CN1045444C - β-内酰胺化合物的制备方法及其有关中间体 - Google Patents
β-内酰胺化合物的制备方法及其有关中间体 Download PDFInfo
- Publication number
- CN1045444C CN1045444C CN94101804A CN94101804A CN1045444C CN 1045444 C CN1045444 C CN 1045444C CN 94101804 A CN94101804 A CN 94101804A CN 94101804 A CN94101804 A CN 94101804A CN 1045444 C CN1045444 C CN 1045444C
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- methyl
- arbitrarily
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title description 10
- 239000000543 intermediate Substances 0.000 title description 4
- 150000003952 β-lactams Chemical class 0.000 title 1
- -1 beta -lactam compound Chemical class 0.000 claims abstract description 48
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 abstract description 8
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 229910052799 carbon Inorganic materials 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 150000001721 carbon Chemical group 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 125000006502 nitrobenzyl group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000010948 rhodium Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000002132 β-lactam antibiotic Substances 0.000 description 6
- 229940124586 β-lactam antibiotics Drugs 0.000 description 6
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 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 4
- 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 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 150000001989 diazonium salts Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- WSHJJCPTKWSMRR-RXMQYKEDSA-N penam Chemical compound S1CCN2C(=O)C[C@H]21 WSHJJCPTKWSMRR-RXMQYKEDSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 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 description 3
- 239000006260 foam Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [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
