JP6427173B2 - tert−ブチル 4−((1R,2S,5R)−6−(ベンジルオキシ)−7−オキソ−1,6−ジアザビシクロ[3.2.1]オクタン−2−カルボキサミド)ピペリジン−1−カルボキシレートの調製 - Google Patents
tert−ブチル 4−((1R,2S,5R)−6−(ベンジルオキシ)−7−オキソ−1,6−ジアザビシクロ[3.2.1]オクタン−2−カルボキサミド)ピペリジン−1−カルボキシレートの調製 Download PDFInfo
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- JP6427173B2 JP6427173B2 JP2016517977A JP2016517977A JP6427173B2 JP 6427173 B2 JP6427173 B2 JP 6427173B2 JP 2016517977 A JP2016517977 A JP 2016517977A JP 2016517977 A JP2016517977 A JP 2016517977A JP 6427173 B2 JP6427173 B2 JP 6427173B2
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- 238000002360 preparation method Methods 0.000 title description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title description 6
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 24
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 19
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 18
- 229910003849 O-Si Inorganic materials 0.000 claims description 18
- 229910003872 O—Si Inorganic materials 0.000 claims description 18
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 14
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 14
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000002596 lactones Chemical class 0.000 claims description 11
- 150000003512 tertiary amines Chemical class 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 125000006242 amine protecting group Chemical group 0.000 claims description 10
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 9
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- 230000001180 sulfating effect Effects 0.000 claims description 9
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- MRSGLMLXOQISES-UHFFFAOYSA-N 4-nitro-n-phenylmethoxybenzenesulfonamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NOCC1=CC=CC=C1 MRSGLMLXOQISES-UHFFFAOYSA-N 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 229910004013 NO 2 Inorganic materials 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 229940124530 sulfonamide Drugs 0.000 claims description 5
- 150000003456 sulfonamides Chemical class 0.000 claims description 5
- 150000003573 thiols Chemical class 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 238000004517 catalytic hydrocracking Methods 0.000 claims description 4
- 150000004682 monohydrates Chemical class 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims description 3
- RZYHXKLKJRGJGP-UHFFFAOYSA-N 2,2,2-trifluoro-n,n-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)N([Si](C)(C)C)C(=O)C(F)(F)F RZYHXKLKJRGJGP-UHFFFAOYSA-N 0.000 claims 2
