WO2004043973A1 - 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 - Google Patents
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 Download PDFInfo
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- WO2004043973A1 WO2004043973A1 PCT/JP2003/014419 JP0314419W WO2004043973A1 WO 2004043973 A1 WO2004043973 A1 WO 2004043973A1 JP 0314419 W JP0314419 W JP 0314419W WO 2004043973 A1 WO2004043973 A1 WO 2004043973A1
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- compound
- general formula
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- compound represented
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- -1 carbapenem compound Chemical class 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 3
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- LAXBNTIAOJWAOP-UHFFFAOYSA-N 2-chlorobiphenyl Chemical compound ClC1=CC=CC=C1C1=CC=CC=C1 LAXBNTIAOJWAOP-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical group C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 abstract description 8
- 239000007858 starting material Substances 0.000 abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 abstract 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 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 102
- 238000006243 chemical reaction Methods 0.000 description 47
- 239000000243 solution Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 238000007363 ring formation reaction Methods 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- 238000010511 deprotection reaction Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 150000003573 thiols Chemical group 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- ZSIAANIILFGLQH-UHFFFAOYSA-N C1(=CC=CC=C1)[ClH]P(=O)(Cl)[ClH]C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)[ClH]P(=O)(Cl)[ClH]C1=CC=CC=C1 ZSIAANIILFGLQH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 150000007944 thiolates Chemical class 0.000 description 6
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- JARXNQUBGBXALE-UHFFFAOYSA-N C(C)[SiH](CC)CC.Cl Chemical compound C(C)[SiH](CC)CC.Cl JARXNQUBGBXALE-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000004210 ether based solvent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 2
- XQFGVGNRDPFKFJ-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydropyrrolo[1,2-b]pyridazine Chemical compound N1CCC=C2CCCN21 XQFGVGNRDPFKFJ-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical group OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-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
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QTZBTBLHYPSFMG-UHFFFAOYSA-N 5-chloro-3-methylpyridin-2-amine Chemical compound CC1=CC(Cl)=CN=C1N QTZBTBLHYPSFMG-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-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
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 235000001484 Trigonella foenum graecum Nutrition 0.000 description 1
- 244000250129 Trigonella foenum graecum Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 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
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 239000007806 chemical reaction intermediate 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000962 organic group Chemical group 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
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 150000007970 thio esters Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D477/10—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
- C07D477/18—Oxygen atoms
-
- 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
Definitions
- the present invention relates to a novel synthetic intermediate of a rubenem compound for oral administration and a method for producing the same.
- the present invention relates to a novel 0-latatam compound which is extremely useful as a common synthetic intermediate of 1] 3-methylcarbapanem compound for oral administration and a method for producing the same.
- 1-Methylcarbapanem compounds are one of the most noticeable antibacterial agents because they exhibit excellent antibacterial activity against a wide range of pathogenic bacteria and also have excellent stability in vivo. Therefore, in recent years, research and development of drugs for oral administration have been energetically advanced. At present, the following method is generally used as a method for producing 1] 3-methylcarbapanem compound for oral administration.
- R represents a thiol residue and But represents a tert-butyl group.
- Examples of the compound represented by the above formula (10) include, for example, the above-mentioned JP-A-8-53453 and JP-A-10-1975076 disclose a compound represented by the formula (11):
- JP-A-8-59663 and JP-A-2000-344774 disclose formula (14):
- R 4 represents a hydroxyl-protecting group
- R 5 represents a thiol residue contained in the product 1 j3-methylcarbene compound
- R 6 represents an organic group.
- R 4 , R 5 , and R 6 have the same meanings as described above, and R 7 , R 8 , and R 9 are all lower alkoxy groups having 1 to 4 carbon atoms, or one is a lower alkoxy group having 1 to 4 carbon atoms. And the remaining two are lower alkoxy groups having 1 to 4 carbon atoms, and a compound represented by the following formula (16):
- R 4 , R 5 and R 6 have the same meanings as described above.
- the present inventors have conducted intensive studies on the development of a novel mono-ratatum compound and a method for producing the same so that a thiol compound can be introduced in one step at the final stage in the synthesis of 1-methylcarbapanem for oral administration.
- the present invention has been achieved. That is, the present invention provides a compound represented by the following general formula (1):
- R 2 represents an aryl group or a heteroaryl group, and R 3 has 1 carbon atom
- the present invention provides a compound represented by the general formula (4), wherein the hydroxyl group of the compound (3) produced as described above is deprotected.