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- LJXTYJXBORAIHX-UHFFFAOYSA-N diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1 LJXTYJXBORAIHX-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 210000002659 acromion Anatomy 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 1
- 125000005256 alkoxyacyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OGQXJNCMYDZGIJ-INWUZDNDSA-N carbapenam Chemical class C1CC(C(O)=O)N2C(=O)C(C)[C@H]21 OGQXJNCMYDZGIJ-INWUZDNDSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- UGWKCNDTYUOTQZ-UHFFFAOYSA-N copper;sulfuric acid Chemical compound [Cu].OS(O)(=O)=O UGWKCNDTYUOTQZ-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- HXBZCHYDLURWIZ-UHFFFAOYSA-N diphenyl hydrogen phosphate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 HXBZCHYDLURWIZ-UHFFFAOYSA-N 0.000 description 1
- 150000007520 diprotic acids Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RFPMGSKVEAUNMZ-UHFFFAOYSA-N pentylidene Chemical group [CH2+]CCC[CH-] RFPMGSKVEAUNMZ-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 239000000725 suspension Substances 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/04—Preparation by forming the ring or condensed ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
提供了式(Ⅰ)β-内酰胺化合物的制备方法,它包括式(Ⅱ)氮杂环丁酮衍生物的环合;所述式(Ⅰ)和式(Ⅱ)化合物中,R1为氢,可任意取代的烷基,或可任意取代的氨基;R2为羧基保护基团;X为可任意插入-O-或-S-,和/或可任意取代的亚烷基;及R3为可任意取代的芳基。
Description
本发明涉及制备β-内酰胺抗生素的实用的方法,特别是涉及制备碳青霉烷(carbapenam)衍生物的方法,该衍生物是β-内酰胺抗生素制备中的有用的中间体;还涉及对本方法有用的中间体。更具体地讲,本发明涉及包括新的和有用的氮杂环丁酮衍生物的环合的制备β-内酰胺抗生素的方法以及此类氮杂环丁酮衍生物的制备方法。
通常β-内酰胺抗生素临床用于治疗感染。β-内酰胺抗生素可以被分成几类,包括属于较新类型的具碳青霉烷或碳青霉烯(carbapenem)核的抗生素。
此法必须包括环合,该环合包括在50-100℃对重氮化合物加热,最好是在催化剂硫酸铜、Pd(OAc)2或Rh2(OAc)4存在下加热。迄今,这种方法已被用在大的工业化规模上。
然而上述方法中的不足之处是:用于该方法的叠氮化合物试剂和重氮化合物当加热时会爆炸。换句话说,处理大量的该重氮化合物是很危险的。由此,上述方法不是理想的制备碳青霉烯抗生素的工业方法。
因此,本申请者研究并发现了制备碳青霉烯抗生素的安全和便利的方法,它不包括应用上述的叠氮试剂和重氮化合物。
R2为羧基保护基,及
上式中,R1的定义中的“烷基”是指直链的或带支链的C1-C6烷基基团,并且优选直链的或带支链的C1-C4烷基基团。烷基上的取代基例如有卤素、可被羟基保护基团取代的羟基等。羟基保护基团包括例如(低级烷氧基)羰基如C1-C4烷氧羰基(如叔丁氧羰基),卤代的(低级烷氧基)羰基如卤代的(C1-C3)烷氧羰基(例如:2-碘乙氧羰基,2,2,2-三氯乙氧羰基),芳基(低级烷氧基)羰基如苯环上可以有取代基的苯基(C1-C4)烷氧羰基(例如:苄氧羰基,邻硝基苄氧羰基,对硝基苄氧羰基,对甲氧基苄氧羰基),三(低基烷基)甲硅烷基象三(C1-C4)烷基甲硅烷基(例如:三甲基甲硅烷基,叔丁基二甲基甲硅烷基),取代的甲基象C1-C4烷氧甲基(如甲氧甲基)、C1-C4烷氧基(C1-C4)烷氧甲基(如2-甲氧乙氧甲基)、C1-C4硫基甲基(如甲硫基甲基),四氢吡喃基,及类似的常规基团。优选R1为羟甲基。
