AU8282198A - Process for synthesizing carbapenem side chain intermediates - Google Patents
Process for synthesizing carbapenem side chain intermediates Download PDFInfo
- Publication number
- AU8282198A AU8282198A AU82821/98A AU8282198A AU8282198A AU 8282198 A AU8282198 A AU 8282198A AU 82821/98 A AU82821/98 A AU 82821/98A AU 8282198 A AU8282198 A AU 8282198A AU 8282198 A AU8282198 A AU 8282198A
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- Australia
- Prior art keywords
- compound
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- formula
- produce
- reacted
- Prior art date
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- Granted
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- 238000000034 method Methods 0.000 title claims description 53
- 230000002194 synthesizing effect Effects 0.000 title claims description 4
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical group C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title description 5
- 239000000543 intermediate Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 76
- -1 N(C1-4 alkyl)2 Chemical group 0.000 claims description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 229910052977 alkali metal sulfide Inorganic materials 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 14
- QPQGTZMAQRXCJW-UHFFFAOYSA-N [chloro(phenyl)phosphoryl]benzene Chemical compound C=1C=CC=CC=1P(=O)(Cl)C1=CC=CC=C1 QPQGTZMAQRXCJW-UHFFFAOYSA-N 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005270 trialkylamine group Chemical group 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 101150009274 nhr-1 gene Proteins 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical group CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910006069 SO3H Inorganic materials 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 3
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052788 barium Inorganic materials 0.000 claims description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- JGIATAMCQXIDNZ-UHFFFAOYSA-N calcium sulfide Chemical compound [Ca]=S JGIATAMCQXIDNZ-UHFFFAOYSA-N 0.000 claims description 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- CJDPJFRMHVXWPT-UHFFFAOYSA-N barium sulfide Chemical compound [S-2].[Ba+2] CJDPJFRMHVXWPT-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- FAYOCELKCDKZCA-UHFFFAOYSA-N 5-hydroxy-2,4-dimethylthiophen-3-one Chemical compound CC1SC(O)=C(C)C1=O FAYOCELKCDKZCA-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical class O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- AJHPGXZOIAYYDW-UHFFFAOYSA-N 3-(2-cyanophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC1=CC=CC=C1C#N AJHPGXZOIAYYDW-UHFFFAOYSA-N 0.000 description 1
- YZRVTSCLFRCFPW-UHFFFAOYSA-N 5-aminothiophene-2-carboxylic acid Chemical compound NC1=CC=C(C(O)=O)S1 YZRVTSCLFRCFPW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- RMQXUAYCXLDUKS-WCCKRBBISA-N [N].OC(=O)[C@@H]1CCCN1 Chemical group [N].OC(=O)[C@@H]1CCCN1 RMQXUAYCXLDUKS-WCCKRBBISA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 229910052976 metal sulfide Inorganic materials 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- JIEJMMLZUMTVPN-OOLPFSOCSA-N n-ethyl-n-propan-2-ylpropan-2-amine;(2s,4r)-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound CCN(C(C)C)C(C)C.O[C@H]1CN[C@H](C(O)=O)C1 JIEJMMLZUMTVPN-OOLPFSOCSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000004763 sulfides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- NRGHTFYSJLCXHO-UHFFFAOYSA-N tert-butyl 3-oxo-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1SC2=O NRGHTFYSJLCXHO-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
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- 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
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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Description
WO 99/02531 PCT/US98/13738 -1 TITLE OF THE INVENTION PROCESS FOR SYNTHESIZING CARBAPENEM SIDE CHAIN INTERMEDIATES 5 BACKGROUND OF THE INVENTION The present invention relates to the synthesis of carbapenem side chains, and in particular, to side chains or portions thereof containing a pyrrolidine group, which is bonded to the carbapenem nucleus through a thioether linkage. Typically, the pyrrolidine is a portion of the side 10 chain, and is substituted at the two position with any of a variety of substituents. Conventionally, these intermediate compounds are prepared from a 4-hydroxyproline derivative of the formula: HO
CONR
1
R
2 N 15 R Such synthetic schemes typically require the extensive use of protecting groups. Similarly, a method of converting trans-4-hydroxy-L-proline to a thiolactone of the formula: 20 0 S N
C(O)CH
3 has been described. However, this thiolactone is unsuitably protected for synthesis of carbapenem antibiotics.