- the present invention provides a compound represented by the general formula (1):
- a method for producing a ⁇ -lactam compound which is a compound represented by the formula:
- the compound represented by the formula (1) is represented by the general formula (5):
- the compound represented by the above formula (3) produced by the process for producing a 3-latatam compound of the present invention is obtained by deprotecting a hydroxyl group to obtain a compound represented by the general formula (4):
- the hydroxyl-protecting group R is a trimethylsilyl group or a triethylsilyl group, particularly preferably a trimethylsilyl group.
- these substituents can be mildly decomposed as much as possible without decomposing other functional groups in the compound.
- the inventor of the present invention has found out that it can be removed under reaction conditions as a result of intensive studies.
- R 2 which is a thiol residue represents an aryl group or a heteroaryl group; a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; a nitro group; It may be substituted by an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or the like.
- aryl group examples include a phenyl group, a halognophenyl group substituted with 1 to 3 chlorine atoms, a bromine atom, a halogen atom such as an iodine atom, a p-trophenyl group, an o-nitrophenyl group, p-Methoxyphenyl, 1-naphthyl, 21-naphthyl and the like.
- heteroaryl group examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2- (4,6-dimethyl) pyrimidyl, 2-benzothiazolyl, 2-benzoimidazolyl, Examples thereof include a 2-benzoxazolyl group and a 2-chel group.
- R 2 is preferably an aryl group, more preferably a phenyl group or a halognophenyl group in terms of availability, economy, reactivity, etc., and as the halognophenyl group, a p-chlorophenol group is preferred. .
- the substituent R 3 is a carboxylic acid in a compound which can be finally developed as a 1-methylcarbapanem compound for oral administration It is included in the alkyloxymethyl group site of the ester residue, and represents an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms.
- Examples of the alkyl group having 1 to 10 carbon atoms include a methyl group, an ethyl group, a normal propynole group, an isopropyl group, a nonolemanolebutyl group, an isopti / le group, a sec-petit / le group, a tert-butyl group, Examples include a normal octyl group and a normal decanyl group.
- the cycloalkyl group having 3 to 10 carbon atoms may have a substituent, and examples of the substituent include an alkyl group having 1 to 4 carbon atoms such as a methyl group and an ethyl group.
- Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclohexyl group, a 1-methylcyclohexyl group, and a 4-methylcyclohexyl group.
- the substituent R 3 a tert-butyl group often used in the development of an orally administrable ruvanem compound is particularly preferable.
- the substituent X represents a halogen atom, and includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. From the viewpoints of easy availability of the compound (6), reactivity, stability, and the like, chlorine Atoms are particularly preferred.
- the compound represented by the formula (5) as a starting material preferably used in the present invention is, for example, Chemical 'and' Pharmaceutical Plutin (Chem.Pharm.Bull.) S 42 vol. It is a compound which can be easily produced by the method described on pages 1381 to 1387, 1994 ', and can be easily synthesized in the form of an optically active substance which is desirable as a synthetic substance of 1] 3-methylcarbapanem compound. Reacting the above compound (5) with an alkanoyloxymethyl halide represented by the above formula (6) in the presence of a base to give a compound represented by the above formula (1)] Can lead to things.
- the reaction is performed using an inert solvent that does not decompose compound (5) and compound (6).
- the inactive solid solvent is not particularly limited, but ether solvents such as tetrahydrofuran, dioxane and getyl ether; aromatic hydrocarbon solvents such as benzene, toluene and xylene; N, N-dimethylformamide; Examples include amide solvents such as N, N-dimethylacetamide; dimethyl sulfoxide, acetonitrile, acetone, methylene chloride, and mixed solvents thereof. From the viewpoint of reaction speed, N, N-dimethylformamide and N, N-dimethylacetamide are particularly preferred.
- the amount of the alkanoyloxymethyl halide (6) used in the reaction must be at least 1.0 times the molar amount of the compound (5), and preferably 1.1 to 3.0 times the amount of the monole. It is.
- the base to be used those generally used in a reaction of forming an ester with a carboxylic acid and an alkyl halide can be used, and examples thereof include organic amines and alkali metal salts. .