R1上氨基的取代基优选具有1-20个碳原子并可以被除去而对分子中其它部分不产生任何不利影响的氨基保护基团,并且该基团已用于青霉素和头孢菌素领域中。典型的取代基包括具1-8个碳原子的烷基(叔丁基,甲氧甲基,甲氧乙氧甲基,三氯乙基,四氢吡喃基,等),具7-20个碳原子的芳烷基(苯甲基,二苯甲基,三苯甲基,甲氧苄基,硝基苄基,甲基苄基等),具6-12个碳原子的芳硫基(硝基苯硫基等),具1-8个碳原子的亚烷基,具7-14个碳原子的芳亚烷基(aralkylidene)(苯亚甲基,或取代的苯亚甲基),酰基[具1-8个碳原子的烷酰基(甲酰基,乙酰基,氯乙酰基,三氯乙酰基,三氟乙酰基等),具7-15个碳原子的芳烷酰基(苯乙酰基,苯甘氨酰基,苯基糖基(phenylglycosyl),phenylmaronyl,噻唑基乙酰基,氨噻唑基-α-羟基亚氨乙酰基等),具7-15个碳原子的芳酰基(苯甲酰基,硝基苯甲酰基等),具2-12个碳原子的烷氧酰基(其中,烷基部分为甲基,乙基,丙基,环丙乙基,异丙基,丁基,戊基,己基,异丁基,三氯乙基,吡啶甲基,环戊基,环己基等),具8-15个碳原子的芳烷氧羰基(其中,芳烷基部分为苯甲基,二苯甲基,硝基苄基等),具3-10个碳原子的二元酸的酰基(丁二酰基,邻苯二甲酰基等),卤磺酰基,具0-10个碳原子的磷酸酯酰基(二烷氧基磷酰基,二氯磷酰基),等],具3-15个碳原子的三烷基甲硅烷基,具3-15个碳原子的三烷基甲锡烷基等,各基团均可被进一步取代。
在上式中,R2的“羧基保护基团”是指例如低级烷基象C1-C4烷基(例如:甲基,乙基,异丙基,叔丁基),卤代低级烷基象C1-C3烷基(例如:2-碘乙基,2,2,2-三氯乙基),低级烷氧甲基象C1-C4烷氧甲基(甲氧甲基,乙氧甲基,异丁氧甲基),低级脂肪族酰氧甲基象C1-C5烷酰氧甲基(例如:乙酰氧甲基,丙酰氧甲基,丁酰氧甲基,新戊酰氧甲基),低级烷氧基羰基氧乙基象1-(C1-C4)烷氧基羰氧基)乙基(例如:1-甲氧羰基氧乙基,1-乙氧羰基氧乙基),可被取代的低级链烯基象可以被C1-C4烷基或苯基取代的C3-C10链烯基(例如:烯丙基,2-甲基烯丙基,3-甲基烯丙基,3-苯基烯丙基),可被取代的单芳基(低级)烷基象苯环上可以被C1-C4烷氧基、硝基、卤素等取代的苯基(C1-C4)烷基(例如:苄基,对甲氧苄基,2,4-二甲氧苄基,邻硝基苄基,对硝基苄基,对氯苄基),可被取代的二芳基(低级烷基)象可以被C1-C4烷氧基等取代的二苯基(C1-C4)烷基(例如:二苯甲基,二对甲氧苯基甲基),芳基象可以被卤素、硝基、C1-C4烷氧基等取代的苯基(例如:苯基,对氯苯基,2,4,5-三氯苯基,对硝基苯基,邻硝基苯基,对甲氧苯基),杂芳基象可以被C1-C4烷基取代的吡啶基或嘧啶基(例如:2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,2-(4,6-二甲基)嘧啶基),phthalydyl及类似的可以保护羧基的常规基团。
在上式中,R3的“芳基”包括可以被卤素、低级烷基、低级烷氧基、羟基、氨基、硝基及其它基团取代的苯基和萘基,特别优选的基团为苯基。
在X的定义中的“亚烷基”中最好包括C1-C5亚烷基,C1-C3亚烷基更好,例如亚甲基,1,2-亚乙基,1,2-亚丙基,亚丁基及亚戊基。该亚烷基可以在其中插入-O-或-S-,和/或被取代基(如:低级烷基,低级烷氧基,低级烷硫基,芳基,低级链烯基等)取代。这包括-OCH2-,-SCH2-,-O(CH2)2-,-S(CH2)2-,或下列式中的基团:优选的基团之一是下式“亚烷基基团”:
CnH2n+1CH=其中n是一等于或大于0的整数,最好是0-5的整数。亚烷基包括乙叉基(CH3CH=),丙叉基(CH3CH2CH=),异丙叉基((CH3)2C=)等,最好为乙叉基。
本发明方法包括由氮杂环丁酮衍生物合成β-内酰胺化合物的步骤。本方法的反应是在对该反应无不利影响的溶剂中进行的,最好是在质子惰性溶剂中进行。优选的质子惰性溶剂包括二氯甲烷,苯,甲苯,四氢呋喃及其它溶剂。
该反应基本上在数十分钟至数十小时内在-20-100℃的温度下完成,最好在-10℃-50℃、尤其是在冰浴至室温的温度下完成。
