CN100582106C - Pyrrolidine sulfsulopenem derivative preparation method and its intermediate - Google Patents
Pyrrolidine sulfsulopenem derivative preparation method and its intermediate Download PDFInfo
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- CN100582106C CN100582106C CN200610023731A CN200610023731A CN100582106C CN 100582106 C CN100582106 C CN 100582106C CN 200610023731 A CN200610023731 A CN 200610023731A CN 200610023731 A CN200610023731 A CN 200610023731A CN 100582106 C CN100582106 C CN 100582106C
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- 238000002360 preparation method Methods 0.000 title claims description 42
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- -1 pyrrolidyl Chemical group 0.000 claims abstract description 37
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 claims description 7
- 229960000895 doripenem Drugs 0.000 claims description 7
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 7
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 150000003018 phosphorus compounds Chemical class 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical group CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- QDHCHVWSKUMZDZ-UHFFFAOYSA-N ethyl dihydrogen phosphite Chemical compound CCOP(O)O QDHCHVWSKUMZDZ-UHFFFAOYSA-N 0.000 claims description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical group CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical group COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- WHAFDJWJDDPMDO-UHFFFAOYSA-N trimethyl(phenyl)phosphanium Chemical compound C[P+](C)(C)C1=CC=CC=C1 WHAFDJWJDDPMDO-UHFFFAOYSA-N 0.000 claims description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- 229940124530 sulfonamide Drugs 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 8
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 150000003456 sulfonamides Chemical class 0.000 abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- 239000002585 base Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000006751 Mitsunobu reaction Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229940041011 carbapenems Drugs 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- HLPKIQYKNZRIJR-UHFFFAOYSA-N chlorosulfonylformyl chloride Chemical compound ClC(=O)S(Cl)(=O)=O HLPKIQYKNZRIJR-UHFFFAOYSA-N 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000004993 haloalkoxycarbonyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The inveniton discloses a method for preparing pyrrolidyl sulfurcarbonpenems derivatives with the fifth position in side chain being mathane sulfonamide, which is the Mitsunobu condensation reaction between said derivatives and sulfonamide or its derivatives. The invention aslo provodes a method for preparing carbpenem antibiotics duolypenem based on it and a new intermediate compound. The inveniton is characterized by simplified prepartion process, non-need special and expensive reagent, reduced cost and suitability for industrial produciton.
Description
Technical field
The present invention relates to a kind of carbapenems (the big class of beta-lactam) antibiotic preparation method's, particularly a kind of pyrrolidine sulfsulopenem derivative the preparation method and the new midbody compound of generation thereof of wide spectrum.
Background technology
U.S. Pat 5317016 (Date ofPatent:1994.5.31), publication number are that the Chinese patent of CN1071428A has been reported the synthetic method of general formula compound (I).This method comprises the pyrrolidin derivatives condensation shown in carbapenem parent nucleus shown in the formula (III) and the formula (II), its Chinese style II compound need by
Formula IV compound just can obtain through the reactions steps in 4 steps at least, specifically also can be referring to publication number
The Chinese patent of CN1113233A (division of CN1071428A), so its entire reaction complex steps.
With Y. Iso, et al.J.Antibiotics, 1996,49 (2): the synthetic route of 199-209 (paper of delivering according to above-mentioned patent) report specifies as follows:
In order to introduce the sulphonamide amido 5 of side chains, at first make compound 1 ' (particular compound in the formula IV compound) successively with methylsulfonyl chloride, potassium phthalimide and hydrazine hydrate reaction, 5 of side chains introduce amino compound 4 '; React again with to methoxyl group benzyloxy base carbonyl sulphonamide chlorine,, get compound 5 ' (particular compound in the formula II compound) at the sulphonamide amine of 5 introducings of side chain to methoxyl group benzyloxy base carbonyl-protection; At last successively through silver nitrate aqueous solution and pyridine, hydrogen sulfide treatment slough trityl-protecting group obtain side chain 6 '.Side chain 6 ' again and beta-methyl carbon penicillenic parent nucleus 7 ' (particular compound in the formula III compound) condensation; behind aluminum chloride and phenylmethylether deprotection; through the macroporous adsorption resin chromatography purifying; last freeze-drying obtains product formula VII compound; be the particular compound among the general formula compound I---carbapenems (the big class of the beta-lactam) microbiotic doripenem (doripenem of wide spectrum; have another name called S-4661; chemical name: (4R; 5S; 6S)-3-[[(3S, 5S)-the 5-[[(sulphonamide) amino] methyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid).