WO 99/02531 PCT/US98/13738 -2 EP 551 993 Al published on July 21, 1993 relates to a synthesis which utilizes active esterifying agents and base, followed by treatment with hydrogen sulfide, or an alkali metal salt of hydrogen sulfide, and base. 5 The present invention is an improvement over these other processes, utilizing a sulfide source which surprisingly improves the process when commercial quantities are synthesized. SUMMARY OF THE INVENTION 10 A process for synthesizing a compound of the formula 1: PINI N* ' 0 S 1 is described wherein P is a protecting group 15 comprising (a) reacting a compound of formula 2: HO,,,, N CO 2 H P 20 2 wherein P is as previously defined with diphenylphosphinic chloride to produce a compound of formula 3: WO 99/02531 PCT/US98/13738 -3 HO,, N O I U 0 3 (b) reacting compound 3 with methanesulfonyl chloride to produce a compound of formula 4: 5 H 3 C S O 3 ,,,, N COP I 0I P 4 and (c) combining compound 4 with an alkali metal sulfide or non-alkali metal sulfide in water to produce a compound of formula 1. 10 More particularly, the process described herein relates to a process for producing a compound of the formula 5: HS
C(O)NR
1
'R
2 N P 5 15 WO 99/02531 PCT/US98/13738 -4 wherein P is a protecting group; R1 and R 2 are independently selected from hydrogen, aryl and heteroaryl, said aryl and heteroaryl groups being unsubstituted or 5 substituted with from 1-3 groups selected from the group consisting of: C1-4 alkyl, C1-4 alkoxy, C 1-4 alkylthio, halo, hydroxy, CO2H, CO2C1-4 alkyl, NH 2 , NHC1-4 alkyl, N(C1-4 alkyl)2, SO3H, CN,
NHC(O)C
1
-
4 alkyl, SO2NH 2 , SO 2 C1- 4 alkyl, aryl and heteroaryl; 10 comprising: (a) reacting a compound of the formula 2: HO,,, N C0 2 H P 2 wherein P is as previously defined with diphenylphosphinic chloride to 15 produce a compound of the formula 3: HO,,,, N O , ,o, 0 3 (b) reacting compound 3 with methanesulfonyl chloride to 20 produce a compound of formula 4: WO 99/02531 PCT/US98/13738 -5 H 3 CS 0 3 ,,, N COP U Ui 4 (c) combining compound 4 with an alkali metal sulfide or non-alkali metal sulfide in water to produce a compound of formula 1: 5 0 S 1 and 10 (d) reacting compound 1 with NHR 1
R
2 wherein R 1 and R 2 are as previously defined to produce a compound of formula 5. DETAILED DESCRIPTION OF THE INVENTION The invention is described using the following definitions 15 unless otherwise specified. Alkyl and the alkyl portions of substituent groups include monovalent hydrocarbon chains containing from 1-4 carbon atoms which are straight or branched as appropriate. Aryl refers to 6-10 membered mono- and bicyclic ring 20 systems, containing carbon atoms with alternating (resonating) double bonds. Preferred aryl groups are phenyl and naphthyl. Heteroaryl refers to aromatic 5-10 membered mono- and bicyclic ring systems, containing from 1-4 heteroatoms, O, S or N.
WO 99/02531 PCT/US98/13738 -6 Preferred nitrogen containing monocyclic heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl and 1, 2, 4-triazolyl. Preferred heteroaryl groups containing oxygen as the only heterotom include furanyl. Preferred heteroaryl groups 5 containing sulfur as the only heterotom include thienyl. Preferred bicyclic heteroaryl groups include benzthiazolyl, benzimidazolyl, quinolinyl and isoquinolinyl, indolyl and isoindolyl. When substituted, the aryl and heteroaryl groups may be substituted with 1-3 groups selected from the group consisting of: C1-4 10 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo, hydroxy, CO2H, CO2C1-4 alkyl,
NH
2 , NHC 1
-
4 alkyl, N(C1- 4 alkyl)2, NHC(O)C1- 4 alkyl, SO3H, CN, SO2NH 2 , SO2C1-4 alkyl, aryl and heteroaryl. When necessary, the substituents which are optionally present on aryl and heteroaryl can be in protected form. 15 Examples of suitable protecting groups include the following without limitation: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyl oxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2 trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 20 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethyl silyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C-lo alkylphosphoryl, diarylphosphoryl and di-ar-C, 1 0 alkylphosphoryl. Preferred silyl 25 protecting groups are trimethylsilyl and triethylsilyl. Preferred carboxyl protecting groups are p-nitrobenzyl and allyl. Preferred phosphoryl based protecting groups include diisopropylphosphoryl. Many other suitable hydroxyl and carboxyl protecting groups are known in the art. See, e.g., Greene, T. W., et al. Protective 30 Groups in Organic Synthesis, John Wiley & Sons, Inc., 1991. P represents a protecting group on the proline nitrogen atom. Thus, in one aspect of the invention, P represents a member selected from the group consisting of: t-butylmethoxyphenylsilyl, t-butoxydiphenyl silyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitro- WO 99/02531 PCT/US98/13738 -7 benzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2-trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl) 5 ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C.