本方法最好在催化剂存在下进行。催化剂可引起化合物(II)的环合。所用催化剂最好包括过渡金属元素且特别是元素铑的盐。铑盐包括由羧酸生成的盐,特别是乙酸盐(Rh2(OAc)4),三氟乙酸盐(Rh2(CF3CO2)4),新戊酸盐(Rh2((CH3)3CCO2)4),辛酸盐(Rh2(C7H15COO)4)。催化剂的用量取决于所用催化剂的种类、反应的温度及其它条件,此量最好是0.001-0.1mol/mol氮杂环丁酮衍生物。
按照另一个实施方案,本发明提供式(II)新的氮杂环丁酮衍生物:其中R1,R2,R3和X的定义同上。此氮杂环丁酮衍生物由式(III)化合物与分子式为:R3-I(Q)2的化合物(其中R3的定义同上,Q为衍生自酸的阴离子部分的取代基)反应而得,所述式(III)化合物结构如下:其中R1,R2和X的定义同上。
在分子式:R3-I(Q)2中,Q为衍生于包括有机酸和无机酸的阴离子部分的取代基。有机酸包括羧酸和磺酸。无机酸包括氢卤酸,如HF,HCl,HBr。优选的R3-I(Q)2化合物包括PhI(OCOCH3)2,PHI(OCOCF3)2,PhIF2。该方法的反应是在碱存在下在溶剂中进行的。此溶剂包括对该反应没有不利影响的溶剂,最好是醇类溶剂如甲醇。有机碱(叔胺,芳香碱),或无机碱(碱金属氧化物或碱土金属氧化物,氢氧化物,碳酸盐,碳酸氢盐等)可用来作为碱。
根据β-内酰胺抗生素领域中的已知方法可以制备分子式(III)的化合物。
也可以根据文献的方法用(PhIO)n,PhI(OH)OTs等代替R3-I(Q)2来制备式(II)化合物[Varvoglis A.,Synthesis,709(1984),和Moriarty R.H.,Valid R.K.,Synthesis,431(1990)]。
本发明提供了由式(II)氮杂环丁酮衍生物制备式(I)β-内酰胺化合物的方法,具体来讲,本发明提供式(I)β-内酰胺化合物的制备方法,它包括将式(III)化合物与分子式为R3-I(Q)2(R3的定义同上)的化合物反应,得氮杂环丁酮衍生物(II),然后后者环合;所述式(I)β-内酰胺化合物、式(III)和式(II)化合物的结构如下:其中R1,R2,R3及X的定义同上。
由本发明方法所得的式(I)化合物可用作如日本专利申请第221767/1992号所述的如下分子式所示的化合物的原料:例如:化合物(I)与磷酸酯反应,酯化得一活性化合物,它与硫醇化合物反应,得2-硫代-碳青霉烯化合物;或氯化得3-氯代碳青霉烯化合物。
本发明由下述实施例和参考实施例详细阐明,但不应认为是对本发明的范围的限制。
实施例1
(1R,5R,6S)-6-[(R)-1-羟乙基]-1-甲基-2-氧代-1-碳青霉烷-3-羧酸二苯甲酯(化合物3.)BH:-CH(Ph)2I.(3S,4R)-3-[(R)-1-羟乙基]-4-[(R)-3-二苯甲氧羰基-1-甲基-2-氧代-3-苯基碘鎓基丙基(3-phenyliodoniopropyl)氮杂环丁-2-酮(化合物2)(方法A)将二乙酸碘代苯(Iodobenzene diacetate)(1.68g,5.22mmol)溶于20ml甲醇中,加入1.26N的甲醇钠溶液(8.28ml,10.4mmol),将此混合物于室温下搅拌10分钟。然后加入化合物1:(3S,4R)-3-[(R)-1-羟乙基]-4-[(R)-3-二苯基甲氧羰基-1-甲基-2-氧代丙基]氮杂环丁-2-酮(2.00g,5.06mmol),将所得混合物室温下搅拌20分钟。将反应混合物浓缩,并向残留物中加入乙酸乙酯(30ml),然后将沉淀的乙酸钠滤掉。将滤液浓缩,并向残留物中加入乙酸乙酯(10ml)和己烷(40ml)。将所得的结晶滤出,得化合物2(2.70g,89%),为淡黄色结晶。(方法B)将二乙酸碘苯(420mg,1.30mmol)溶于5ml甲醇中,并加入碳酸钾(180mg,1.30mmol),所得混合物于室温下搅拌10分钟。然后,将化合物1(500mg,1.27mmol)加入其中,所得混合物于室温下搅拌20分钟。将反应混合物浓缩并向残留物中加入乙酸乙酯(8ml),然后将沉淀的乙酸钾过滤掉。将滤液浓缩,并向残留物中加入乙酸乙酯(4ml)和己烷(20ml)。将所得结晶过滤,得淡黄色结晶的化合物2(702mg,93%)。化合物2:熔点:109-111℃。1H-NMR(CDCl3)δ:7.66(2H,d,J=8.2Hz),7.53(1H,t,J=8.2Hz),7.4-7.2(12H,m),6.86(1H,s),6.05(1H,brs),4.14-3.88(2H,m),3.77(1H,dd,
J=1.8Hz,8.3Hz),2.69(1H,dd,J=1.8Hz,8.8Hz),1.26(3H,d,J=6.4Hz)
1.20(3H,d,J=6.8Hz);
IR(CHCl3)cm-1:3400(br),1752,1655,1560,1545,1538,1380,
1370,1340.