In a word, there is remarkable defective in background technology: the entire reaction step is tediously long; Use special reagent and expensive reagent, as triphenyl sodium methyl mercaptide, potassium phthalimide, to methoxyl group benzyloxy base carbonyl SULPHURYL CHLORIDE, Silver Nitrate etc.; Polystep reaction needs column chromatography purification; The cost height is difficult to industrialized production.
Summary of the invention
The technical problem to be solved in the present invention promptly is to overcome above-mentioned defective of the prior art, purpose provides a kind of step and simplifies, need not special reagent and expensive reagent, cut off the multistep column chromatography purification, thereby be suitable for the preparation method of the pyrrolidine sulfsulopenem derivative of industrialized production.
Technical scheme of the present invention is: a kind of preparation method of formula I compound pyrrolidine sulfsulopenem derivative, and it carries out condensation reaction by formula V compound and formula VI compound; R wherein
1Be hydrogen or low alkyl group; R
2, R
3And R
4Be hydrogen independently, can substituted low alkyl group or amino protecting group, perhaps R
2And R
3Form saturated or undersaturated cyclic group, perhaps R with the nitrogen-atoms that they connected
2And R
4, or R
3And R
4Interconnection and form-CH
2-CH
2-or-CH
2-CH
2-CH
2-; Each ring-type
Group can comprise further that at least one is selected from the atom of oxygen, sulphur and nitrogen, and each cyclic group all can be substituted; X
1Be hydrogen or hydroxyl protecting group; X
2Be hydrogen, carboxyl-protecting group, ammonium, basic metal or alkaline-earth metal; Y
2Be hydrogen or amino protecting group.
Wherein, the carbonatoms of above-mentioned term " low alkyl group " is 1～6, preferred 1～4; The substituting group of " can substituted low alkyl group " comprises hydroxyl, alkoxyl group, amino, amide group, low-grade alkyl amino, formamyl, elementary alkyl amido methanoyl, carbamoyloxy, low-grade alkyl amino methanoyl and cyano group etc.; " hydroxyl protecting group " and " amino protecting group " comprises lower alkoxycarbonyl, lower alkanols alkenyloxycarbonyl, haloalkoxy carbonyl, aralkoxycarbonyl, trialkylsilanyl and diazo etc.; " carboxyl-protecting group " is selected from those that this area is familiar with, and its function is when carry out at other position that is reflected at molecule, carboxyl is sealed, such as C
1-5Alkyl, C
3-8Alkenyl, C
7-19Aralkyl etc.; As for " R
2And R
3Form saturated or undersaturated cyclic group with their connections and nitrogen-atoms ", " each cyclic group can comprise further that at least one is selected from the atom of oxygen, sulphur and nitrogen, and each cyclic group all can be substituted " in cyclic group can be saturated or undersaturated 3-8 unit residue; can further contain one or more nitrogen, sulphur and/or Sauerstoffatom if desired, and preferably include heteroatomic 5 or 6 yuan of monocycle residues; These define more specifically and example such as above-mentioned patent documentation disclosed.
According to the present invention, preferably, X
1It is the hydroxyl protecting group that is selected from TMS, tert.-butoxy dimethylsilyl, triethyl silyl and allyloxy carbonyl.
Preferably, X
2Be to be selected to nitrobenzyl, to the carboxyl-protecting group of methoxy-benzyl, diphenyl methyl, allyl group and the tertiary butyl.
And the said amino protecting group of the present invention is selected from tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl and diazo; Wherein, R
4The preferred tertiary butoxy carbonyl, Y
2Preferably to nitro benzyloxycarbonyl, tert-butoxycarbonyl or allyloxy carbonyl.
In preparation method of the present invention, R more preferably
1Be methyl, R
2And R
3Be hydrogen.
In fact, preparation method of the present invention makes formula V compound and formula VI compound carry out the Mitsunobu reaction.Wherein, formula V compound is to be the pyrrolidine sulfsulopenem derivative of methylol on 5 of the side chains, and its general formula and preparation method are disclosed by patent US 6180622 and US 4962103; And formula VI compound (sulphonamide amine and derivative thereof) and preparation method thereof is by document R.Graf.Chem Ber, 1963,96, and 56-67 and Y. Masui, et al.Tetrahedron Lett, 2004,45 (9): 1853-1856 is disclosed.The reference of relevant Mitsunobu reaction is referring to O.Mitsunobu, Synthesis 1981:1-28; D.L. Hughes, Org.React.1983,29:1-162.
