl halide) are selected from Trifluoromethanesulfonic anhydride, sulfuric acid dioctyl phthalate, Tetrafluoroboric acid alkyl oxygen, aluminum chloride, O-benzyl tribromo-acetyl imidization thing, triphenylphosphine (triphenylphosine), tetracol phenixin or triphenylphosphine (triphenylphosphine)/carbon tetrabromide as those.
8, according to the method for claim 7, wherein said reagent is Tetrafluoroboric acid trimethylammonium oxygen.
9, according to the process of claim 1 wherein said compound be the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone.
10, according to the method for claim 9, wherein said 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone is a camptothecin analogues.
11, according to the method for claim 10, wherein said camptothecin analogues be can be water-soluble camptothecin analogues.
12,, wherein saidly can water-soluble camptothecin analogues be selected from that Top is safe to agree and Yi Linuo is safe agree according to the method for claim 11.
13, according to the method for claim 12, wherein the camptothecin analogues of said water soluble is that Top is safe willing.
14, according to the process of claim 1 wherein that said compound is 8-methyl-7-(oxygen propyl group)-indolizino [1,2-b] quinoline-9(11H)-ketone.
15, according to the method for claim 14, wherein said 8-methyl-7-(oxygen propyl group)-indolizino [1,2-b] quinoline-9(11H)-ketone is Mai Pixing.
16, according to the method for claim 14, wherein said 8-methyl-7-(oxygen propyl group)-indolizino [1,2-b] quinoline-9(11H)-ketone is Nothapodytine B.
17, a kind of preparation 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] method of quinoline-9(11H)-ketone, said method comprises from 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone deutero-vinyl trifluoromethayl sulfonic acid ester (vinyltriglate) and the anionic coupling step of uncle's propanedioic acid.
18, a kind of preparation 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-method of diketone, said method comprises the steps:
(a) last activatory acetylene moiety intramolecularly [4+2] cycloaddition of the N-aryl imidization thing (N-arylimidate) of formula IV compound part and described compound forms the 2-(acetic ester) pyrrolo-[3, the 4-b] quinoline that replaces,
Wherein: X=OH, OAlCl
2, Cl, Br, I, F, OR, OSO
2CF
3Or any good leavings group or H;
R
1=H, OH, or OR, wherein R is an ester protecting group;
R
2=H, NO
2, or protected amine functions base;
R
3=H, C
2H
5Or trialkylsilkl;
R
4=H, or CH
2COOEt;
R
5=COOMe or tosyl group; Or
R
4And R
5Connect together and form the pyridone IV of a replacement:
Y=OH, OAlCl
2, Cl, Br, I, F, OR, OSO
2CF
3Any good leaving group because of or H
Wherein: A=H, COOR, or the functional group of methylol (C-17) part of preparation E cyclic lactone;
B=H, OH, suitable leavings group such as halogenide or O(trifluoromethayl sulfonic acid ester) functional group of or the E cyclic lactone partial C of preparation camptothecine-(18-21);
(b) pyrrolo-[3,4-b] the quinoline cyclisation of Qu Daiing said 2-(acetic ester) is formed on C-7 by 5 of (alkyl propanedioic acid) diester replacement, 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(c) said 7-hydroxyl-5,6-dihydro indolizino [1,2-b] the vinyl trifluoromethayl sulfonic acid ester (vinyl triflate) that replaces of the 7-of quinoline-9(11H)-ketone and the coupling of uncle's propanedioic acid negatively charged ion be formed on C-7 by (alkyl propanedioic acid) diester replace 5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone; With
(d) transform said 7-(1,1-is two-alkoxy carbonyl) propyl group-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone for lactone E ring-the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone.
19,18 method as requested, wherein said step (a) also comprises the compound of heating-type III, the compound of corresponding and said formula IV, said heating condition is in polar solvent, be about 20-85 ℃ in temperature, carry out being selected from the presence of the following reagent, said reagent is strong alkylating agent, those can production 0-alkylimide fat or imide fat, and the reagent of imido halogen (imidoyl halide) and those can encircle the inferior amide derivatives of dehydration.