10 alkylphosphoryl, diarylphosphoryl and di-ar-Cl- 1 0 alkylphosphoryl. More particularly, P represents a protecting group which is selected from the group consisting of: t-BOC, diisopropylphosphoryl and 10 p-nitrobenzyloxycarbonyl. Most particularly, P represents diisopropylphosphoryl. Compound 2 used herein as a starting material is N protected trans-4-hydroxy-L-proline. The 2-carboxyl group is activated using the compound diphenylphosphinic chloride, which is reacted with 15 compound II in a solvent in the presence of excess base. Solvents which are useful herein include dichloromethane, acetonitrile, toluene, fluorobenzene, tetrahydrofuran, or mixtures thereof. Bases which are useful for this reaction include trialkylamines. Preferred trialkylamines include diisopropylethylamine (DIPEA) and triethylamine. 20 Typically an amount of diphenylphosphinic chloride which is about equimolar to the starting compound can be used. The reaction between compound 2 and diphenylphosphinic chloride is typically run at reduced temperature, below about 0OC to as low as about -40 0 C. Preferably, the reaction temperature is maintained at about -10 0 C. 25 Compound 3, with the diphenylphosphinyloxycarbonyl group at position two, is reacted with methanesulfonyl chloride (MsC1) to produce compound 4. This reaction is conducted in a solvent, in the presence of a slight molar excess of pyridine, collidine, lutidine and the like, using a slight molar excess of MsC1. This mesylation reaction may 30 be conducted over about 1-4 hours, at a reduced temperature, e.g., about 0OC to as low as about -40oC. Preferably, the reaction temperature is maintained at about -10 0 C. Compound 4 is thereafter combined with an alkali metal sulfide or non-alkali metal sulfide and water to form the thiolactone 1.
WO 99/02531 PCT/US98/13738 -8 Essentially the reaction can be conducted at about -10 0 C to about room temperature. Preferably the sulfide and water are added quickly, and the reaction is aged for several hours at ambient temperature. As used herein, "alkali metal sulfide" refers to the group I 5 metal sulfides, such as the sulfides of sodium and potassium. Preferably the alkali metal sulfide is Na 2 S. As used herein, "non-alkali metal sulfides" and "alkaline earth metals" are used interchangeably to include the group II alkaline earth metal sulfides selected from the group consisting of: magnesium, 10 calcium and barium. Preferred are calcium and barium. The preferred non-alkali metal sulfide, most notably CaS, provides an unexpected advantage in that side products of the reaction have low solubility in water, and thus can be removed as a precipitate. In a preferred aspect of the process described herein, the 15 amine HNR 1
R
2 is m-aminobenzoic acid. In another preferred aspect of the process, the compound of formula 5 is reacted with an acid to produce a compound of formula 6: HS CNN C(O)NR 1
R
2 N H 6 20 More particularly, a compound of formula 2': H O,, O N_0 2 H P(O)(OiPr) 2 2' 25 is reacted with diphenylphosphinic chloride to produce a compound of formula 3': WO 99/02531 PCT/US98/13738 -9 HO,,, C02P(O)(Ph)2 N P(O)(OiPr) 2 3' compound 3' is reacted with mesyl chloride to produce compound 4': 5 MsO,, M N- C0 2 P(O)(Ph) 2 N P(O)(OiPr) 2 4' compound 4' is reacted with a member selected from the group consisting of: Na 2 S, K2S, CaS and BaS to produce a compound of formula 1': 10 (iPrO) 2 P(0) N' 0 S 1' compound 1' is reacted with m-aminobenzoic acid to produce 5': WO 99/02531 PCT/US98/13738 -10 C02H HS N C(0)NH P(O)(OiPr)2 5' and compound 5' is reacted with acid to produce a compound of formula 6': 5 C02H HS -- N C(0) NHd 'N H 6' or a salt or solvate thereof. 10 In a preferred aspect of the invention, the thiolactone compound 1 is reacted with the amine HNR'R 2 in the presence of an organic acid to produce compound 5. Examples of suitable organic acids include formic acid, acetic acid and propionic acid. Most preferably, the 15 reaction is conducted in the presence of acetic acid. After the conversion of compound 4' to compound 1', the latter is combined with ammonia or a primary or secondary amine to form compounds of formula 5', which can be deprotected to give compound 6' or salt thereof. In the isolation of 6' solvents, such as C,-s 20 alcohols, C1-3 alkanoic acids, toluene, acetonitrile, ethyl acetate and others may be added to improve crystallization, or otherwise facilitate isolation.