II.标题化合物3
将乙酸铑(1.5mg,0.0034mmol)加至由步骤I所得的化合物2(200mg,0.335mmol)悬浮于6ml二氯甲烷制得的悬浮液中,所得的混合物在室温下搅拌20分钟。反应混合物用二氯甲烷稀释,稀释物用水洗一次,盐水洗一次,用无水硫酸钠干燥,并浓缩。所得残留物用层析法纯化(用甲苯∶乙酸乙酯∶乙酸=250∶250∶1作洗脱剂),得113mg无色泡沫状化合物3(86%)。化合物3:1H-NMR(CDCl3)δ:7.4-7.2(10H,m),6.87(1H,s),4.76(1H,s),4.29(1H,五重峰,J=6.5Hz),4.22(1H,dd,J=2.3Hz,7.9Hz),3.24(1H,dd,J=2.3Hz,7.0Hz),2.77 1H,五重峰,J=7.7Hz),1.37(3H,d,J=6.2Hz),1.20(3H,d,J=7.8Hz);IR(CHCl3)cm-1:3600,3500(br),1765,1750(肩峰),1495,1455,1380 1360 1295。
实施例2
(1R,5R,6S)-6-[(R)-1-叔丁基-二甲基甲硅烷基氧乙基]-1-甲基-2-二苯基磷酰氧基-1-碳青霉-2-烯(1-carba-2-penem)-3-羧酸对硝基苄酯(化合物6)。PNB:对硝基苄基
I.(3S,4R)-3-[(R)-1-叔丁基二甲基甲硅烷基氧乙基]-4-[(R)-1-甲基-3-对硝基苄氧羰基-2-氧代-3-苯基碘鎓基丙基]氮杂环丁-2-酮(化合物5)。
将化合物4(3S,4R)-3-[(R)-1-叔丁基二甲基甲硅烷基氧乙基]-4-[(R)-1-甲基-3-对硝基苄氧羰基-2-氧代丙基]氮杂环丁-2-酮(500mg,1.04mmol)溶于1ml甲醇中,并将之冷至-5℃。将氢氧化钾(136mg,2.08mmol)溶于1ml甲醇的溶液加至此冷却的溶液中,然后再加入二乙酸碘苯(337mg,1.05mmol)溶于2ml甲醇的溶液,并将所得的混合物在-10--5℃下搅拌40分钟。将冰水加至此混合物中,所得的混合物以二氯甲烷萃取二次。有机层以无水硫酸钠干燥,然后浓缩得606mg淡黄色结晶化合物5(86%)。
化合物5:1H-NMR(CDCl3)δ:8.18-8.14(2H,m),7.7-7.3(7H,m),6.10(1H,brs),5.17(2H,s),4.36-4.22(1H,m),4.22-4.08(1H,m),3.86(1H,dd,J=2.1Hz,4.1Hz),3.04-2.97(1H,m),1.17(3H,d,J=6.8Hz),1.14(3H,d,J=6.2Hz),0.84(9H,s),0.05(3H,s),0.04(3H,s).
II.标题化合物6
将8mg乙酸铑(0.018mmol)加至由上所得的化合物5(120mg,0.176mmol)溶于1ml二氯甲烷制得的溶液中,并将之搅拌20分钟。将反应混合物过滤,并将滤液浓缩。将含(1R,5R,6S)-6-[(R)-1-叔丁基-二甲基甲硅烷基氧乙基]-1-甲基-2-氧代-1-碳青霉-2-烯-3-羧酸对硝基苄酯的残留物溶于2ml乙腈中,再将44μl的氯磷酸二苯酯(0.212mmol)和37μl的二异丙基乙基胺(0.212mmol)在冰冷却下加入其中,将所得的混合物搅拌50分钟。反应混合物用乙酸乙酯稀释并用稀盐酸、5%碳酸氢钠水溶液和盐水各洗涤一次。然后有机层用无水硫酸钠干燥并浓缩。残留物用层析法纯化(用甲苯∶乙酸乙酯=10∶1作洗脱剂)得50mg无色泡沫状化合物6(40%)。化合物6:1H-NMR(CDCl3)δ:8.2-8.1(2H,m),7.6-7.15(12H,m),5.33,5.23(2H,ABq,J=13.6Hz),4.32-4.15(1H,m),4.19(1H,dd,J=3.0Hz,7.6Hz),3.54-3.34(1H,m),3.28(1H,dd,J=3.0Hz,5.7Hz),1.23(3H,d,J=6Hz),1.20(3H,d,J=6Hz),0.86(9H,s),0.07(3H,s),0.06(3H,s).