- organic amines examples include 1, ryethylamine, diisopropylethylamine, dihexylhexylamine, 1,8-diazavicix [5. 4.0] pendeicene (DBU), and morpholine. Is exemplified. The amount used is based on compound (5) A molar amount of 1.0 or more is necessary, and a molar amount of 1.1 to 2.0 is preferable.
- alkali metal salt examples include alkali carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; and sodium bicarbonate and bicarbonate such as sodium bicarbonate.
- the amount of the compound used should be at least 0.5 times the molar amount of the compound (5) when using an alkali carbonate, and at least 1.0 times the amount when using an alkali bicarbonate. A molar amount of 1 to 2.0 times is preferred.
- an additive may be added as a reaction accelerator, if necessary.
- the additive include alkali metal halides such as sodium iodide and lithium bromide, tetrabutylammonium bromide, and chloride. And quaternary ammonium halides such as benzyltriethylammonium.
- the amount used is preferably at least 1.0 times the molar amount of compound (6), and most preferably 1.0 to 1.5 times the molar amount.
- the above reaction is usually carried out at 0 to 80 ° C, but is preferably carried out at 10 to 40 ° C for the reason of suppressing the decomposition of the reactants and products.
- the reaction time is usually 1 to 50 hours, but is preferably 2 to 30 hours for the above-mentioned reason.
- TLC thin layer chromatography
- HPLC high performance liquid chromatography
- the target compound (1) can be isolated from the mixture after the reaction through operations such as H control, extraction, liquid separation, washing, concentration, and purification.
- the compound (1) obtained by the above reaction is a novel compound, and is useful by the present inventors for producing a common synthetic intermediate for producing 1 jS-methylcarbapanem compound for oral administration. It is a compound that has been confirmed to be a useful precursor.
- the compound (1) obtained by the above reaction is subsequently converted to the compound (2) by protecting the hydroxyl group.
- the reaction is a reaction for introducing a silinole protecting group into a hydroxyl group.
- a silyl protecting group as described in pp. 39-50, 1981 can be employed.
- a trimethylsilyl group or a triethylsilyl group is introduced.
- the amount of the salted trimethylsilane or triethylsilane chloride must be at least 1.0 times the molar amount of the compound (1), and is preferably 1.1 to 3.0 times the molar amount.
- amine used as the base examples include triethylamine, diisopropylethylamine, pyridine, imidazole and the like.
- the amount thereof must be at least 1.0 times the molar amount of the compound (1), and is preferably 1.1 to 3.0 times the molar amount.
- the inert solvent is not particularly limited as long as it is inactive so as not to decompose the above-mentioned trialkylsilane.
- Ether solvents such as tetrahydrofuran, dioxane, and ethyl ether; benzene, toluene, xylene and the like; Aromatic hydrocarbon solvents; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetoamide; dimethylsulfoxide, acetonitrile, acetone, methylene chloride, and mixtures thereof.
- the above reaction is usually carried out at 0 to 100 ° C, but is preferably carried out at 10 to 60 ° C for the reason of suppressing the decomposition of the reactants and products.
- the reaction time is usually 0.5 to 50 hours, but is preferably 1 to 30 hours for the above-mentioned reason.
- the progress of the reaction can be tracked using analytical means.
- compound (2) can be isolated through procedures such as pH adjustment, extraction, liquid separation, washing, concentration and purification that are often used in organic reactions. At this time, if compound (2) is subjected to acidic conditions, the protective group on the hydroxyl group will be deprotected and will return to starting compound (1). Must.
- the compound (2) obtained by the above reaction is converted into the compound (3) by cyclization in the presence of a strong base and then treatment with diphenylphosphoric acid.
- Suitable strong bases used in the cyclization reaction of compound (2) include alkali metal alkoxides such as potassium tert-butoxide and sodium tert-butoxide; lithium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl). Examples thereof include alkali metal amides such as amide and potassium bis (trimethinoresilinole) amide; and alkali metal hydrides such as sodium hydride and hydrogenation hydride.
- alkali metal alkoxides such as potassium tert-butoxide and sodium tert-butoxide
- lithium bis (trimethylsilyl) amide lithium bis (trimethylsilyl) amide
- sodium bis (trimethylsilyl) examples thereof include alkali metal amides such as amide and potassium bis (trimethinoresilinole) amide; and alkali metal hydrides such as sodium hydride and hydrogenation hydride.