WO 99/02531 PCT/US98/13738 -11 Also, addition of a trialkyl or triaryl phosphine, e.g., tri-n-butylphosphine, at this stage may be useful in reducing the formation of disulfides corresponding to compound 6' and/or improving the rejection of other impurities. 5 Most primary and secondary amines HNR 1
R
2 wherein R 1 and/or R 2 represent H, aryl or heteroaryl react with compound 1 upon slight heating. Generally, the reaction proceeds from about RT to about 100oC over a few minutes to several hours. The acid that is used to convert compound 5' to compound 10 6' can be varied within wide limits. For example, concentrated HCI can be used and is preferred. The invention described herein can be conducted in essentially a single reaction vessel, thus allowing for economical production of compounds 6' from compound 2. 15 The invention is further illustrated with the following non limiting examples. EXAMPLE ONE (1 S, 4S)-5-DIISOPROPYLPHOSPHORYL-2-THIA-5 20 AZABICYCLO [2.2.11HEPTAN-3-ONE HO, Cdiphenylphosphinic NN-CO2 H chloride Nv P(O)(OiPr) 2 1-2 HO/ % methanesulfonyl CO2 chloride P(O)(OiPr) 2 1-3 WO 99/02531 PCT/US98/13738 -12 MsO, CO S aSlurry N 1-4 /S P(O)(OiPr) 2 (iPrO) 2 ()Pl 0 S 1-1 5 The following starting materials were utilized: Starting Material Quantity Diisopropylphosphoryl 5.0 g, 16.93 mmol hydroxyproline Diisopropylethylamine 6.34 mL, 36.44 mmol Diphenylphosphinic 3.36 mL, 17.61 mmol chloride Pyridine 1.48 mL, 18.29 mmol Methanesulfonyl chloride 1.43 mL, 18.46 mmol Calcium sulfide 1.49 g, 20.66 mmol Dichloromethane 100 mL Water 350 mL The mesylate mixed anhydride was formed according to WO 97/06154 published on February 20, 1997, incorporated herein by 10 reference, and stirred with cooling at -15oC for 15 min. Calcium sulfide (1.49 g) was added as a solid and washed with water (30 mL), resulting in a three phase reaction mixture. The mixture was stirred rapidly and the cooling bath removed, allowing the mixture to reach room temperature.
WO 99/02531 PCT/US98/13738 -13 The solids quickly went into solution, and a white solid precipitate was formed. The mixture was stirred for 45 min and then filtered through a coarse filter. The solid on the filter was washed with dichloromethane 5 and the filtrate separated. The organic layer (approx. 200 mL) was washed with 1 M HCI (50 mL), and 8% NaHCO 3 (50 mL). The aqueous bicarbonate layer was back extracted and the combined extracts were washed with brine and the layers weighed. The presence of the title compound (4.04 g) was 10 confirmed by HPLC. EXAMPLE TWO H O,, OH diphenylphosphinic chloride I t-BOC 0 2-2 H ,,,O II methanesulfonyl O- F chloride t-BOC O 0 2-3 15 WO 99/02531 PCT/US98/13738 -14 Ms O,, 0- ICaS N 1/\ H 2 0 t-BOC 0 2-4 t-BOC 0 S 2-1 A. Synthesis of trans-N-t-butoxycarbonyl-2 diphenylphosphinvloxycarbonyl-4-hydroxy-L-proline HO H 0DIPEA OH dry THF -20 0 C N I diphenylphosphinic t-BOC O chloride 2-2 HO O t-BOC O 5 2-3 A solution of compound 2-2 (35.0 g, 151 mmol.) and DIPEA (60 mL, 344 mmol) in dry THF (1.0 L) was combined over 20 min with a WO 99/02531 PCT/US98/13738 -15 solution of diphenylphosphinic chloride (37.5 g, 155 mmol) in THF (50 mL) at -20oC. The reaction mixture was stirred at -20oC for 90 minutes to produce compound 2-3, which can be isolated and characterized or used in the next part without isolation. 5 B. Synthesis of trans-N-t-butoxycarbonyl-2-diphenylphosphinyl oxycarbonyl-4-methanesulfonyloxy-L-proline HO,o .. methanesulfonyl O P chloride N t-BOC 0 2-3 Ms OfO OP t-BOC O0 2-4 10 Without isolation and characterization, after stirring the reaction mixture from part A for 90 minutes at -20oC, pyridine (13.0 mL, 161 mmol) was added followed by a solution of methanesulfonyl chloride (19.8 g, 171 mmol) in THF (50 mL) over 15 minutes. The reaction 15 mixture was stirred at -20oC for 2 hours and allowed to warm to -5 0 C over an additional 30 minutes producing compound 2-4. The methanesulfonyl substituted compound can be isolated and characterized, or used in the next reaction without isolation and characterization.