- 239000012736 aqueous medium Substances 0.000 claims 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims 1
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical compound ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 230000008569 process Effects 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- -1 sulfoxy Chemical group 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000002002 slurry Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- NXVXWMDWVRBRRO-WPRPVWTQSA-N (1S,4S)-5-(2-nitrophenyl)sulfonyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one Chemical compound [N+](=O)([O-])C1=C(C=CC=C1)S(=O)(=O)N1[C@@H]2C(O[C@H](C1)CC2)=O NXVXWMDWVRBRRO-WPRPVWTQSA-N 0.000 description 7
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000003781 beta lactamase inhibitor Substances 0.000 description 6
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 6
- KQDDQXNVESLJNO-UHFFFAOYSA-N chloromethanesulfonyl chloride Chemical compound ClCS(Cl)(=O)=O KQDDQXNVESLJNO-UHFFFAOYSA-N 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 5
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 4
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 4
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- AOERXOCCTLXMMH-UHFFFAOYSA-N 7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Chemical class NC(=O)C1CCC2NC(=O)N1C2 AOERXOCCTLXMMH-UHFFFAOYSA-N 0.000 description 4
- 0 CC(*(C(*)N1C)N*)N(*)N1I Chemical compound CC(*(C(*)N1C)N*)N(*)N1I 0.000 description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- LFLCNBLTOXIVOQ-UHFFFAOYSA-N hydron;octan-3-yl sulfate Chemical compound CCCCCC(CC)OS(O)(=O)=O LFLCNBLTOXIVOQ-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- FDTPBIKNYWQLAE-UHFFFAOYSA-N 2,4-dichlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C(Cl)=C1 FDTPBIKNYWQLAE-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- SMOBCLHAZXOKDQ-ZJUUUORDSA-N [(2s,5r)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound O=C([C@H]1N2C[C@@](CC1)(N(C2=O)OS(O)(=O)=O)[H])NC1CCNCC1 SMOBCLHAZXOKDQ-ZJUUUORDSA-N 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 229910052741 iridium Inorganic materials 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 2
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000005537 sulfoxonium group Chemical group 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- RKEYKDXXZCICFZ-UHFFFAOYSA-N trans-5-OH-L-pipecolic acid Natural products OC1CCC(C(O)=O)NC1 RKEYKDXXZCICFZ-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LVLANIHJQRZTPY-UHFFFAOYSA-N vinyl carbamate Chemical compound NC(=O)OC=C LVLANIHJQRZTPY-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