Particularly, formula V compound and formula VI compound react in the presence of a kind of trivalent phosphorous compound and a kind of azoformic acid derivative; The preferred three valent phosphors organic compound of wherein said trivalent phosphorous compound can be trialkyl phosphine, triaryl phosphine or phosphorous acid ester; Said azoformic acid derivative is azoformic acid dialkyl, azo dintrile, Cellmic C 121, azoformic acid two (dialkyl amide) or 1,1 '-(azo dicarbapentaborane) two alkylene amines.
More specifically, said trialkyl phosphine comprises triethyl phosphine, tributylphosphine etc., and triaryl phosphine comprises triphenylphosphine, trimethylphenyl phosphine etc., and phosphorous acid ester comprises methyl phosphite, phosphorous acid ethyl ester or phenyl-phosphite etc.
And said azoformic acid dialkyl comprises azo acid dimethyl ester, diethyl azodiformate, diisopropyl azodiformate etc., azoformic acid two (dialkyl amide) comprises azoformic acid two (dimethyl) acid amides, azoformic acid two (diethyl) acid amides, and 1,1 '-(azo dicarbapentaborane) two alkylene amines comprise 1,1 '-(azo dicarbapentaborane) two tetramethyleneimine or 1,1 '-(azo dicarbapentaborane) two piperidines etc.
Among the present invention, formula V compound and formula VI compound carry out Mitsunobu reaction available solvent and comprise: hydro carbons, as pentane, hexane, heptane, benzene, toluene and dimethylbenzene; Halogenated hydrocarbon is as methylene dichloride, chloroform, tetrachloromethane, ethylene dichloride and chlorobenzene; Nitrogenous hydro carbons is as Nitromethane 99Min. and oil of mirbane; Ethers is as ether, methyl-isobutyl ether, dioxan and tetrahydrofuran (THF); Ketone is as acetone, methyl ethyl ketone and pimelinketone; The ester class is as ethyl acetate, isobutyl acetate and methyl benzoate; Nitrile is as acetonitrile and cyanobenzene; Amides is as methane amide, ethanamide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide; The sulfone class is as methyl-sulphoxide; Organic bases is as triethylamine, hexahydroaniline, benzylamine, pyridine, quinoline; And other inert solvents or their mixture.The preferred solvent of the present invention is selected from tetrahydrofuran (THF), methylene dichloride and ethyl acetate.
Among the present invention, when formula V compound and formula VI compound carry out the Mitsunobu reaction, the ratio of the mole number of formula V compound, formula VI compound, trivalent phosphorous compound, azoformic acid derivative preferred 1: 1～5: 1～5: 1～5, more preferably 1: 1.5～3: 1.2～2: 1.2～2.
Among the present invention, the Mitsunobu that formula V compound and formula VI compound carry out is reflected at and carries out more favourablely under the anhydrous condition, can carry out under protection of inert gas.Temperature of reaction is-80 ℃ to 100 ℃, and-70 ℃ to 50 ℃ preferable, and more preferably 0～40 ℃, best is 10～20 ℃.Reaction times is 10min to 30h, and 0.5h to 20h is better.After reaction finished, target product can carry out separation and purification with common means, as extraction, filtration, chromatography, crystallization, precipitation etc.Preferred post-treating method is that reaction solvent is removed in underpressure distillation, in the gained residue, add hydro carbons (as pentane, hexane, heptane, benzene, toluene and dimethylbenzene etc.), the impurity that generates in the reaction is separated out, remove by filter impurity, filtrate concentrating obtains target product.
Another purpose of the present invention provides a kind of new preparation process of the formula VII compound doripenem based on above-mentioned preparation method.This preparation method is made after the formula I compound by formula V compound and the reaction of formula VI compound condensation, and the deprotection reaction through routine gets formula VII compound doripenem again; Wherein, X
1It is hydroxyl protecting group.Preferably, X
2It is carboxyl-protecting group; R
4And Y
2It is amino protecting group; More preferably, R
1Be methyl, R
2And R
3Be hydrogen.Here term hydroxyl protecting group, carboxyl-protecting group and amino protecting group is described as defined above.One of synthetic route that described preparation method is preferable is as follows.
As seen, this method comprises at first the pyrrolidin derivatives condensation shown in carbapenem parent nucleus shown in the formula III and the formula IV is obtained formula V compound, obtains formula I compound with formula VI compound condensation again.In above-mentioned reaction scheme, formula III ' and formula III " compound is selected from compound of formula III, formula III " compound can make the X in the formula through hydroxyl protecting group conventionally by formula III ' compound
3Be leavings group, for example active ester groups of hydroxyl, alkyl sulphinyl, aryl sulfonyl kia, alkyl sulphonyl or aryl sulfonyl; Formula IV ' compound can be by Y
1For taking off sulfhydryl protected base through routine, the formula IV compound of sulfhydryl protected base makes; More specifically, can be referring to the disclosed content of the patent documentation of mentioning in the background technology.