- potassium tert-butoxide sodium bis (trimethylsilyl) Amide
- the amount used is desirably an amount sufficient for the cyclization reaction to proceed sufficiently, and is preferably 2 to 3 times the molar amount of compound (2).
- a metal thiolate is by-produced as the cyclization proceeds. Therefore, it is preferable to use a scavenger for converting the metal thiolate into a compound having no adverse effect in the subsequent reaction.
- the scavenger examples include alkylating agents such as methyl iodide, propyl iodide, aryl bromide, benzyl bromide, and methyl toluenesulfonate; sulfonylation such as p-toluenesulfol chloride and methanesulfonyl chloride Agents: Phosphate esterifying agents such as diphenyl phosphoric acid and the like.
- the amount of the metal thiolate to be used is preferably the same as that of the metal thiolate by-produced from the compound (2), and it is preferably used in an amount of 1.0 to 1.5 times the molar amount of the compound (2).
- the compound (3) is produced by the reaction of the reaction intermediate in which the compound (2) is cyclized with diphenylphosphoric acid chloride. This reaction is usually performed in the same reactor as the previous cyclization reaction.
- the amount of diphenylphosphoric acid to be used needs to be sufficient to allow the reaction to proceed sufficiently, and is preferably 1.0 to 1.5 times the molar amount of compound (2).
- diphenylphosphoric acid chloride also serves as a scavenger for by-produced metal thiolate as described above.
- the metal thiolate can be supplemented by adding at least twice the molar amount to the compound (2), and can also be used as a phosphate esterifying agent. it can.
- the above-mentioned cyclization and phosphorylation reactions are performed in an inert solvent.
- the inert solvent is not particularly limited, but preferred examples thereof include ether solvents such as tetrahydrofuran, dioxane and getyl ether; and aromatic solvents such as benzene, toluene and xylene. Hydrocarbon solvents; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; dimethylsulfoxide, acetonitrile, acetone, methylene chloride, and mixed solvents thereof.
- Tetrahydrofuran or a mixed solvent of toluene and toluene is optimal from the viewpoint of the solubility of the base and the compound (2), but the mixing ratio is not particularly limited as long as the reaction reagent is dissolved.
- the above-mentioned cyclization and phosphoric esterification reaction is usually carried out at a temperature of 178 to 60 ° C, but is preferably carried out at a temperature of -78 to 10 ° C for the reason of suppressing decomposition of the reactants and products.
- the cyclization reaction time is usually 1 minute to 20 hours, preferably 5 minutes to 5 hours.
- the reaction time of the phosphoric acid ester is usually 5 minutes to 30 hours, preferably 30 minutes to 10 hours.
- the progress of the reaction can be tracked using analytical means.
- the compound (3) is isolated from the mixture after the operations such as pH adjustment, extraction, liquid separation, washing, concentration and purification that are often used in organic reactions.
- the compound (3) obtained by the above reaction is a novel compound, and is a synthetic compound useful for producing a common synthetic intermediate when producing the 1-methylcarbapanem compound for oral administration by the present inventors. It is a compound whose use as a precursor has been confirmed.
- the compound (3) can be derived into the compound (4) by deprotecting 1 ⁇ which is a protecting group for a hydroxyl group.
- the acidic condition used in this case is not particularly limited as long as the pH is 7 or less, but is preferably pH 2 to 6, and the silyl protecting group is very easily released at pH. .
- the acidic conditions for example, phosphoric acid, aqueous citric acid, hydrochloric acid, and the like can be added to the mixture.
- Compound (4) is a novel compound, and as described below, is a compound for which, for the first time, a useful use as a common synthetic intermediate of 1-methylcarbapanem compound for oral administration has been recognized by the present inventors. is there.
- the compound (2) is cyclized as described above, and the phosphoric acid esterification reaction with difluorophosphoric acid is performed to obtain a compound (3). Then, it is reacted with a thiol compound (R'-SH) in the presence of a base.
- a thiol compound R'-SH
- the base used in the reaction with the thiol compound may be the same as or different from the strong base used in the cyclization reaction described above.
- organic amines ⁇ alkali metal salts can be used as the base other than the strong base used in the cyclization of the compound (2) described above.
- organic amines triethylamine, disopropylethyl and the like can be used.
- alkali metal salt examples include alkali carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; and alkali carbonates such as sodium bicarbonate and bicarbonate.
- the reaction can be promoted by adding an inert solvent different from that used in the cyclization reaction.