PG1は、それが付着しているアミノ窒素と共にカルバメート、ベンジルアミンまたはスルホンアミドを形成する第一のアミン保護基であり;
PG2は、(i)カルバメートおよび(ii)ベンジルアミンから選択される第二のアミン保護基であり;
kは、0、1または2に等しい整数であり;
R2およびR3は、以下のように定義され:
(a)R2は、H、C1−6アルキル、−O−C1−6アルキル、−O−Si(−C1−6アルキル)3もしくは−O−Si(−C1−6アルキル)(−フェニル)2であり、
および各々のR3は、独立して、HもしくはC1−6アルキルである;または
(b)あるいはkが1もしくは2であるという条件で、R2およびR2に隣接するR3は、各々が付着している炭素原子と共に、その各々が独立してC1−6アルキル、−O−C1−6アルキル、−O−Si(−C1−6アルキル)3もしくは−O−Si(−C1−6アルキル)(−フェニル)2である1から3個の置換基で置換されていてもよいC5−7シクロアルキルを形成し;ならびに任意の他のR3は、HまたはC1−6アルキルである;
R4は:
(1)その各々が独立してC1−4アルキル、C1−4ハロアルキル、−O−C1−4アルキル、−O−C1−4ハロアルキル、Cl、Br、FもしくはNO2である1から3個の置換基で置換されていてもよいフェニル;
(2)C1−4アルキル;または
(3)C1−4ハロアルキルであり;
R5は、HまたはC1−3アルキルであり;
R6およびR8は、独立して、H、C1−3アルキル、−O−C1−3アルキルまたは−N(−C1−3アルキル)2であり;
各々のR7およびR9は、独立して、HまたはC1−6アルキルであり;
Wは、ハロゲンであり;
pは、0、1または2であり;
qは、0、1または2であり;ならびに
p+q=0、1、2または3である、方法を提供する。
(1a)kは、0または1である;
(1b)kは、0である;
(1c)kは、1である;
(2a)R2はH、C1−4アルキル、−O−C1−4アルキル、−O−Si(−C1−4アルキル)3または−O−Si(−C1−4アルキル)(フェニル)2であり、各々のR3はHまたはC1−4アルキルである;
(2b)R2はH、CH3、−OCH3、−O−トリメチルシリル(TMS)、−O−t−ブチルジフェニルシリル(TBDPS)、−O−t−ブチルジメチルシリル(TBS)または−O−トリイソプロピルシリル(TIPS)であり、各々のR3はHまたはCH3である;
(2c)R2はHまたはCH3であり、各々のR3はHまたはCH3である;
(2d)R2はHであり、各々のR3はHである;
(2e)kが1または2であるという条件で、R2およびR2に隣接するR3は、各々が付着している炭素原子と共にC5−6シクロアルキルを形成し;ならびに任意の他のR3はHである。
(C)式IIIの化合物を、塩基の存在下、N−4−ニトロベンゼンスルホニル−O−ベンジルヒドロキシルアミンで処理し、その後に求核性試薬、例えばチオールなどで処理することで、式IV:
(3a)R5は、HまたはCH3である;
(3b)R5は、Hである;
(4a)R6は、HまたはC1−3アルキルである;
(4b)R6は、HまたはCH3である;
(4c)R6は、Hである;
(5a)pは1であり、qは1である;
(5b)pは1であり、qは0である。
(D)化合物(IV)を、第三級アミンの存在下でホスゲン、ジホスゲン、トリホスゲンまたはホスゲン等価物、例えばカルボジイミダゾールまたはハロホルメートなどと接触させ、次いで酸の水溶液を加えることで、式V:
(E)化合物Vを、水素化分解触媒の存在下で水素の供給源と接触させることで、式VI:
(C)化合物3を、塩基の存在下、N−4−ニトロベンゼンスルホニル−O−ベンジルヒドロキシルアミンで処理し、その後に求核性試薬、例えばチオールなどで処理することで、化合物4:
(D)化合物4を、トリ−C1−4アルキルアミンの存在下でホスゲン、ジホスゲンもしくはトリホスゲン、またはホスゲン等価物、例えばカルボジイミダゾールもしくはハロホルメートなどと接触させ、次いで酸の水溶液を加えることで、化合物5:
(E)化合物5を、Pd触媒ならびに任意選択でジ−t−ブチルカーボネートおよびBoc−ONよりなる群から選択されるBoc生成剤の存在下で水素と接触させることで、化合物6:
PG1は、それが付着しているアミノ窒素と共にカルバメート、ベンジルアミンまたはスルホンアミドを形成する第一のアミン保護基であり;
PG2は、(i)カルバメートおよび(ii)ベンジルアミンから選択される第二のアミン保護基であり;
kは、0、1または2に等しい整数であり;
R2およびR3は、以下のように定義され:
(a)R2は、H、C1−6アルキル、−O−C1−6アルキル、−O−Si(−C1−6アルキル)3もしくは−O−Si(−C1−6アルキル)(−フェニル)2であり、
および各々のR3は、HもしくはC1−6アルキルである;または
(b)あるいはkが1もしくは2であるという条件で、R2およびR2に隣接するR3は、各々が付着している炭素原子と共に、その各々が独立してC1−6アルキル、−O−C1−6アルキル、−O−Si(−C1−6アルキル)3もしくは−O−Si(−C1−6アルキル)(−フェニル)2である1から3個の置換基で置換されていてもよいC5−7シクロアルキルを形成し;ならびに任意の他のR3は、HまたはC1−6アルキルである;
R4は:
(1)その各々が独立してC1−4アルキル、C1−4ハロアルキル、−O−C1−4アルキル、−O−C1−4ハロアルキル、Cl、Br、FまたはNO2である1から3個の置換基で置換されていてもよいフェニル;