At the formula I compound that utilizes preparation method of the present invention to prepare to be with protecting group, and during formula VII compound, also unexpectedly obtain new midbody compound.Therefore, a further object of the present invention provides new midbody compound.
When the formula I compound that utilizes preparation method of the present invention to prepare to be with protecting group, the midbody compound that is selected from general formula V compound that obtains has: structural formula is as shown in the formula the compound (4R shown in 4,5S, 6S)-3-[[(3S, 5S)-1-is to nitro benzyloxycarbonyl-5-methylol-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(trimethyl silicane alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy;
Or structural formula is as shown in the formula the compound (4R shown in 12,5S, 6S)-3-[[(3S, 5S)-1-tert-butoxycarbonyl-5-methylol-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(trimethyl silicane alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid benzhydryl ester;
Or structural formula is as shown in the formula the compound (4R shown in 17,5S, 6S)-3-[[(3S, 5S)-1-allyloxy carbonyl-5-methylol-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-allyl carboxylate.
And when utilizing preparation method's preparation formula VII compound of the present invention, the new midbody compound that is selected from compound of Formula I that obtains has: structural formula is as shown in the formula the compound (4R shown in 5,5S, 6S)-3-[[(3S, 5S)-1-is to nitro benzyloxycarbonyl-5-[[N-sulphonamide-N-(tert-butoxycarbonyl) amino] methyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(trimethyl silicane alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy;
Perhaps structural formula is as shown in the formula the compound (4R shown in 18,5S, 6S)-3-[[(3S, 5S)-1-allyloxy carbonyl-5-[[N-sulphonamide-N-(tert-butoxycarbonyl) amino] methyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-allyl carboxylate.
Provide shortenings used herein below:
Tr: trityl; PMZ: to methoxyl group benzyloxy base carbonyl, PMB: to methoxy-benzyl, Ms: methylsulfonyl; PNZ: to the nitro benzyloxycarbonyl; TMS: TMS, PNB: to nitrobenzyl, BOC: tert-butoxycarbonyl; BH: diphenyl-methyl; TBDMS: tertiary butyl dimethylsilyl, Alz: allyl group, Ac: ethanoyl.
Preparation method of the present invention has simplified reactions steps, need not special reagent and expensive reagent, has cut off the multistep column chromatography purification, has reduced cost, is more suitable for suitability for industrialized production.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
Synthetic route is as follows:
1. the preparation of compound 2:
Under the nitrogen protection, compound 1 (can be according to document D.H.Shih, et al.Heterocycles, 1984,21 (1): 29-40 is synthetic voluntarily, also has commercially available) (23.8g) is dissolved in methylene dichloride (250ml).Be chilled to 0 ℃, add trimethylchlorosilane (8.6g), triethylamine (8g) successively, stir 20min at 0 ℃ again.Reaction mixture is used saturated sodium bicarbonate aqueous solution, 5% salt solution and water washing successively.Behind the anhydrous sodium sulfate drying, concentrating under reduced pressure obtains light yellow oil, and promptly compound 2, directly drops into the next step.
2. the preparation of compound 4
Under the nitrogen protection, will go up step reaction gained compound 2 and compound 3 (according to document G.Emmer, et al.J.Antibiotics, 1985,38 (2): 1371-1386 is synthetic) and (15g) be dissolved in acetonitrile (300ml).Be chilled to 0 ℃, drip diisopropyl ethyl amine (DIEA) (6.2g).0 ℃～5 ℃ are stirred 4.5h.In the mixed solution that the impouring of gained reaction mixture is made up of ethyl acetate (400ml) and water (400ml).Divide and get organic layer, use 5% salt solution, water washing respectively.Behind the anhydrous sodium sulfate drying, concentrating under reduced pressure obtains light yellow oil (26.3g), i.e. compound 4:ES-MS:751.25[M+Na]
+, 727.31[M-H]
-
3. the preparation of compound 5
Under the nitrogen protection, with compound 4 (41.7g), triphenylphosphine (PPh3) (17.7g), tert-butoxycarbonyl sulphonamide amine (16.8g) is dissolved in anhydrous tetrahydro furan (400ml).Under 10 ℃～15 ℃, drip diisopropyl azodiformate (DIAD) (13.9g).After reaction mixture at room temperature stirs 3h, concentrating under reduced pressure.The gained residue is dissolved in toluene, cooling and stirring, behind the solid that filtering is separated out, concentrating under reduced pressure obtains light yellow oil, i.e. compound 5:ES-MS 929.30[M+Na]
+, 906.3 1 [M-H]
-
4. the preparation of compound 6
To go up step gained light yellow oil compound 5 and be dissolved in acetonitrile (400ml), and be chilled to-10 ℃, behind the adding 1mol/L hydrochloric acid (23ml), equality of temperature stirs 20min.Add ethyl acetate (800ml) and stir 5min.In gained mixture impouring cold water (800ml).Divide and get organic layer, water (2 * 400ml) washings.Combining water layer is with counter the carrying of ethyl acetate (600ml).Merge organic layer, concentrating under reduced pressure obtains water white oil, i.e. compound 6 (34.8g).