20,19 method as requested, wherein said polar solvent is selected from methylene dichloride, and 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone and N-Methyl pyrrolidone.
21,20 method as requested, wherein said polar solvent is an acetonitrile.
22,19 method as requested, wherein said temperature is 60-85 ℃.
23,22 method as requested, wherein said temperature is the reflux temperature of about acetonitrile.
24,19 method as requested, wherein said strong alkylating agent or those can produce or reagent or those imide derivatives that can encircle dehydration of 0-alkylimide ester or imide ester, imido halogen (imidoyl halide) are selected from Trifluoromethanesulfonic anhydride.Methyl-sulfate, Tetrafluoroboric acid alkyl oxygen, aluminum chloride, 0-benzyl tribromo-acetyl imidization thing (O-benzyltrichloroacelimidate), triphenylphosphine (triphenylphosine)/tetracol phenixin or triphenylphosphine (triphenylphosphine)/carbon tetrabromide.
25,19 method as requested, wherein said reagent is Tetrafluoroboric acid trimethylammonium oxygen.
26,18 method as requested, wherein said compound is a camptothecin analogues.
27,26 method as requested, wherein said camptothecin analogues is the camptothecin analogues of water soluble.
28,27 method as requested, wherein the camptothecin analogues of said water soluble is selected from that Top is safe to agree and Yi Linuo is safe agree.
29,28 method as requested, wherein to be that Top is safe agree the camptothecin analogues of said water soluble.
30,1 method as requested, the R of wherein said formula IV compound
4And R
5Connect together and form the pyridone that replaces.
31, the safe method of agreeing of a kind of total synthetic Top, said method comprises the steps:
(a) in polar solvent, under about 20-85 ℃ temperature, in the presence of following reagent, compound by the heating-type III, corresponding to formula IV compound, make N-aryl imidization thing (N-arylimidate) part of formula IV and non-activated acetylene moiety intramolecularly [4+2] cycloaddition of described compound, be created on the pyrrolo-[3 that C-2 is replaced by acetic ester, 4-b] quinoline
Wherein: X=OH, OAlCl
2, Cl, Br, I, F, OR, OSO
2CF
3Or any good leavings group or H;
R
1＝OMe;
R
2＝H;
R
3＝H;
R
4＝CH
2COOEt;
R
5＝COOMe;
Y=H or Y, R
1=-OCH
2O-,
Said reagent is that strong alkylating agent or those can transform inferior acid amides and become its corresponding O-alkylimide ester or imide ester.The reagent of imido halogen (imidoyl halide) maybe can cause the strong acid (as aluminum chloride) that ring dewaters;
(b) use the carbamate functional group of pyrrolo-[3, the 4-b] quinoline that the C-2 that obtained by step (a) by the saturated acetolysis of HBr replaces, obtain Tricyclic amine;
(c) said Tricyclic amine and monoalkyl malonyl chloride, preferred monomethyl malonyl chloride coupling obtains the half amide of diester malonate;
(d) in the presence of a kind of alkoxide, make described malonic ester half amide carry out the Michael Diekmann condensation, obtain the Fourth Ring enol;
(e) vinyl trifluoromethayl sulfonic acid ester (vinyl tritlate) and the said trifluoromethayl sulfonic acid ester and the coupling of uncle's propanedioic acid negatively charged ion of the said Fourth Ring of formation enol, form 7-(1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(f) at 5,6 keys, 1 of hydrogen, the 2-cancellation obtains 7-(1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-indolizino [1,2-b] quinoline-9(11H)-ketone;
(g) 7-(1,1-two tert-butoxycarbonyls) propyl group-8-methoxycarbonyl-indolizino [1,2-b] the 8-methoxycarbonyl reduction of quinoline-9(11H)-ketone, then in C-7 two ester group hydrolysis-decarboxylations and form lactone, obtain 4-ethyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone;
(h) form tertiary alcohol α to described 4-ethyl-9-methoxyl group-1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone E cyclocarbonyl on, obtain 10-Methoxycamptothecine;
(i) methyl esters of said 10-Methoxycamptothecine splits, and obtains 10-hydroxycamptothecine;
(j) by with N, N, N ' N '-tetramethyl-diamino methane (BDAM) reaction, 9 alkylations of said 10-hydroxycamptothecine obtain that Top is safe to agree.
