CN1085210C - 碳代青霉烯抗菌剂的合成方法 - Google Patents
碳代青霉烯抗菌剂的合成方法 Download PDFInfo
- Publication number
- CN1085210C CN1085210C CN97196581A CN97196581A CN1085210C CN 1085210 C CN1085210 C CN 1085210C CN 97196581 A CN97196581 A CN 97196581A CN 97196581 A CN97196581 A CN 97196581A CN 1085210 C CN1085210 C CN 1085210C
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- aryl
- pharmaceutically acceptable
- acceptable salt
- 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 - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract 3
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 229940043279 diisopropylamine Drugs 0.000 claims abstract description 18
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 150000001412 amines Chemical class 0.000 claims abstract description 9
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 claims abstract description 7
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 abstract description 7
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 abstract 1
- -1 salt of wormwood Chemical compound 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000003513 alkali Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical group SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 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
- 150000001768 cations Chemical class 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 125000006502 nitrobenzyl group Chemical group 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- HHMGSYLNFMCNDP-UHFFFAOYSA-L O.O.O.S(=O)([O-])[O-].[Na+].[Na+] Chemical compound O.O.O.S(=O)([O-])[O-].[Na+].[Na+] HHMGSYLNFMCNDP-UHFFFAOYSA-L 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- PYCKVIXZIACHAI-NSHDSACASA-N [O-][N+](C1=CC=C(CON(CCC2)[C@@H]2C(O)=O)C=C1)=O Chemical compound [O-][N+](C1=CC=C(CON(CCC2)[C@@H]2C(O)=O)C=C1)=O PYCKVIXZIACHAI-NSHDSACASA-N 0.000 description 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 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 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002892 organic cations Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D477/10—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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- 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