WO 99/02531 PCT/US98/13738 -16 C. Synthesis of N-t-butoxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan 3-one MsO,, O \CaS/H 2 0 N Slurry t-BOC 0 2-4 t-BOC ll O S 2-1 5 After allowing the reaction from part B to warm to -5oC, a slurry of CaS (45.0 g, 187 mmol) in H20 (60 mL) is added in one portion. The mixture is allowed to warm to room temperature and is stirred for 6 hrs. The resulting suspension is filtered and the filtrate is 10 then partitioned between toluene and water. The organic layer is washed with HC1 (2.0 M), NaHCO3 (1.0 M) and brine, dried over MgSO4 and concentrated in vacuo. EXAMPLE THREE 15 HS tBOC N 0 _____ t-BOCN' C(0)NR'R 2 S N 2-1 1 t-BOC 3-5 WO 99/02531 PCT/US98/13738 -17 The thiolactone 2-1 from Example Two without isolation, can be combined with the amine shown below in column one to produce the cis N-protected 4-thiol substituted proline derivative shown below in column two. 5 TABLE ONE Amine Product (3) (3-1) HS NH4Cl
C(O)NH
2 N I t-BOC 3-5-1 (3-2) HS
NH
2 C(0)NH- j N I I I t-BOC 3-5-2 (3-3)
NH
2 HS C(0)NH/
SCO
2 H
CO
2 H 2 t-BOC 3-5-3 WO 99/02531 PCT/US98/13738 -18 (3-4) HSo C(O)NH CO2H H2N S CO2H I t-BOC 3-5-4 (3-5) HS
NH
2 HS C(O)NH N CO 2 H / CO 2 H K(O)(OiPr) 2 C02H 3-5-5 (1) 4.0 eq. of NH 4 Cl in Et 3 N; solvent CH3OH; reaction time: 30 min at RT; (2) 1.25 eq. of aniline; solvent toluene; reaction time: 5 2 hrs at 100'C; (3) 1.25 eq. of 3-aminobenzoic acid; solvent toluene; reaction time: 2 hrs at 100 0 C; (4) 1.25 eq. of 5-amino-2-carboxythiophene; solvent toluene; 2 hrs at 100oC; 10 (5) P represents diisopropylphosphoryl. (iPr = isopropyl). EXAMPLE FOUR Using the procedures set forth in Example Two, Part A, the 15 compounds of column one are reacted with diphenylphosphinic chloride to produce the compounds in column two.
WO 99/02531 PCT/US98/13738 -19 TABLE TWO H O,,,,. HHO, "" _./.CO02P(O)(Ph) 2
CO
2 H N NN 2 Ph = phenyl 4-2-1 HO,,,,, HO,,,,,
CO
2 H
CO
2 P(o)(Ph) 2 N N 00 00 4-2-2 4-3-1 HO,,,, H O,,,,
-"CO
2 H
CO
2 P(O)(Ph) 2 CN N 0/ ,,0 0/10 4-2-3 4-3-3 SUBSTITUTE SHEET (RULE 26) WO 99/02531 PCT/US98/13738 -20 EXAMPLE FIVE Using the procedures set forth in Example One, Part B, the compounds of column one are reacted with methanesulfonyl chloride to 5 produce the compounds in column two. TABLE THREE 5-4-1 M SO,,, M ,.... C02P(0)(Ph) 2 4-3-1 N O/O
NO
2 Ph = phenyl 5-4-2 4-3-2 MsO,,,,
CO
2 P(0)(Ph) 2 N 0O WO 99/02531 PCT/US98/13738 -21 5-4-3 4.- 3 -3 Ms O,,,, 4-3- MCO 2 P(O)(Ph) 2 N EXAMPLE SIX Using the procedures set forth in Example Two, Part C, the 5 compounds of column one are reacted with CaS in water to produce the compounds in column two. TABLE FOUR 6-1-1
NO
2 5-4-1 ON 0
S
WO 99/02531 PCT/US98/13738 -22 6-1-2 5-4-2 0 O~N 0 0
S
6-1-3 5-4-3 O0 joAN/- O EXAMPLE SEVEN 5 Using the procedures set forth in Example Three, the compounds of column one are reacted with the amine in column two to produce the compounds in column three.