1HNMR(CDCl
3)δ?1.24(d，J＝7.2Hz，3H)，1.37(d，J＝6.4Hz，3H)，1.47(s，9H)，1.54(m，1H)，2.58-2.66(m，1H)，3.27-3.34(m，3H)，3.63-3.70(m，2H)，4.06-4.17(m，3H)，4.24(m，1H)，4.26(m，1H)，4.54(m，1H)，5.18(s，2H)，5.23(d，J＝13.6，1H)，5.48(d，J＝13.2，1H)，5.74(s，2H)，7.49(d，J＝8.0Hz，2H)，7.64(d，J＝8.4Hz，2H)，8.20-8.23(m，4H)；ES-MS：857.26[M+Na]
+，873.24[M+K]
+。
5. the preparation of compound 7
Under the nitrogen protection, aluminum trichloride (anhydrous) (4.7g) is dissolved in the mixed solution of being made up of methyl-phenoxide (35ml) and methylene dichloride (35ml).In-40 ℃～-30 ℃ methylene dichloride (40ml) solution that drip compound 6 (8g), stir 3.5h at-30 ℃ again.In the gained reaction mixture, add saturated sodium bicarbonate aqueous solution (100ml) and ethyl acetate (200ml) successively.After concentrating under reduced pressure is removed methylene dichloride, add ethyl acetate (200ml) and water (200ml) again and stir.Divide and get organic layer, water (200ml) washing.Concentrating under reduced pressure, gained residue ethyl acetate and toluene recrystallization obtain white solid, i.e. compound 7 (5.6g, 79 %):
1HNMR (DMSO-d
6) δ 1.16 (d, J=6.4Hz, 3H), 1.18 (d, J=6.8Hz, 3H), 1.91 (m, 1H), 2.54 (m, 1H), 3.17 (m, 1H), 3.27 (m, 1H), 3.30 (m, 1H), 3.55 (m, 1H), 3.82 (m, 1H), 4.01 (m, 2H), 4.05 (m, 1H), 4.07 (m, 1H), 4.25 (m, 1H), 5.00,5.01 (m, 1H), 5.23 (s, 2H), 5.30 (d, J=14.0Hz, 1H), 5.46 (d, J=14.0Hz, 1H), 6.46 (s, 2H), 6.70 (m, 1H), 7.66 (d, J=8.4Hz, 2H), 7.71 (d, J=8.8Hz, 2H), 8.21 (d, J=8.4Hz, 4H); ES-MS:757.1 7[M+Na]
+, 773.1 4[M+K]
+
6. the preparation of compound VI I:
Compound 7 (90g) and 10% palladium charcoal (50g) are added in the mixed solution of being made up of tetrahydrofuran (THF) (500ml), deionized water (500ml).Under 0.5MPa hydrogen, 30 ℃ are stirred 2h.Filter, with deionized water (100ml) washing leaching cake.Merging filtrate and washing lotion, after tetrahydrofuran (THF) was removed in decompression, (5 * 100ml) washed obtained aqueous solution with ethyl acetate.Then, be cooled to 0 ℃, add methyl alcohol (300ml) and crystal seed, stir 3h.Drip methyl alcohol (1500ml) to the gained suspension liquid, stir 6h at 0 ℃ again.Filter, use methanol wash, dry compound VI I (36.8g): the ES-MS:421.51[M+H that gets]
+
Embodiment 2
Synthetic route is:
1, the preparation of compound 9
Compound 8 (synthetic according to document US 5317016) (16.5g) is dissolved in methyl alcohol (30ml), is chilled to-15 ℃, add the methanol solution (40ml) of 4.5mol/L sodium methylate, stir 30min.In gained reaction solution impouring water (100ml) and ethyl acetate (300ml).With in the hydrochloric acid and after, divide and to get organic layer, with the saturated brine washing, anhydrous sodium sulfate drying, concentrating under reduced pressure get compound 9 (12.6g).