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- 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
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Abstract
一种式(I)化合物或其药物上可接受的盐或酯的合成方法，其中每个P独立地表示H或保护基，并且R1和R2独立地表示H、C1-10烷基、芳基或杂芳基，或者取代的C1-10烷基、芳基或杂芳基，所述方法包括：在选自二异丙基胺(DIPA)、二环己基胺(DCHA)、2，2，6，6-四甲基哌啶(TMP)、1，1，3，3-四甲基胍(TMG)、1，8-二氮杂双环[4.3.0]十一碳-7-烯(DBU)和1，5-二氮杂双环[4.3.0]壬-5-烯的胺存在下，将所述化合物(II)或其药物上可接受的盐或酯与化合物(III)或其药物上可接受的盐或酯反应(其中X表示OP(O)(OR)3或OSO2R，其中R表示C1-6烷基、芳基或氟代C1-6烷基)，制得式(I)化合物。
Description
发明背景
本发明涉及碳代青霉烯抗菌剂的合成方法。现已发现，在此类反应中，与使用叔胺时所观测到的结果相比，本文所述偶合反应包含仲胺在内的可明显地并且令人惊奇地提高反应速率，使反应时间缩短并可在较低温度下相对完全地进行转化反应。
已有报导，三乙胺和二异丙基乙基胺可用于这些反应中，但从商业角度上看，所述反应时间和条件是不能接受的。例如，1993年8月5日公开的WO 93/15078涉及在例如二异丙基乙基胺的叔胺或例如碱金属碳酸盐如碳酸钾的无机碱存在下的类似反应，此反应在-25℃至环境温度下进行。
本发明的一个目的是以足够快的速率进行所述碳代青霉烯基本分子和所述2-位侧链的反应，并且有效地减少副产物的形成以及避免不适宜的高温和低温及其他反应条件的需要。
本发明另一个目的是避免使用催化剂以及其他反应组份，若在最终产物中含有痕量的所述组份就需要分立的脱除步骤。
这些目的以及其他目的对于本文所述技术内容来讲是显而易见。
发明概述
本发明公开了一种下列式I化合物或其药物上可接受的盐或酯的合成方法：
其中每个P独立地表示H或保护基，并且R1和R2独立地表示H、C1-10烷基、芳基或杂芳基，或者取代的C1-10烷基、芳基或杂芳基，所述方法包括：在选自二异丙基胺(DIPA)、二环己基胺(DCHA)、2，2，6，6-四甲基哌啶(TMP)、1，1，3，3-四甲基胍(TMG)、1，8-二氮杂双环[4.3.0]十一碳-7-烯(DBU)和1，5-二氮杂双环[4.3.0]壬-5-烯(DBN)的胺存在下，将下式化合物或其药物上可接受的盐或酯：
与下式化合物或其药物上可接受的盐或酯反应，
其中X表示OP(O)(OR)2或OSO2R，其中R表示C1-6烷基、C1-6烷芳基、芳基或全氟C1-6烷基，制得式I化合物。发明详述
现已发现，本文所述胺使式II和III化合物之间的反应更加容易。对于式II和III化合物，这些化合物可以例如按照并入本文作为参考文献的1991年7月23日授权的美国专利5,034,384和1991年2月19日授权的美国专利4,994,568中所述方法制备。
同样，例如化合物IIa和IIIa的化合物也可按照并入本文作为参考文献的1995年12月26日授权的美国专利5,478,820制备。
本文所述反应优选在极性非质子传递溶剂中进行。极性非质子传递溶剂的优选实例包括二甲基甲酰胺、N-乙基吡咯烷酮和乙腈。
本发明优选地是公开了一种下列式Ia化合物或其药物上可接受的盐或酯的合成方法：中每个P独立地表示H或保护基，所述方法包括：在选自二异丙基胺(DIPA)、二环己基胺(DCHA)、2，2，6，6-四甲基哌啶(TMP)、1，1，3，3-四甲基胍(TMG)、1，8-二氮杂双环[4.3.0]十一碳-7-烯(DBU)和1，5-二氮杂双环[4.3.0]壬-5-烯(DBN)的胺存在下，将下式化合物或其药物上可接受的盐或酯：
与下式化合物或其药物上可接受的盐或酯反应，
其中Ph表示苯基，制得式Ia化合物。
除非另有说明，本文更详细描述本发明时所用术语如下定义。
除非另有定义，所述术语“烷基”是指含有1-15个碳原子的一价链烷(烃)衍生的基团，其可以是直链或支链基团，并且当其大小合适时，例如C3-15，也可以是环状基团。优选的直链或支链烷基包括甲基、乙基、丙基、异丙基、丁基和叔丁基。优选的环烷基包括环丙基、环戊基和环己基。