- the 1] 3-methylcarbapanem compound obtained above can be obtained by a general method for deprotection of a hydroxyl group as described above, preferably such that other functional groups in the compound are not decomposed as much as possible. By the deprotection method under the same conditions as described above, it can be converted to the desired 13-methylcarbapanem compound for oral administration.
- reaction solution was diluted with 40 ml of ethyl acetate, washed several times with 5% aqueous sodium bicarbonate and water, and the resulting ethyl acetate solution was dried over sodium sulfate. The solvent was distilled off to give the title compound 1. 88 g were obtained.
- reaction solution was diluted with 50 ml of toluene, and the toluene solution washed several times with 2.5% aqueous sodium bicarbonate and water under ice cooling was dried over sodium sulfate, and the solvent was distilled off to obtain the title compound. .
- reaction solution was diluted with 20 ml of toluene, and the toluene solution washed several times with 2.5% aqueous sodium bicarbonate and water under ice cooling was dried over sodium sulfate, and the solvent was distilled off to obtain the title compound. .
- reaction solution was diluted with 5 Om 1 of toluene, and the toluene solution washed several times with 2.5% aqueous sodium bicarbonate and water under water cooling was dried over sodium sulfate, and the solvent was distilled off to obtain the title compound. .
- the resulting oily residue was dissolved by adding 10 ml of tetrahydrofuran, cooled to 160 ° C., added with 0.45 g (4. Ommo 1) of potassium tert-butoxide, and then stirred for 20 minutes. Then, at 50 ° C, 0.28 g (2.Ommo 1) of methyl iodide was added, and after stirring for 25 minutes, 0.56 g (2.lmmo 1) of diphenylphosphoric acid chloride was continuously added. The mixture was stirred for 1.7 hours.
- reaction solution was diluted with 20 ml of toluene, and the toluene solution washed several times with 2.5% aqueous sodium bicarbonate under ice-cooling was dried over sodium sulfate. The solvent was distilled off to remove the title compound. Got.
- a novel common synthetic intermediate (4) which enables efficient synthesis of various 1 ⁇ -methylcarbapanem compounds for oral administration, which has been actively researched and developed in recent years, (4)
- the compounds of the precursors (1) and (3) and methods for producing them are provided, and the present invention is industrially useful.
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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US10/533,868 US7538212B2 (en) | 2002-11-13 | 2003-11-13 | Intermediate for carbapenem compound for oral administration and process for producing the same |
AU2003284545A AU2003284545A1 (en) | 2002-11-13 | 2003-11-13 | Novel intermediate for carbapenem compound for oral administration and process for producing the same |
JP2004551226A JP4481829B2 (ja) | 2002-11-13 | 2003-11-13 | 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 |
EP03774004A EP1582526A4 (en) | 2002-11-13 | 2003-11-13 | NOVEL INTERMEDIATE FOR CARBAPENEM COMPOUND FOR ORAL ADMINISTRATION AND METHOD OF PRODUCING THE SAME |
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JP2002330127 | 2002-11-13 | ||
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US (1) | US7538212B2 (ja) |
EP (1) | EP1582526A4 (ja) |
JP (1) | JP4481829B2 (ja) |
KR (1) | KR101031143B1 (ja) |
CN (2) | CN101172962B (ja) |
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Cited By (2)
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JP2006176418A (ja) * | 2004-12-21 | 2006-07-06 | Kaneka Corp | 経口投与用カルバペネム化合物の製造方法と新規β−ラクタム化合物 |