2, the preparation of compound 11
Under the nitrogen protection, with compound 10 (according to document M.Kume, et al.Tetrahedron; 1997,53 (5): 1635-1646 is synthetic) (25g) be dissolved in methylene dichloride (250ml), be chilled to 0 ℃; add trimethylchlorosilane (8.6g), triethylamine (8g) successively, stir 20min at 0 ℃.Reaction mixture is used saturated sodium bicarbonate, 5% salt solution and water washing successively.Behind the anhydrous sodium sulfate drying, concentrating under reduced pressure obtains light yellow oil, and promptly compound 11, are directly used in the next step.
3, the preparation of compound 12
Under the nitrogen protection, will go up step gained compound 11 and be dissolved in acetonitrile (300ml) with compound 9 (10.5g).Be chilled to 0 ℃, and under this temperature, be added dropwise to diisopropyl ethyl amine (6.2g).Drip and finish, stir 4.5h at 0 ℃～5 ℃ again.In the mixed solution with gained reaction mixture impouring ethyl acetate and water composition.Divide and get organic layer, use 5% salt solution, water washing respectively.Behind the anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound 12, ES-MS:703.99[M+Na]
+
4, the preparation of compound 13
Under the nitrogen protection, compound 12 (7.4g), triphenylphosphine (3.36g), tertbutyloxycarbonyl sulphonamide amine (3.2g) are dissolved in anhydrous ethyl acetate (80ml).At 10 ℃～15 ℃, drip diisopropyl azodiformate (2.64g).After reaction mixture at room temperature stirs 3h, concentrating under reduced pressure.In the gained residue, add toluene, cooling and stirring.Behind the solid that filtering is separated out, concentrating under reduced pressure obtains compound 13.
5, the preparation of compound 14
Above-claimed cpd 13 is dissolved in acetonitrile (100ml), is chilled to-10 ℃, add 1mol/L hydrochloric acid (5ml).Under this temperature, stir 20min.Add ethyl acetate (200ml) again and stir 5min.In gained mixture impouring cold water (200ml).Stir the back branch and get organic layer, wash with water.Combining water layer is carried with ethyl acetate is counter.Merge organic layer, concentrating under reduced pressure obtains compound 14.
1HNMR(CDCl
3)?1.29(d，J＝7.2Hz，3H)，1.36(d，J＝6.4Hz，3H)，1.41(s，9H)，1.44(s，9H)，1.8-1.88(m，1H)，2.47-2.66(m，1H)，3.13-3.36(m，2H)，3.33(dd，J＝7.2Hz，J＝2.4Hz，1H)，3.55-3.79(m，2H)，3.93-4.18(m，2H)，4.29(dd，J＝7.0Hz，J＝2.4Hz，1H)，4.22-4.39(m，1H)，4.48-4.69(m，1H)，6.06(br?s，2H)，6.99(s，1H)，7.23-7.65(m，10H)；ES-MS：810.35[M+Na]
+。
6, compound 14 promptly obtains formula VII compound doripenem according to US 5317016 reported method deprotections.
Embodiment 3
Synthetic route is:
1, the preparation of compound 17
Under the nitrogen protection; with compound 15 (according to document Kondo; K.; et al.J Org Chem; 1995,60 (5): 1096-1097 is synthetic) (7.35g) and compound 16 (synthetic) according to U.S. Pat 5095013 (3.12g) be dissolved in acetonitrile (90ml), be chilled to 0 ℃; drip diisopropyl ethyl amine (1.86g).Drip and finish, stir 4.5h at 0 ℃～5 ℃ again.In the mixed solution that the impouring of gained reaction mixture is made up of ethyl acetate and water.Divide and get organic layer, use 5% salt solution, water washing successively.Behind the anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound 17, ES-MS:603.95[M+Na]
+
2, the preparation of compound 18
Under the nitrogen protection, compound 17 (6.3g), triphenylphosphine (3.36g), tertbutyloxycarbonyl sulphonamide amine (3.2g) are dissolved in anhydrous methylene chloride (90ml).At 10 ℃～15 ℃, drip diisopropyl azodiformate (2.64g).After reaction mixture at room temperature stirs 3.5h, concentrating under reduced pressure.In the gained residue, add toluene, cooling and stirring.Behind the solid that filtering is separated out, concentrating under reduced pressure obtains compound 18, ES-MS:782.53[M+Na]
+
3, the preparation of compound 19
Above-claimed cpd 18 is dissolved in acetonitrile (100ml).Be chilled to-10 ℃, add 1mol/L hydrochloric acid (10ml), under this temperature, stir 30min.Add ethyl acetate (200ml) again and stir 5min.In gained mixture impouring cold water (200ml).Stir the back branch and get organic layer, wash with water.Combining water layer is carried with ethyl acetate is counter.Merge organic layer, concentrating under reduced pressure obtains compound 19.