烷基还包括被环烷基取代的烷基，例如环丙基甲基。
烷基还包括含有或者被亚环烷基部分间隔的直链或支链烷基。例如下列基团：其中：x’和y’＝0-10；并且w和z＝0-9。
所述烷基中的亚烷基和一价烷基部分可以与所述亚环烷基部分上的任何适宜的连接部位相连。
当存在取代的烷基时，其是指被所定义的彼此不同的1-3个基团取代的如上定义的直链、直链或环状烷基。
杂烷基是指含有2-15个碳原子并且被1-4个选自O、S和N的杂原子间隔的烷基。
所述术语“链烯基”是指含有2-15个碳原子和至少一个碳-碳双键的直链、支链或环状烃基。优选含有一个碳-碳双键，并且可以至多含有四个非芳族(非共振)碳-碳双键。优选的链烯基包括乙烯基、丙烯基、丁烯基和环己烯基。如上述烷基部分所述，所述链烯基的直链、支链或环状部分可以含有双键并且作为取代的链烯基时还可以被取代。
所述术语“链炔基”是指含有2-15个碳原子和至少一个碳-碳三键的直链、支链或环状烃基。其至多可以含有三个碳-碳三键。优选的链炔基包括乙炔基、丙炔基和丁炔基。如上述烷基部分所述，所述链炔基的直链、支链或环状部分可以含有双键并且作为取代的链炔基时还可以被取代。
芳基是指芳族环例如苯基、取代的苯基等以及稠合的环例如萘基等。此类芳基可含有至少一个含有至少6个原子的环，至多两个此类环，其中含有至多10个原子、相邻碳原子间有交替的(共振)双键。优选的芳基包括苯基和萘基。同样，芳基也可如下所述被取代。优选的取代的芳基包括被1-3个选自卤素、烷基和三氟甲基的基团取代的苯基和萘基。
所述术语“杂芳基”是指含有至少一个杂原子，O、S或N的、含有5或6个环原子的单环芳族烃，或者含有8-10个原子的双环芳族烃，其中一个碳原子或氮原子是连接点，和其中另一个碳原子可任意地被选自O或S的杂原子取代，和其中另外的1-3个碳原子可任意地被氮杂原子取代。所述杂芳基可任意地被至多3个基团取代。
杂芳基包括含有一个或多个杂原子的芳族和部分芳族基团。此类基团的实例有噻吩、嘌呤、咪唑并吡啶、吡啶、噁唑、噻唑、噁嗪、吡唑、四唑、咪唑、吡啶、嘧啶、吡嗪和三嗪。部分芳族基团的实例有如下定义的四氢咪唑并[4，5-c]吡啶、2-苯并[c]呋喃酮基和糖精基。
取代的烷基、芳基和杂芳基，以及芳烷基、芳基烷氧基、杂芳基烷基、杂芳基烷氧基等基团的取代基部分可被1-3个选自下列的基团取代，所述基团为卤素、羟基、氰基、酰基、酰氨基、芳基烷氧基、烷基磺酰基、芳基磺酰基、烷基磺酰氨基、芳基磺酰氨基、烷氨基羰基、烷基、烷氧基、芳基、芳氧基、芳基烷氧基、氨基、烷氨基、二烷氨基、羧基和磺酰氨基。
所述术语“杂环烷基”和“杂环基”是指其中所述环中的一个碳原子被选自O、S(O)y或N的杂原子替代并且其中至多另外的三个碳原子可被所述杂原子替代的环烷基(非芳族)。当在所述杂环中含有三个杂原子时，它们不都连在一起。
杂环的实例有哌啶基、吗啉基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、咪唑啉基、哌嗪基、吡咯烷-2-酮、哌啶-2-酮等。
本文所用酰基是指-C(O)C1-6烷基和-C(O)-芳基。
酰氨基是指基团-NHC(O)C1-6烷基和-NHC(O)芳基。
芳基烷氧基是指基团-OC1-6烷基芳基。
烷基芳基是指C1-6烷基-芳基-。
烷基磺酰基是指基团-SO2C1-6烷基。
烷基磺酰氨基是指基团-NHSO2C1-6烷基。
芳基磺酰氨基是指基团-NHSO2芳基。
烷氨基羰基是指基团-C(O)NHC1-6烷基。
芳氧基是指基团-O-芳基。
磺酰氨基是指基团-NHSO3H。
卤素独立地选自Cl、F、Br和I。
本发明所述化合物可以以各种药物上可接受的盐形式使用。所述术语“药物上可接受的盐”是指药物化学领域显而易见的盐形式，例如基本无毒的并且可提供所需药物代谢动力学特性、可口性、吸收作用、分布、代谢或排泄的盐。实际上更实用的其他因素在选择中也是很重要的，它们包括原料消耗、结晶难易、所得药物的产率、稳定性、吸湿性和流动性。通常，药物组合物可由所述活性成份与药物上可接受的载体混合制得。
所述式I化合物药物上可接受的盐包括常规无毒盐以及例如与无机或有机阳离子基团形成的式I化合物的季铵盐。例如，这些盐可含有为了保持总电荷呈中性所需的与所述化合物一起存在的电荷平衡阳离子。所述电荷种类典型地是药物上可接受的成盐离子，例如钠、钾、镁等。当所述抗衡离子含有二价阳离子例如Ca2+时，为了达到总电荷呈中性，典型地是其以所述碳代青霉烯基团相应的适宜的量存在。这样，为了保持总电荷呈中性，可含有半个摩尔当量的Ca2+。所有此类实施方案均包括在本发明内。
Berge，S.M.，等人在J.Pharm.Sci.66(1)：1-16(1977)中引证了大量成盐离子，这些教导均并入本文作为参考。
优选的成盐阳离子可选自钠、钾、钙和镁。
更优选的阳离子选自Na+、Ca2+和K+。