(2)C1−4アルキル;または
(3)C1−4ハロアルキルであり;
R5は、HまたはC1−3アルキルであり;
R6およびR8は、独立して、H、C1−3アルキル、−O−C1−3アルキルまたは−N(−C1−3アルキル)2であり;
各々のR7およびR9は、独立して、HまたはC1−6アルキルであり;
Wは、ハロゲンであり;
pは、0、1または2であり;
qは、0、1または2であり;ならびに
p+q=0、1、2または3である、化合物に関する。
ステップB:tert−ブチル 4−((2S,5S)−1−((2−ニトロフェニル)スルホニル)−5−(((2−ニトロフェニル)スルホニル)オキシ)ピペリジン−2−カルボキサミド)ピペリジン−1−カルボキシレート(3)の調製
tert−ブチル 4−({[(2S,5R)−6−ヒドロキシ−7−オキソ−1,6−ジアザビシクロ[3.2.1]オクタ−2−イル]カルボニル}アミノ)ピペリジン−1−カルボキシレート16(0.54g、1.5mmol)、THF(5.4mL)、2−ピコリン(0.29mL、2.9mmol)およびピリジン−SO3錯体(0.70g、4.4mmol)を窒素下でバイアルに入れた。不均一な混合物を一晩(約15時間)かき混ぜておいた。反応混合物を−10℃まで冷却し、次いでジクロロメタン(5.4mL)を加えた。0.5M K2HPO4(4.5mL、2.3mmol)を10分かけて加えた。Bu4NHSO4(0.53g、1.54mmol)を次いで10分かけて加えた。二相性の混合物を30分間かき混ぜ、相を切り分け、水層を1mlのDCMで逆抽出した。合わせたDCM溶液を水(2.0mL)で洗浄し、相を切り分け、有機溶液を、ベッドボリュームの3倍のMeCNを使用した真空蒸留によりMeCN(3.2mL)に溶媒切替した。生成物をそのまま次のステップにおいて用いた(1000ppm未満の水分含量)。
Claims (24)
- 式III:
(B)式II:
その後に式II−Su:
合物を得ることを含む方法であり、式中:
PG1は、それが付着しているアミノ窒素と共にカルバメート、ベンジルアミンまたはス
ルホンアミドを形成する第一のアミン保護基であり;
PG2は、(i)カルバメートおよび(ii)ベンジルアミンから選択される第二のアミ
ン保護基であり;
kは、0、1または2に等しい整数であり;
R2およびR3は、以下のように定義され:
(a)R2は、H、C1−6アルキル、−O−C1−6アルキル、−O−Si(−C1−
6アルキル)3もしくは−O−Si(−C1−6アルキル)(−フェニル)2であり、
および各々のR3は、HもしくはC1−6アルキルである;または
(b)あるいはkが1もしくは2であるという条件で、R2およびR2に隣接するR3は
、各々が付着している炭素原子と共に、その各々が独立してC1−6アルキル、−O−C
1−6アルキル、−O−Si(−C1−6アルキル)3もしくは−O−Si(−C1−6
アルキル)(−フェニル)2である1から3個の置換基で置換されていてもよいC5−7
シクロアルキルを形成し;ならびに任意の他のR3は、HまたはC1−6アルキルである
;
R4は
(1)その各々が独立してC1−4アルキル、C1−4ハロアルキル、−O−C1−4ア
ルキル、−O−C1−4ハロアルキル、Cl、Br、FもしくはNO2である1から3個
の置換基で置換されていてもよいフェニル;
(2)C1−4アルキル;または
(3)C1−4ハロアルキルであり;
R5は、HまたはC1−3アルキルであり;
R6およびR8は、独立して、H、C1−3アルキル、O−C1−3アルキルまたはN(
−C1−3アルキル)2であり;
各々のR7およびR9は、独立して、HまたはC1−6アルキルであり、
Wは、ハロゲンであり;
pは、0、1または2であり;
qは、0、1または2であり;ならびに
p+q=0、1、2または3である、前記方法。 - 酸がトリメチルシリルヨージド(TMSI)である、請求項19に記載の方法。
- TMSIがN,O−ビス(トリメチルシリル)アセトアミド(BSA)またはN,O−
ビス(トリメチルシリル)トリフルオロアセトアミド(BSTFA)の存在下にある、請
求項20に記載の方法。 - 化合物8が反応混合物から一水和物として直接的に結晶化される、請求項19の方法。
-
PG1は、それが付着しているアミノ窒素と共にスルホンアミドを形成する第一のアミン
保護基であり;
PG2は、カルバメートよりなる群から選択される第二のアミン保護基であり;
kは、0、1または2に等しい整数であり;
R2およびR3は、以下のように定義され:
(a)R2は、H、C1−6アルキル、−O−C1−6アルキル、−O−Si(−C1−
6アルキル)3もしくは−O−Si(−C1−6アルキル)(−フェニル)2であり、
および各々のR3は、HもしくはC1−6アルキルである;または
(b)あるいはkが1もしくは2であるという条件で、R2およびR2に隣接するR3は
、各々が付着している炭素原子と共に、その各々が独立してC1−6アルキル、−O−C
1−6アルキル、−O−Si(−C1−6アルキル)3もしくは−O−Si(−C1−6
アルキル)(−フェニル)2である1から3個の置換基で置換されていてもよいC5−7
シクロアルキルを形成し;ならびに任意の他のR3は、HまたはC1−6アルキルである
;
R4は:
(1)その各々が独立してC1−4アルキル、C1−4ハロアルキル、−O−C1−4ア
ルキル、−O−C1−4ハロアルキル、Cl、Br、FもしくはNO2である1から3個
の置換基で置換されていてもよいフェニル;
(2)C1−4アルキル;または
(3)C1−4ハロアルキルであり;
R5は、HまたはC1−3アルキルであり;
R6およびR8は、独立して、H、C1−3アルキル、O−C1−3アルキルまたはN(
−C1−3アルキル)2であり;
各々のR7およびR9は、独立して、HまたはC1−6アルキルであり、