1HNMR(CDCl
3)1.29(d，J＝6.8Hz，3H)，1.34(d，J＝6.4Hz，3H)，1.49(s，9H)，2.59-2.73(m，1H)，3.23-3.46(m，3H)，3.63-3.71(m，2H)，4.07-4.38(m，6H)，4.52-4.69(m，4H)，4.73-4.94(m，2H)，5.25-5.58(m，4H)，5.8-6.1(m，3H)；ES-MS：656.3?8[M+Na]
+。
4, compound 19 promptly obtains formula VII compound doripenem according to WO2004/072073 reported method deprotection successively.
Tertbutyloxycarbonyl sulphonamide amine (NH in the foregoing description
2SO
2NHBOC) be according to document (Y.Masui, et al.Tetrahedron Lett, 2004,45 (9): 1853-1856) synthetic: below 0 ℃, drip the trimethyl carbinol (42g) in toluene (700ml) solution of Sulfuryl chloride isocyanate (80g), 0 ℃ is stirred 30min.Drip pyridine (98g), stir 30min at 0 ℃ again.Then, dripping 25% ammoniacal liquor (230g) below 0 ℃.Add water (66ml), 0 ℃ is stirred 3h.Layering.Water layer with toluene wash after, being acidified to pH with the vitriol oil is 2.The precipitation that the filter collection is separated out, washing, the dry tert-butoxycarbonyl sulphonamide amine (99g) that gets: mp 128-130 ℃.
In the foregoing description not the reagent of specified otherwise be conventional commercial reagent.
Claims (11)
1, a kind of preparation method of formula I compound pyrrolidine sulfsulopenem derivative, it in the presence of a kind of trivalent phosphorous compound and a kind of azoformic acid derivative, carries out condensation reaction by formula V compound and formula VI compound in organic solvent; Wherein said trivalent phosphorous compound is trialkyl phosphine, triaryl phosphine or phosphorous acid ester; Said azoformic acid derivative is azoformic acid dialkyl, azo dintrile, Cellmic C 121, azoformic acid two (dialkyl amide) or 1,1 '-(azo dicarbapentaborane) two alkylene amines;
R wherein
1Be hydrogen or low alkyl group; R
2, R
3And R
4Be hydrogen independently, can substituted low alkyl group or amino protecting group, perhaps R
2And R
3Form saturated or undersaturated cyclic group, perhaps R with the nitrogen-atoms that they connected
2And R
4, or R
3And R
4Interconnection and form-CH
2-CH
2-or-CH
2-CH
2-CH
2-; Each cyclic group can comprise further that at least one is selected from the atom of oxygen, sulphur and nitrogen; X
1Be hydrogen or hydroxyl protecting group; X
2Be hydrogen, carboxyl-protecting group, ammonium, basic metal or alkaline-earth metal; Y
2Be hydrogen or amino protecting group;
The substituting group of " can substituted low alkyl group " is selected from hydroxyl, alkoxyl group, amino, amide group, low-grade alkyl amino, formamyl, elementary alkyl amido methanoyl, carbamoyloxy, low-grade alkyl amino methanoyl and cyano group;
The carbonatoms of above-mentioned term " low alkyl group " is 1～6.
2, preparation method as claimed in claim 1 is characterized in that X
1It is the hydroxyl protecting group that is selected from TMS, tert.-butoxy dimethylsilyl, triethyl silyl and allyloxy carbonyl.
3, preparation method as claimed in claim 1 is characterized in that X
2Be to be selected to nitrobenzyl, to the carboxyl-protecting group of methoxy-benzyl, diphenyl methyl, allyl group and the tertiary butyl.
4, preparation method as claimed in claim 1, it is characterized in that said amino protecting group be selected from tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl and diazo.
5, preparation method as claimed in claim 4 is characterized in that R
4Be tert-butoxycarbonyl, Y
2For to nitro benzyloxycarbonyl, tert-butoxycarbonyl or allyloxy carbonyl.
6, preparation method as claimed in claim 1 is characterized in that R
1Be methyl, R
2And R
3Be hydrogen.