实施例3
I.(3S,4R)-3-[(R)-1-羟乙基]-4-[(R)-1-甲基-3-对硝基苄氧羰基-2-氧代-3-苯基碘鎓基丙基]氮杂环丁-2-酮(化合物12)
将196mg碳酸钾(1.42mmol)加至由456mg二乙酸碘苯溶入5ml甲醇制得的溶液中,将此混合物在室温下搅拌20分钟。将所得混合物冷至-78℃,将500mg化合物11(3S,4R)-3-[((R)-1-羟乙基]-4-[(R)-1-甲基-3-对硝基苄氧羰基-2-氧代丙基]氮杂环丁-2-酮加入其中,所得混合物在该相同的温度下搅拌30分钟。将反应混合物浓缩并向残留物中加入8ml乙酸乙酯。将不溶的乙酸钾滤掉,并将滤液浓缩。将5ml乙酸乙酯和15ml己烷加至残留物中以生成结晶,过滤后得到结晶。所得结晶经水洗,干燥,得676mg化合物12,为白色晶体(87%)。化合物12:mp:88-89℃1H-NMR(CDCl3)δ:8.17(2H,d,J=8.5Hz),7.74(2H,d,J=8.5Hz),7.58(1H,t,J=8Hz),7.43-7.35(4H,m),6.15(1H,brs),5.20(2H,s),4.2-3.85(2H,m),3.81(1H,dd,J=1.9Hz,8.5Hz),3.74(1H,s),2.72(1H,brd,J=8Hz),1.28(3H,d,J=6.8Hz),1.24(3H,d,J=7.4Hz).IR(CHCl3)cm-1:3400(br),1750,1655,1520,1380,1370,1340,
II.标题化合物13
将1.6mg乙酸铑(0.0036mmol)加入由将200mg上面所得的化合物12(0.353mmol)溶入6ml二氯甲烷而得的溶液中,将所得混合物在室温下搅拌20分钟。反应液用二氯甲烷稀释并将之用水洗一次,用盐水洗一次,再经无水硫酸钠干燥并浓缩。残留物以用甲苯∶乙酸乙酯∶乙酸=250∶250∶1洗脱的硅胶层析纯化,得107mg无色泡沫状化合物13,其中含有5%的由该层析产生的1-α异构物。化合物131H-NMR(CDCl3)δ:8.24(2H,d,J=8.6Hz),7.54(2H,d,J=8.6Hz),5.34and 5.27(2H,ABq,J=13.3Hz),4.75(1H,s),4.34(1H,quintet,J=6.5Hz),4.25(1H,dd,J=2.2Hz,7.8Hz),3.28(1H,dd,J=2.2Hz,6.5Hz),2.84(1H,quintet,J=7.8Hz),1.39(3H,d,J=6.5Hz),1.23(3H,d,J=7.8Hz):IR(CHCl3)cm-1:3590,3500(br),1760,1605,1523,1455,1375,1345。
Claims (5)
2.权利要求1的方法,其中,环合在催化剂存在下进行。
3.权利要求1的方法,其中,氮杂环丁酮衍生物通过式(III)化合物与分子式如下所示的化合物反应来制备:
R3I(Q)2其中,R3是苯基,以及Q是衍生自酸的阴离子部分的取代基;所述式(III)化合物的结构如下:其中,R1为氢、可任意取代的烷基或可任意取代的氨基,
R2为羧基保护基团,和
X为可任意插入-O-或-S-和/或可任意取代的亚烷基。
4.权利要求1至3中任一权项的方法,其中,R3为苯基,和Q为乙酰氧基。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2245193 | 1993-02-10 | ||
JP022451/93 | 1993-02-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1097424A CN1097424A (zh) | 1995-01-18 |
CN1045444C true CN1045444C (zh) | 1999-10-06 |
Family
ID=12083086
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94101804A Expired - Fee Related CN1045444C (zh) | 1993-02-10 | 1994-02-09 | β-内酰胺化合物的制备方法及其有关中间体 |
Country Status (9)
Country | Link |
---|---|
US (1) | US5580976A (zh) |
EP (1) | EP0611115B1 (zh) |
KR (1) | KR100289512B1 (zh) |
CN (1) | CN1045444C (zh) |
AT (1) | ATE200674T1 (zh) |
DE (1) | DE69427100T2 (zh) |
ES (1) | ES2157952T3 (zh) |
PT (1) | PT611115E (zh) |
TW (1) | TW277059B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8841444B2 (en) * | 2008-07-30 | 2014-09-23 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
WO2017132321A1 (en) | 2016-01-29 | 2017-08-03 | The Johns Hopkins University | Novel inhibitors of bacterial growth |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4122086A (en) * | 1977-07-26 | 1978-10-24 | Smithkline Corporation | Isopenicillins |
EP0528678A1 (en) * | 1991-08-20 | 1993-02-24 | SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. | A pyrrolidylthiocarbapenem derivative |
-
1994
- 1994-02-04 ES ES94300860T patent/ES2157952T3/es not_active Expired - Lifetime
- 1994-02-04 EP EP94300860A patent/EP0611115B1/en not_active Expired - Lifetime
- 1994-02-04 DE DE69427100T patent/DE69427100T2/de not_active Expired - Fee Related