本发明药物上可接受的盐可以用常规化学方法合成。通常，所述盐可在适宜溶剂或溶剂混合物中通过将所述游离碱或酸与化学计算量或过量的所需成盐无机或有机酸或碱反应制得。
用于本发明的优选的一组胺包括二异丙基胺和二环己基胺。这些胺可与二苯基磷酸形成结晶盐，此偶合反应混合物中所得结晶为脱除所述反应中的磷酸副产物提供了机会。
利用上述胺，可意想不到地提高所述反应速率。
本发明制备的所述化合物可含有不对称中心并且可以以外消旋物、外消旋混合物以及单一的非对映体形式存在。合成过程中所有此类异构体包括光学异构体均包括在本发明中。
所述碳代青霉烯的3-位羧基和8-位羟基、所述吡咯烷基氮原子、和存在时，所述间羧基苯基基团可保持阻断状态，直至制得最终产物。这些阻断基团可很容易地被脱除，例如，如果需要的话，它们可以通过不会引起所述分子的保留部分裂解或其他破裂的方法脱除。此类方法包括化学和酶促水解法、在温和条件下用化学还原剂或氧化剂处理、用氟离子处理、用过渡金属催化剂和亲核试剂处理以及催化氢化法。
适宜的羟基保护基的实例有：叔丁基甲氧基苯基甲硅烷基、叔丁氧基二苯基甲硅烷基、三甲基甲硅烷基、三乙基甲硅烷基、邻硝基苄氧羰基、对硝基苄氧羰基、苄氧羰基、叔丁氧羰基、2，2，2-三氯乙氧羰基和烯丙氧基羰基。优选的羟基保护基为三甲基甲硅烷基和三乙基甲硅烷基。
适宜的羧基保护基的实例有：二苯甲基、邻硝基苄基、对硝基苄基、2-萘甲基、烯丙基、2-氯烯丙基、苄基、2，2，2-三氯乙基、三甲基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、2-(三甲基甲硅烷基)乙基、苯甲酰甲基、对甲氧基苄基、丙酮基、对甲氧基苯基、4-吡啶甲基和叔丁基。优选的羧基保护基为对硝基苄基。
许多其他适宜的羟基和羧基保护基是本领域公知的，例如参见T.W.Greene，Protective Groups in Organic Synthesis，John Wiley& Sons，Inc.，1981(第2和5章)。
本发明将在下列非限定性实施例中得以阐明。
制备实施例1(2S，4S)-1-(对硝基苄氧羰基)-2-(3-羧基苯基氨基甲酰基)-吡咯烷-4-基硫醇：侧链硫醇(B)
于THF(225ml)和甲苯(75ml)混合物中将PNZ羟基脯氨酸(15g)进行搅拌并将所述混合物冷却至-10℃。加入二异丙基乙基胺(13.4g)，随后加入12.1g二苯基磷酰氯的15ml甲苯溶液，将混合物于-10℃下老化2小时并加入4.1g吡啶的4ml甲苯溶液，随后加入6.29g甲磺酰氯的4ml甲苯溶液。4小时后，加入硫化钠三水合物(7.0g)的75ml水溶液并将混合物温热至20℃，老化14小时。分层，有机层用HCl(150ml，1.0N)、碳酸氢钠(280ml，5％，40-45℃)和NaCl水溶液(150ml，饱和溶液，20-25℃)萃取。
向1L烧瓶中加入540ml萃取液、6.6g间氨基苯甲酸和1.0ml三丁基膦。将所述混合物进行脱气并经常压下蒸馏浓缩至200ml。继续蒸馏下加入甲苯，直至馏出液的温度达到110℃。加入乙酸(200ml)和1-丙醇(200ml)，将所得混合物冷却至15-20℃，并老化18小时。经过滤分离所述产物，用1-丙醇洗涤，并于80℃真空干燥，得到15.4g侧链硫醇。
实施例1
将化合物A(594mg，1.0mmol)和化合物B(454mg，1.02mmol)合并并加入DMF(2.0ml)。将混合物脱气，所得溶液冷却至-50℃至-30℃，加入二异丙基胺(204mg，0.28ml)，在2-3小时内，反应完成，转化率＞98％。
对比实施例
除了用等摩尔量的二异丙基乙基胺代替二异丙基胺以外，按照实施例1所述方法，18小时后完成所述反应(转化率为98％)。
实施例2
利用实施例1所述方法，用二异丙基乙基胺(DIPEA)代替所述碱二异丙基胺。
就A与B’反应制备C’的反应速率而言，DIPA以及所述其他胺明显高于DIPEA
表I
| 转化率达98％所需时间 | 检测产率(％) | 面积％纯度 | |
| DBU | ＜0.25h | - | - |
| DIPA | 0.5h | 98 | 97.3 |
| TMG | 2h | 98 | 98.0 |
| TMP | 2h | - | - |
| DIPEA | ＞4ha | 92b | - |
在-20℃下，用1.1当量的碱，在0.1M下用等摩尔量A和B’进行反应。
a4小时时的转化率约为90％。b4小时时的产率。
Claims (5)
1.一种下列式I化合物或其药物上可接受的盐或酯的合成方法：