32,31 method as requested, wherein said polar solvent is selected from methylene dichloride, and 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, acetonitrile, acetone and N-Methyl pyrrolidone.
33,32 method as requested, wherein said polar solvent is an acetonitrile.
34,19 method as requested, wherein said temperature is 60-85 ℃.
35,34 method as requested, wherein said temperature is the reflux temperature of about acetonitrile.
36,31 method as requested, wherein said strong alkylating agent maybe can produce or O-alkylimide ester or imide ester, the reagent of imido halogen (imidoyl halide) or the imide derivative that picture can encircle dehydration are selected from Trifluoromethanesulfonic anhydride, methyl-sulfate, Tetrafluoroboric acid alkyl oxygen, aluminum chloride, the inferior amidate of O-benzyl three chloroethenes, triphenylphosphine (triphenylphoslne)/tetracol phenixin or triphenylphosphine (triphenylphosphine)/carbon tetrabromide.
37,32 method as requested, wherein said reagent is Tetrafluoroboric acid trimethylammonium oxygen.
38, a kind of preparation lacks the method for the camptothecin analogues of lactone E ring, and said method comprises the steps:
(a) intramolecularly [4+2] cycloaddition of the N-aryl imidization thing (N-arylimidate) of formula IV compound part and the non-activated acetylene moiety of described compound obtains pyrrolo-[3, the 4-b] quinoline that replaced by acetic ester at C-2,
Wherein: X=OH, OAlCl
2, Cl, Br, I, F, OR, OSO
2CF
3Or any good leavings group or H;
R
1=H, OH, or OR, wherein R is an ester protecting group;
R
2=H, NO
2, or protected amine function group;
R
3=H, C
2H
5Or trialkylsilkl;
R
4=H, or CH
2COOEt;
R
5=COOMe or tosyl group; Or
R
4And R
5Connect together and form the pyridone IV of a replacement:
Y=H or Y, R
1=-OCH
2O-;
Wherein: A=H, COOR, or the functional group of methylol (C-17) part of preparation E cyclic lactone;
B=H, OH, suitable leavings group such as halogenide or O(trifluoromethayl sulfonic acid ester) functional group of or the E cyclic lactone partial C of preparation camptothecine-(18-21);
(b) pyrrolo-[3, the 4-b] quinoline of cyclisation 2-replacement is formed on 7-hydroxyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(c) 7-hydroxyl-5, the 7-trifluoromethayl sulfonic acid ester derivative and the coupling of uncle's propanedioic acid negatively charged ion of 6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone, be formed on C-7 by (alkyl) diester malonate replace 5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone;
(d) transform 7-(1,1-pair-alkoxy carbonyl) propyl group-8-methoxycarbonyl-5,6-dihydro indolizino [1,2-b] quinoline-9(11H)-ketone become cyclic lactone E ring the 1H-pyrans also [3 ', 4 ': 6,7] indolizino [1,2-b] quinoline-3,14(4H, 12H)-diketone; Preferred camptothecin analogues; With
(e) according to selected termination step, the E that opens said camptothecin analogues with the carbonic acid gas of extruding encircles, and obtains lacking the camptothecin analogues of lactone E ring, preferred wheat skin star or Nothapodytine B.
39, according to the method for claim 38, the wherein said camptothecin analogues that lacks lactone E ring is 8-methyl-7-(oxygen propyl group)-indolizino [1,2-b] quinoline-9(11H)-ketone.
40, according to the method for claim 39, wherein said 8-methyl-7-(oxygen propyl group)-indolizino [1,2-b] quinoline-9(11H)-ketone is Mai Pixing.