WO2006104131A1 (ja) * | 2005-03-29 | 2006-10-05 | Kaneka Corporation | 結晶形態の1β-メチルカルバペネム中間体 |
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CN102532117B (zh) * | 2010-12-22 | 2014-05-14 | 深圳万乐药业有限公司 | 1-(4,5-二氢噻唑-2-基)-3-巯基-n-杂环丁烷盐酸盐的制备方法 |
CN102775410B (zh) * | 2011-05-10 | 2016-07-20 | 上海医药工业研究院 | 一种替比培南匹伏酯的制备方法 |
CN103059026A (zh) * | 2011-10-20 | 2013-04-24 | 北京康健源科技有限公司 | 一种替比培南匹夫酯的制备方法 |
CN102702204A (zh) * | 2012-06-25 | 2012-10-03 | 江苏济川制药有限公司 | 一种制备替比培南匹伏酯的方法 |
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EP0559533A1 (en) * | 1992-03-06 | 1993-09-08 | Tanabe Seiyaku Co., Ltd. | Process for preparing beta-lactam derivative and synthetic intermediate thereof |
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NZ214691A (en) | 1984-12-27 | 1988-08-30 | Sumitomo Pharma | The preparation of carbapenem derivatives and beta-lactam intermediates |
TW513430B (en) * | 1996-07-12 | 2002-12-11 | Merck & Co Inc | Process for synthesizing carbapenem antibiotics |
DE69930616T2 (de) * | 1998-03-02 | 2006-11-23 | Merck & Co., Inc. | Verfahren zur synthese von carbapenem-antibiotika |
AR035728A1 (es) * | 2001-01-16 | 2004-07-07 | Merck & Co Inc | Proceso perfeccionado para la sintesis de carbapenem |
EP1561748A4 (en) * | 2002-10-18 | 2011-03-02 | Meiji Seika Kaisha | MONOESTERS OF MALONIC ACID AND METHOD OF MAKING SAME |
JPWO2004035539A1 (ja) | 2002-10-18 | 2006-02-16 | 明治製菓株式会社 | カルバペネム類の製造方法およびその製造に用いられる中間体 |
JPWO2004043961A1 (ja) * | 2002-11-13 | 2006-03-09 | 株式会社カネカ | 経口投与用カルバペネム化合物の製造方法 |
-
2003
- 2003-11-13 AU AU2003284545A patent/AU2003284545A1/en not_active Abandoned
- 2003-11-13 CN CN2007101547133A patent/CN101172962B/zh not_active Expired - Fee Related
- 2003-11-13 KR KR1020057008453A patent/KR101031143B1/ko not_active IP Right Cessation
- 2003-11-13 US US10/533,868 patent/US7538212B2/en not_active Expired - Fee Related
- 2003-11-13 CN CNB2003801019645A patent/CN100347179C/zh not_active Expired - Fee Related
- 2003-11-13 WO PCT/JP2003/014419 patent/WO2004043973A1/ja active Application Filing
- 2003-11-13 JP JP2004551226A patent/JP4481829B2/ja not_active Expired - Fee Related
- 2003-11-13 EP EP03774004A patent/EP1582526A4/en not_active Withdrawn
Patent Citations (1)
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EP0559533A1 (en) * | 1992-03-06 | 1993-09-08 | Tanabe Seiyaku Co., Ltd. | Process for preparing beta-lactam derivative and synthetic intermediate thereof |
Non-Patent Citations (2)
Title |
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SAKURAI O. ET AL: "A New Synthesis of 1&1t;SYM98>-Alkylcarbapenems Utilizing Eschenmoser Sulfide Contraction of the Novel Thiazinone Intermediates", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, no. 22, 1996, pages 7889 - 7894, XP002986759 * |
See also references of EP1582526A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006176418A (ja) * | 2004-12-21 | 2006-07-06 | Kaneka Corp | 経口投与用カルバペネム化合物の製造方法と新規β−ラクタム化合物 |
WO2006104131A1 (ja) * | 2005-03-29 | 2006-10-05 | Kaneka Corporation | 結晶形態の1β-メチルカルバペネム中間体 |
JP5016480B2 (ja) * | 2005-03-29 | 2012-09-05 | 株式会社カネカ | 結晶形態の1β−メチルカルバペネム中間体 |
KR101256692B1 (ko) | 2005-03-29 | 2013-04-19 | 가부시키가이샤 가네카 | 결정 형태의 1β-메틸카르바페넴 중간체 |
Also Published As
Publication number | Publication date |
---|---|
CN100347179C (zh) | 2007-11-07 |
KR101031143B1 (ko) | 2011-04-27 |
KR20050075392A (ko) | 2005-07-20 |
JP4481829B2 (ja) | 2010-06-16 |
EP1582526A4 (en) | 2008-08-06 |
CN1708504A (zh) | 2005-12-14 |
CN101172962A (zh) | 2008-05-07 |
US7538212B2 (en) | 2009-05-26 |
EP1582526A1 (en) | 2005-10-05 |
CN101172962B (zh) | 2010-09-08 |
US20060252929A1 (en) | 2006-11-09 |
JPWO2004043973A1 (ja) | 2006-03-09 |
AU2003284545A1 (en) | 2004-06-03 |
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