其中每个P独立地表示H或者羧基或羟基保护基，并且R1和R2独立地表示H、C1-10烷基、芳基或杂芳基，或者被选自卤素、羟基、氰基、酰基、酰氨基、芳基烷氧基、烷基磺酰基、芳基磺酰基、烷基磺酰氨基、芳基磺酰氨基、烷氨基羰基、烷基、烷氧基、芳基、芳氧基、芳基烷氧基、氨基、烷氨基、二烷氨基、羧基和磺酰氨基的1-3个基团取代的C1-10烷基、芳基或杂芳基，所述方法包括：在选自二异丙基胺(DIPA)、2，2，6，6-四甲基哌啶(TMP)、1，1，3，3-四甲基胍(TMG)和1，8-二氮杂双环[4.3.0]十一碳-7-烯(DBU)的胺存在下，将下式化合物或其药物上可接受的盐或酯：
与下式化合物或其药物上可接受的盐或酯反应，其中X表示OP(O)(OR)2或OSO2R，其中R表示C1-6烷基、C1-6烷芳基、芳基或全氟C1-6烷基，制得式I化合物。
2.一种下列式Ia化合物或其药物上可接受的盐或酯的合成方法：
其中每个P独立地表示H或者羧基或羟基保护基，所述方法包括：在选自二异丙基胺(DIPA)、2，2，6，6-四甲基哌啶(TMP)、1，1，3，3-四甲基胍(TMG)和1，8-二氮杂双环[4.3.0]十一碳-7-烯(DBU)的胺存在下，将下式化合物或其药物上可接受的盐或酯：
与下式化合物或其药物上可接受的盐或酯反应，其中Ph表示苯基，制得式Ia化合物。
3.根据权利要求1所述方法，其中所述仲胺为二异丙基胺(DIPA)。
4.根据权利要求3所述方法，其中所述合成在极性非质子传递溶剂中进行。
5.根据权利要求4所述方法，其中所述极性非质子传递溶剂选自二甲基甲酰胺、N-乙基吡咯烷酮和乙腈。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2164996P | 1996-07-12 | 1996-07-12 | |
| US60/021,649 | 1996-07-12 | ||
| GB9617417.2 | 1996-08-20 | ||
| GBGB9617417.2A GB9617417D0 (en) | 1996-08-20 | 1996-08-20 | Process for synthesizing carbapenem antibodies |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1225636A CN1225636A (zh) | 1999-08-11 |
| CN1085210C true CN1085210C (zh) | 2002-05-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN97196581A Expired - Lifetime CN1085210C (zh) | 1996-07-12 | 1997-07-08 | 碳代青霉烯抗菌剂的合成方法 |
Country Status (18)
| Country | Link |
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| EP (1) | EP0912576B1 (zh) |
| CN (1) | CN1085210C (zh) |
| AR (1) | AR008255A1 (zh) |
| AT (1) | ATE210664T1 (zh) |
| AU (1) | AU3720997A (zh) |
| BR (1) | BR9710360A (zh) |
| CY (1) | CY2310B1 (zh) |
| CZ (1) | CZ9199A3 (zh) |
| DE (1) | DE69709113T2 (zh) |
| DK (1) | DK0912576T3 (zh) |
| EA (1) | EA001152B1 (zh) |
| ES (1) | ES2167762T3 (zh) |
| HK (1) | HK1017356A1 (zh) |
| PT (1) | PT912576E (zh) |
| SK (1) | SK283298B6 (zh) |
| TW (1) | TW513430B (zh) |
| UA (1) | UA54444C2 (zh) |
| WO (1) | WO1998002439A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7538212B2 (en) * | 2002-11-13 | 2009-05-26 | Kaneka Corporation | Intermediate for carbapenem compound for oral administration and process for producing the same |
| EP1926732B1 (en) | 2005-09-05 | 2013-11-06 | Ranbaxy Laboratories Limited | A process for the preparation of carbapenem compounds |