41, according to the method for claim 39, wherein said 8-methyl-7-(oxygen propyl group)-indolizino [1,2-b] quinoline-9(11H)-ketone is Nothapodytine B.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94149692A | 1992-09-08 | 1992-09-08 | |
| US941,496 | 1992-09-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1096297A true CN1096297A (en) | 1994-12-14 |
Family
ID=25476581
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93119287A Pending CN1096297A (en) | 1992-09-08 | 1993-09-08 | The method of synthetic camptothecine and Mai Pi star and their analogue and allied compound |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0660835A4 (en) |
| JP (1) | JPH08501104A (en) |
| KR (1) | KR950702987A (en) |
| CN (1) | CN1096297A (en) |
| AU (2) | AU5102393A (en) |
| CA (1) | CA2144048A1 (en) |
| MX (1) | MX9305517A (en) |
| NZ (1) | NZ255942A (en) |
| TW (1) | TW246674B (en) |
| WO (1) | WO1994005672A1 (en) |
| ZA (1) | ZA936580B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105859716A (en) * | 2016-05-06 | 2016-08-17 | 华东师范大学 | Method for synthesizing 5-6 parallel-ring structure in camptothecin compounds |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6660861B1 (en) * | 2003-03-27 | 2003-12-09 | Council Of Scientific And Industrial Research | Process for preparing Topotecan from 10-hydroxy-4-(S) camptothecin |
| CN2757510Y (en) | 2004-12-06 | 2006-02-08 | 鸿富锦精密工业（深圳）有限公司 | Radiator buckle |
| US7520313B2 (en) | 2006-03-16 | 2009-04-21 | Fu Zhun Precision Industry (Shen Zhen) Co., Ltd. | Locking device for heat sink |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5626677B2 (en) * | 1973-03-26 | 1981-06-19 | ||
| JPS5217499A (en) * | 1975-07-31 | 1977-02-09 | Nippon Chemiphar Co Ltd | Preparation of mappicine |
| DE2534601C2 (en) * | 1975-08-02 | 1987-01-22 | Basf Ag, 6700 Ludwigshafen | Process for the preparation of camptothecin and camptothecin derivatives |
| CA1332413C (en) * | 1987-06-25 | 1994-10-11 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| JP2711728B2 (en) * | 1989-08-29 | 1998-02-10 | 株式会社ヤクルト本社 | Novel quinoline derivative and method for producing the same |
| US5155225A (en) * | 1990-09-28 | 1992-10-13 | Smithkline Beecham Corporation | Method for making certain pyrano[3',4':6,7]indolizino-[1,2-B]quinolinones |
-
1993
- 1993-09-07 ZA ZA936580A patent/ZA936580B/en unknown
- 1993-09-08 CN CN93119287A patent/CN1096297A/en active Pending
- 1993-09-08 EP EP93920496A patent/EP0660835A4/en not_active Withdrawn
- 1993-09-08 AU AU51023/93A patent/AU5102393A/en not_active Abandoned
- 1993-09-08 CA CA002144048A patent/CA2144048A1/en not_active Abandoned
- 1993-09-08 NZ NZ255942A patent/NZ255942A/en unknown
- 1993-09-08 WO PCT/US1993/008434 patent/WO1994005672A1/en not_active Application Discontinuation
- 1993-09-08 KR KR1019950700883A patent/KR950702987A/en not_active Application Discontinuation
- 1993-09-08 JP JP6507518A patent/JPH08501104A/en active Pending
- 1993-09-08 MX MX9305517A patent/MX9305517A/en unknown
- 1993-11-02 TW TW082109133A patent/TW246674B/zh active
-
1997
- 1997-07-11 AU AU28591/97A patent/AU2859197A/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105859716A (en) * | 2016-05-06 | 2016-08-17 | 华东师范大学 | Method for synthesizing 5-6 parallel-ring structure in camptothecin compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08501104A (en) | 1996-02-06 |
| MX9305517A (en) | 1994-05-31 |
| AU2859197A (en) | 1997-10-23 |
| CA2144048A1 (en) | 1994-03-17 |
| EP0660835A4 (en) | 1995-08-16 |
| WO1994005672A1 (en) | 1994-03-17 |
| ZA936580B (en) | 1994-08-01 |
| TW246674B (en) | 1995-05-01 |
| AU5102393A (en) | 1994-03-29 |
| KR950702987A (en) | 1995-08-23 |
| EP0660835A1 (en) | 1995-07-05 |
| NZ255942A (en) | 1996-11-26 |
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