WO 99/02531 PCT/US98/13738 -23 TABLE FIVE Amine NHR 1
R
2 Pyrrolidine 7-5-1 1 HS (1)
C(O)NH
2 6-1-1 NH4C1I N
OO
NO
2 7-5-2 1 (2) HS
NH
2 C(O)NH-Ph 6-1-1 N 00 I
NO
2 Ph = Phenyl 7-5-31 (3) HSc
NH
2 C(O)NH 6-1-1
CO
2 H 0
CO
2 H C02H NO 2 WO 99/02531 PCT/US98/13738 -24 7-5-4 1 (4 ) H S C C(O)NH/ 6-1-1
H
2 N- N 2 H C2H S CO2H OO2
SNO
2 7-5-5 1 HS (1) 6-1-2 C(O)NH 2 NH4C I O O 7-5-6 1 (2) HS 6-1-2 NH 2 C(O)NH-Ph 00\ Ph = Phenyl 7-5-7 1 (3) HS 6-1-2
NH
2 N C(0)NH Co02H 0ON CO 2
H
WO 99/02531 PCT/US98/13738 -25 7-5-8 1 (4) HSC()NH 6-1-2 H 2 N CO2H N C(O)NH S CO 2 H HN s I00 2 H 0 N0 7-5-9 1 HS (1)
C(O)NH
2 6-1-3 NH4C1 N 0 7-5-10 1 (2) HS
NH
2 ' C(O)NH-Ph 6-1-3 N Ph = Phenyl 7-5-11 1 (3) HS
NH
2 C(0)NH / 6-1-3 O
CO
2 HO O CO 2
H
WO 99/02531 PCT/US98/13738 -26 (4) 7-5-12 1 HS4 6-1-3 H 2 N CO 2 H S N C(O)NH CO 2 H _C02H_0_0_C020 (3) 7-5-13 1
NH
2 HS 1-1 C(0)NH /
CO
2 H
CO
2 H k(O)(OiPr)2 1: Tri-n-butylphosphine may be added. While certain preferred embodiments have been described 5 herein in detail, numerous alternative embodiments are contemplated as falling within the scope of the invention.
Claims (39)
1. A process for synthesizing a compound of the formula 1: PN 0 S 5 1 wherein P is a protecting group, comprising (a) reacting a compound of the formula 2: 10 HO,,, N CO 2 H I P 2 wherein P is as previously defined with diphenylphosphinic chloride to produce a compound of the formula 3: 15 H O,, 3 3 WO 99/02531 PCT/US98/13738 -28 (b) reacting compound 3 with methanesulfonyl chloride to produce a compound of formula 4: H 3 CS0 3 ",,. N O P 0 0 4 ,and 5 (c) combining compound 4 with an alkali metal sulfide or non-alkali metal sulfide in water to produce a compound of formula 1.
2. A process of producing a compound of the formula 5: 10 HS C(O)NR'R 2 N P 5 wherein P is a protecting group; 15 R 1 and R 2 are independently selected from hydrogen, aryl and heteroaryl, said aryl and heteroaryl groups being unsubstituted or substituted with from 1-3 groups selected from the group consisting of: C1-4 alkyl, C1-4 alkoxy, C 1-4 alkylthio, halo, hydroxy, CO2H, CO2C1-4 alkyl, NH2, NHC 1-4 alkyl, N(C1-4 alkyl)2, SO3H, CN, 20 NHC(O)C1- 4 alkyl, SO2NH2, SO2C1-4 alkyl, aryl and heteroaryl; comprising: (a) reacting a compound of the formula 2: WO 99/02531 PCT/US98/13738 -29 HO,, N CO 2 H P 2 wherein P is as previously defined with diphenylphosphinic chloride to 5 produce a compound of the formula 3: HO,,.. N O 3 (b) reacting compound 3 with methanesulfonyl chloride to 10 produce a compound of formula 4: H 3 CSO 3,, 4,,.. N 4 WO 99/02531 PCT/US98/13738 -30 (c) combining compound 4 with an alkali metal sulfide or non alkali metal sulfide in water to produce a compound of formula 1: PN 0 S 1 5 and (d) reacting compound 1 with NHR 1 R 2 wherein RI and R 2 are as previously defined to produce a compound of formula 5.
3. A process in accordance with claim 1 wherein 10 P represents a member selected from the group consisting of: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2 trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 15 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2 (trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C-,o alkylphosphoryl, diarylphosphoryl and di-ar-CI- 10 alkylphosphoryl. 20
4. A process in accordance with claim 3 wherein P is selected from t-BOC, p-nitrobenzyloxycarbonyl and diisopropylphosphoryl. 25
5. A process in accordance with claim 4 wherein P represents diisopropylphosphoryl.
6. A process in accordance with claim 2 wherein 1 and NHR'R 2 are reacted to produce a compound of formula 5 in the presence 30 of an organic acid. WO 99/02531 PCT/US98/13738 -31
7. A process in accordance with claim 6 wherein the organic acid is selected from formic acid, acetic acid and propionic acid. 5
8. A process in accordance with claim 6 wherein 1 and NHR 1 R 2 are reacted in an organic solvent.
9. A process in accordance with claim 8 wherein the organic solvent is methylene chloride. 10
10. A process in accordance with claim 1 wherein compound 2 is reacted with diphenylphosphinic chloride in the presence of a base. 15
11. A process in accordance with claim 3 wherein the base is a trialkylamine.
12. A process in accordance with claim 11 wherein the trialkylamine is selected from the group consisting of 20 diisopropylethylamine and triethylamine.