- 1994-02-04 PT PT94300860T patent/PT611115E/pt unknown
- 1994-02-04 AT AT94300860T patent/ATE200674T1/de not_active IP Right Cessation
- 1994-02-07 TW TW083101017A patent/TW277059B/zh active
- 1994-02-08 KR KR1019940002353A patent/KR100289512B1/ko not_active IP Right Cessation
- 1994-02-09 CN CN94101804A patent/CN1045444C/zh not_active Expired - Fee Related
-
1995
- 1995-04-18 US US08/425,225 patent/US5580976A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4122086A (en) * | 1977-07-26 | 1978-10-24 | Smithkline Corporation | Isopenicillins |
EP0528678A1 (en) * | 1991-08-20 | 1993-02-24 | SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. | A pyrrolidylthiocarbapenem derivative |
Also Published As
Publication number | Publication date |
---|---|
EP0611115B1 (en) | 2001-04-18 |
PT611115E (pt) | 2001-07-31 |
ES2157952T3 (es) | 2001-09-01 |
ATE200674T1 (de) | 2001-05-15 |
DE69427100D1 (de) | 2001-05-23 |
KR940019681A (ko) | 1994-09-14 |
CN1097424A (zh) | 1995-01-18 |
DE69427100T2 (de) | 2001-11-22 |
KR100289512B1 (ko) | 2001-09-17 |
US5580976A (en) | 1996-12-03 |
EP0611115A1 (en) | 1994-08-17 |
TW277059B (zh) | 1996-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4631150A (en) | Process for the preparation of penems | |
GB2042520A (en) | 2-penem compounds and a method for preparing them | |
JPH0557980B2 (zh) | ||
US4155912A (en) | 2-Methylpenem-3-carboxylic acid antibiotics | |
EP0008514B1 (en) | Beta-lactam anti-bacterials, compositions containing them and a process for their preparation | |
GB2159818A (en) | Carbapenem intermediates | |
CN1045444C (zh) | β-内酰胺化合物的制备方法及其有关中间体 | |
US4683303A (en) | Reduction process for the preparation of 4-unsubstituted azetidin-2-ones | |
US4427586A (en) | 2-Oxoazetidine derivatives and production thereof | |
JPH0339514B2 (zh) | ||
EP0000645A1 (en) | Isopenicillins, processes for their preparation, and compositions containing them | |
US5563264A (en) | Preparation of βlactam compounds | |
JP4481829B2 (ja) | 経口投与用カルバペネム化合物の新規合成中間体及びその製造方法 | |
JP3543016B2 (ja) | β−ラクタム系化合物の製法 | |
JP3406669B2 (ja) | β−ラクタム系化合物の製造方法及びその中間体 | |
JPS6034970A (ja) | 2―ヘテロサイクリル―低級アルキル―2―ペネム化合物、その製法および該化合物を含有する医薬製剤 | |
JPWO2004043961A1 (ja) | 経口投与用カルバペネム化合物の製造方法 | |
JP2696807B2 (ja) | カルバペネム誘導体の製法 | |
AU644805B2 (en) | Process for penems | |
EP0574784B1 (en) | Process for preparing (1'R,3S,4R)4-acylthio azetidinones | |
EP0163452A1 (en) | A novel process for carbon-carbon bond formation at the C-4 position of 3-acylaminoazetidinones | |
US4169833A (en) | Novel phosphorane intermediates for use in preparing penem antibiotics | |
US5604222A (en) | Method for the preparation of 2-chloro sulfinyl azetidinones | |
US4663451A (en) | Process for the synthesis of penems and penams | |
JPH06220054A (ja) | カルボキシル基保護基の除去方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 19991006 |