7, preparation method as claimed in claim 1 is characterized in that said trialkyl phosphine is triethyl phosphine or tributylphosphine, and triaryl phosphine is triphenylphosphine or trimethylphenyl phosphine, and phosphorous acid ester is methyl phosphite, phosphorous acid ethyl ester or phenyl-phosphite; Said azoformic acid dialkyl is azo acid dimethyl ester, diethyl azodiformate or diisopropyl azodiformate, azoformic acid two (dialkyl amide) is azoformic acid two (dimethyl) acid amides or azoformic acid two (diethyl) acid amides, 1,1 '-(azo dicarbapentaborane) two alkylene amines are 1,1 '-(azo dicarbapentaborane) two tetramethyleneimine or 1,1 '-(azo dicarbapentaborane) two piperidines.
8, preparation method as claimed in claim 7 is characterized in that said trivalent phosphorous compound is a triphenylphosphine, and the azoformic acid derivative is a diisopropyl azodiformate, and organic solvent is selected from tetrahydrofuran (THF), methylene dichloride and ethyl acetate.
9, a kind of preparation method of formula VII compound doripenem is characterized in that being made after the formula I compound by the reaction of formula V compound and formula VI compound condensation, carries out conventional deprotection reaction again;
Described in the chemical structure such as claim 1 of described formula V compound and formula VI compound, X wherein
1Be hydroxyl protecting group, X
2Be carboxyl-protecting group, R
4And Y
2Be amino protecting group independently, R
1, R
2And R
3Definition such as claim 1 or 6 described in.
10, formula V compound, its structural formula as shown in claim 1, R wherein
1Be methyl, Y
2For to nitro benzyloxycarbonyl, X
1Be TMS, X
2For to nitrobenzyl, be formula 4 compound (4R, 5S, 6S)-3-[[(3S, 5S)-1-is to nitro benzyloxycarbonyl-5-methylol-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(trimethyl silicane alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy;
Perhaps R
1Be methyl, Y
2Be tert-butoxycarbonyl, X
1Be TMS, X
2Be diphenyl-methyl, be formula 12 compound (4R, 5S, 6S)-3-[[(3S, 5S)-1-tert-butoxycarbonyl-5-methylol-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(trimethyl silicane alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid benzhydryl ester;
Perhaps R
1Be methyl, Y
2Be allyloxy carbonyl, X
1Be tertiary butyl dimethylsilyl, X
2
Be allyl group, be formula 17 compound (4R, 5S, 6S)-3-[[(3S, 5S)-1-allyloxy carbonyl-5-methylol-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-allyl carboxylate.
11, formula I compound, its structural formula as shown in claim 1, R wherein
1Be methyl, R
2With R
3Be hydrogen, R
4Be tert-butoxycarbonyl, Y
2For to nitro benzyloxycarbonyl, X
1Be TMS, X
2For to nitrobenzyl, be formula 5 compound (4R, 5S, 6S)-3-[[(3S, 5S)-1-is to nitro benzyloxycarbonyl-5-[[N-sulphonamide-N-(tert-butoxycarbonyl) amino] methyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(trimethyl silicane alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy;
Perhaps R
1Be methyl, R
2With R
3Be hydrogen, R
4Be tert-butoxycarbonyl, Y
2Be allyloxy carbonyl, X
1Be tertiary butyl dimethylsilyl, X
2Be allyl group,
Be formula 18 compound (4R, 5S, 6S)-3-[[(3S, 5S)-1-allyloxy carbonyl-5-[[N-sulphonamide-N-(tert-butoxycarbonyl) amino] methyl]-the 3-pyrrolidyl] sulfenyl]-6-[(1R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-methyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-2-allyl carboxylate.
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| US5539102A (en) * | 1992-02-21 | 1996-07-23 | Shionogi Seiyaku Kabushiki Kaisha | Production method for sulfamide |
| CN1259949A (en) * | 1997-06-16 | 2000-07-12 | 麦克公司 | Stabilized carbapenem intermediates and synthetic use |
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| CN1071428A (en) * | 1991-08-20 | 1993-04-28 | 盐野义制药株式会社 | Pyrroliaylthiocarbapderivatives derivatives |
| US5539102A (en) * | 1992-02-21 | 1996-07-23 | Shionogi Seiyaku Kabushiki Kaisha | Production method for sulfamide |
| CN1098104A (en) * | 1992-12-21 | 1995-02-01 | 株式会社钟根堂 | 2-(tetramethyleneimine-4-yl that 2-replaces) sulfo--Carbpenem derivants |
| WO1995029913A1 (en) * | 1994-05-02 | 1995-11-09 | Shionogi & Co., Ltd. | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same |
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