| CN101357920B (zh) * | 2007-06-22 | 2011-01-12 | 山东轩竹医药科技有限公司 | 含有巯基吡咯烷甲酰胺基三嗪的培南化合物 |
| CN101367807B (zh) * | 2007-06-28 | 2011-01-12 | 山东轩竹医药科技有限公司 | 被巯基吡咯烷甲酰胺基吡啶取代的培南衍生物 |
| CN101367806B (zh) * | 2007-06-28 | 2010-11-17 | 山东轩竹医药科技有限公司 | 甲酰苯胺取代的巯基吡咯烷碳青霉烯类化合物 |
| CN101343272B (zh) * | 2007-07-13 | 2011-02-09 | 山东轩竹医药科技有限公司 | 含有环己烷的碳青霉烯化合物 |
| CN101362757A (zh) * | 2007-08-09 | 2009-02-11 | 山东轩竹医药科技有限公司 | 磺酰基取代的碳青霉烯类化合物 |
| CN101362763B (zh) * | 2007-08-12 | 2011-01-12 | 山东轩竹医药科技有限公司 | 含有巯基吡咯烷的碳青霉烯衍生物 |
| CN101412719B (zh) * | 2007-08-30 | 2010-11-17 | 山东轩竹医药科技有限公司 | 碳代青霉烯类衍生物 |
| US8097719B2 (en) * | 2008-07-15 | 2012-01-17 | Genesen Labs | Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem |
| CN101875665B (zh) | 2009-04-30 | 2013-02-06 | 石药集团中奇制药技术（石家庄）有限公司 | 一种厄他培南中间体、含其的组合物及其制备方法 |
| CN102260264A (zh) * | 2010-05-25 | 2011-11-30 | 浙江海翔药业股份有限公司 | 一种非钯体系制备厄他培南的方法 |
| JP2015533142A (ja) | 2012-10-12 | 2015-11-19 | サンド・アクチエンゲゼルシヤフト | エルタペネム中間体の製造 |
| CN106565579A (zh) * | 2016-06-26 | 2017-04-19 | 宁夏海诚电化信息科技有限公司 | 一种尔它培南侧链生产工艺 |
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| GB9202298D0 (en) * | 1992-02-04 | 1992-03-18 | Ici Plc | Antibiotic compounds |
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Also Published As
| Publication number | Publication date |
|---|---|
| SK3299A3 (en) | 1999-07-12 |
| UA54444C2 (uk) | 2003-03-17 |
| ATE210664T1 (de) | 2001-12-15 |
| EA199900099A1 (ru) | 1999-06-24 |
| AU3720997A (en) | 1998-02-09 |
| HK1017356A1 (en) | 1999-11-19 |
| TW513430B (en) | 2002-12-11 |
| SK283298B6 (sk) | 2003-05-02 |
| EA001152B1 (ru) | 2000-10-30 |
| CZ9199A3 (cs) | 1999-06-16 |
| EP0912576B1 (en) | 2001-12-12 |
| PT912576E (pt) | 2002-05-31 |
| CY2310B1 (en) | 2003-11-14 |
| DK0912576T3 (da) | 2002-03-25 |
| DE69709113D1 (de) | 2002-01-24 |
| CN1225636A (zh) | 1999-08-11 |
| BR9710360A (pt) | 1999-08-17 |
| DE69709113T2 (de) | 2002-07-11 |
| AR008255A1 (es) | 1999-12-29 |
| ES2167762T3 (es) | 2002-05-16 |
| EP0912576A1 (en) | 1999-05-06 |
| WO1998002439A1 (en) | 1998-01-22 |
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