13. A process in accordance with claim 1 wherein compound 3 is reacted with methanesulfonyl chloride to produce a compound of formula 4 in the presence of a base. 25
14. A process in accordance with claim 13 wherein the base is selected from the group consisting of pyridine, collidine and lutidine. 30
15. A process in accordance with claim 1 wherein compound 4 is reacted with a non-alkali metal sulfide to produce a compound of formula 1. WO 99/02531 PCT/US98/13738 -32
16. A process in accordance with claim 15 wherein the non-alkali metal sulfide in water is reacted with compound 4 to produce a compound of formula 1 at a temperature of about -10oC to about room temperature. 5
17. A process in accordance with claim 1 wherein P represents t-butoxycarbonyl, diisopropylphosphoryl or p-nitrobenzyloxycarbonyl. 10
18. A process in accordance with claim 2 wherein compound 2 is reacted with diphenylphosphinic chloride in the presence of a base.
19. A process in accordance with claim 18 wherein the 15 base is a trialkylamine.
20. A process in accordance with claim 19 wherein the trialkylamine is selected from the group consisting of diisopropylethylamine and triethylamine. 20
21. A process in accordance with claim 2 wherein compound 3 is reacted with methanesulfonyl chloride to produce a compound of formula 4 in the presence of a base. 25
22. A process in accordance with claim 19 wherein the base is selected from the group consisting of pyridine, collidine and lutidine.
23. A process in accordance with claim 1 wherein the 30 non-alkali metal sulfide in water is reacted with compound 4 to produce a compound of formula 1 at a temperature of about -10oC to about room temperature. WO 99/02531 PCT/US98/13738 -33
24. A process in accordance with claim 2 wherein P represents t-butoxycarbonyl, diisopropylphosphoryl or p nitrobenzyloxycarbonyl. 5
25. A process in accordance with claim 2 wherein NHR 1 R 2 is selected from the group consisting of: NH 2 NH 2 NH4C1, H2NCO 2 H and _ C02 H C02 H and
26. A process in accordance with claim 15 wherein the 10 non-alkali metal sulfide is selected from a sulfide of calcium, barium and magnesium.
27. A process in accordance with claim 26 wherein the non-alkali metal sulfide is comprised of calcium sulfide. 15
28. A process in accordance with claim 26 wherein the non-alkali metal sulfide is comprised of barium sulfide.
29. A process in accordance with claim 1 wherein: 20 P represents diisopropylphosphoryl and compound 4 is reacted with CaS in water to produce a compound of formula 1.
30. A process in accordance with claim 1 wherein: P represents diisopropylphosphoryl and compound 4 is reacted with Na 2 S 25 in water to produce a compound of formula 1.
31. A process in accordance with claim 2 wherein the amine HNR 1 R 2 is m-aminobenzoic acid. WO 99/02531 PCT/US98/13738 -34
32. A process in accordance with claim 2, further comprising reacting a compound of formula 5 with an acid to produce a compound of formula 6: HS HS C(O)NR' R 2 N H 5 6
33. A process in accordance with claim 32 in which trialkyl or triarylphosphines is optionally added. 10
34. A process in accordance with claim 33 in which the trialkylphosphine is tri-n-butylphosphine.
35. A process in accordance with claim 32 in which a solvent selected from the group consisting of C,- 5 alcohols, C,- 3 alkanoic 15 acids, toluene, acetonitrile, ethyl acetate and others is optionally added.
36. A process in accordance with claim 2, wherein a compound of formula 2': HOI, C0 2 H N P(O)(OiPr) 2 20 2' is reacted with diphenylphosphinic chloride to produce a compound of formula 3': WO 99/02531 PCT/US98/13738 -35 HO,,,, O C0 2 P(O)(Ph) 2 N P(O)(OiPr) 2 3' compound 3' is reacted with mesyl chloride to produce a compound of formula 4': 5 MsO,, C0 2 P(O)(Ph) 2 N P(O)(OiPr) 2 4' compound 4' is reacted with a member selected from the group consisting of: Na 2 S, K2S, CaS and BaS to produce a compound of formula 1': 10 (iPrO) 2 P(0) .N' 0 S 1' compound 1' is reacted with m-aminobenzoic acid to produce 5': WO 99/02531 PCT/US98/13738 -36 C0 2 H HS N C(O)NH N P(O)(OiPr) 2 5' and compound 5' is reacted with acid to produce a compound of formula 6': CO 2 H HS C(O)NH N 5 H 6' or a salt or solvate thereof.
37. A process in accordance with claim 32 in which 10 trialkyl or triarylphosphines is optionally added.
38. A process in accordance with claim 33 in which the trialkylphosphine is tri-n-butylphosphine. 15
39. A process in accordance with claim 32 in which a solvent selected from the group consisting of C 1 . 5 alcohols, C1-3 alkanoic acids, toluene, acetonitrile, ethyl acetate and others is optionally added. 20
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5203297P | 1997-07-09 | 1997-07-09 | |
US60/052032 | 1997-07-09 | ||
GB9810184 | 1998-05-13 | ||
GBGB9810184.3A GB9810184D0 (en) | 1998-05-13 | 1998-05-13 | Process for synthisizing carbapenem side chain intermediates |
PCT/US1998/013738 WO1999002531A1 (en) | 1997-07-09 | 1998-07-02 | Process for synthesizing carbapenem side chain intermediates |
Publications (2)
Publication Number | Publication Date |
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AU8282198A true AU8282198A (en) | 1999-02-08 |
AU731586B2 AU731586B2 (en) | 2001-04-05 |
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Application Number | Title | Priority Date | Filing Date |
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AU82821/98A Ceased AU731586B2 (en) | 1997-07-09 | 1998-07-02 | Process for synthesizing carbapenem side chain intermediates |
Country Status (5)
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EP (1) | EP1019411A4 (en) |
JP (1) | JP2002504156A (en) |
AU (1) | AU731586B2 (en) |
CA (1) | CA2294342C (en) |
WO (1) | WO1999002531A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2294341C (en) * | 1997-07-10 | 2007-09-25 | Merck & Co., Inc. | Crystalline forms of antibiotic side chain intermediates |
JP2003525297A (en) * | 2000-03-01 | 2003-08-26 | メルク エンド カムパニー インコーポレーテッド | Crystal form of antibiotic side chain intermediate |
ES2256311T3 (en) * | 2000-11-20 | 2006-07-16 | Sankyo Company, Limited | PROCESSES FOR THE PREPARATION OF CARBAPENEM TYPE ANTIBACTERIAL AGENTS. |
JP2008509909A (en) * | 2004-08-11 | 2008-04-03 | ウィリアムスバーグ・ホールディングス・エルエルシー | Non-cardiotoxic pharmaceutical compounds |
WO2010073706A1 (en) * | 2008-12-25 | 2010-07-01 | 株式会社カネカ | Improved process for producing intermediate for side chain of carbapenem |
CN106565579A (en) * | 2016-06-26 | 2017-04-19 | 宁夏海诚电化信息科技有限公司 | Ertapenem side chain production technology |
Family Cites Families (4)
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US4340738A (en) * | 1979-06-21 | 1982-07-20 | Janssen Pharmaceutica, N.V. | 2,3-Dihydro-imidazo[2,1-b]benzothiazoles |
AU644008B2 (en) * | 1990-08-10 | 1993-12-02 | Sumitomo Pharmaceuticals Company, Limited | Beta-lactam compounds, and their production and use |
JP3091297B2 (en) * | 1992-01-10 | 2000-09-25 | 住友製薬株式会社 | Pyrrolidine derivative and method for producing the same |
PT842166E (en) * | 1995-08-04 | 2001-04-30 | Merck & Co Inc | PROCESS FOR SYNTHETIZING CARBAPENEM SIDE CHAIN INTERMEDIARIES |
-
1998
- 1998-07-02 CA CA002294342A patent/CA2294342C/en not_active Expired - Fee Related
- 1998-07-02 AU AU82821/98A patent/AU731586B2/en not_active Ceased
- 1998-07-02 JP JP50875599A patent/JP2002504156A/en not_active Ceased
- 1998-07-02 WO PCT/US1998/013738 patent/WO1999002531A1/en active IP Right Grant
- 1998-07-02 EP EP98933069A patent/EP1019411A4/en not_active Withdrawn
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EP1019411A4 (en) | 2003-08-13 |
AU731586B2 (en) | 2001-04-05 |
JP2002504156A (en) | 2002-02-05 |
EP1019411A1 (en) | 2000-07-19 |
WO1999002531A1 (en) | 1999-01-21 |
CA2294342A1 (en) | 1999-01-21 |
CA2294342C (en) | 2006-03-14 |
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