Wは、ハロゲンであり;
pは、0、1または2であり;
qは、0、1または2であり;ならびに
p+q=0、1、2または3である、前記化合物。
Applications Claiming Priority (5)
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US201361833108P | 2013-06-10 | 2013-06-10 | |
US61/833,108 | 2013-06-10 | ||
US201361886759P | 2013-10-04 | 2013-10-04 | |
US61/886,759 | 2013-10-04 | ||
PCT/US2014/040983 WO2014200786A1 (en) | 2013-06-10 | 2014-06-05 | Preparation of tert-butyl 4-((1r,2s,5r)-6- (benzyloxy)-7-0x0-1,6-diazabicycl0[3.2.i]octane-2- carboxamido)piperidine-1-carboxylate |
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EP (1) | EP3008069B1 (ja) |
JP (1) | JP6427173B2 (ja) |
KR (1) | KR102265772B1 (ja) |
CN (1) | CN105283458B (ja) |
AU (1) | AU2014278556B2 (ja) |
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WO2016089718A1 (en) | 2014-12-02 | 2016-06-09 | Merck Sharp & Dohme Corp. | Process for the preparation of tert-butyl 4-((2s,5r)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate and analogs thereof |
WO2017136254A1 (en) | 2016-02-04 | 2017-08-10 | Merck Sharp & Dohme Corp. | Methods of preparing hydroxylamine derivatives useful in the preparation of anti-infective agents |
EP3515915B1 (en) * | 2016-09-19 | 2021-08-04 | Merck Sharp & Dohme Corp. | Process for preparing beta-lactamase inhibitor hydroxylurea intermediates |
CN112930338A (zh) * | 2018-09-21 | 2021-06-08 | 株式会社Api | 氨基酸衍生物的制备方法 |
CN114206851A (zh) * | 2019-04-26 | 2022-03-18 | 默沙东公司 | 可用于制备(2s,5r)-7-氧代-n-哌啶-4-基-6-(硫酸基)-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺的中间体的制备方法 |
CN111606844A (zh) * | 2020-05-29 | 2020-09-01 | 江西富祥药业股份有限公司 | 一种瑞利巴坦中间体的制备方法 |
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DE59206796D1 (de) * | 1991-04-11 | 1996-08-29 | Hoffmann La Roche | Beta-Lactame |
FR2812635B1 (fr) * | 2000-08-01 | 2002-10-11 | Aventis Pharma Sa | Nouveaux composes heterocycliques, preparation et utilisation comme medicaments notamment comme anti- bacteriens |
KR20060027338A (ko) * | 2003-06-12 | 2006-03-27 | 아스텔라스세이야쿠 가부시키가이샤 | 벤즈 아미드 유도체 또는 그 염 |
US20100009957A1 (en) | 2006-09-27 | 2010-01-14 | Blizzard Timothy A | Novel inhibitors of beta-lactamase |
RU2445314C9 (ru) * | 2008-01-18 | 2013-04-10 | Мерк Шарп Энд Домэ Корп. | Ингибиторы бета-лактамаз |
US20120053350A1 (en) * | 2009-04-30 | 2012-03-01 | Ian Mangion | Preparation of alkyl esters of n-protected oxo-azacycloalkylcarboxylic acids |
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KR20160018524A (ko) | 2016-02-17 |
EP3008069A4 (en) | 2016-11-30 |
RU2015155607A3 (ja) | 2018-03-14 |
AU2014278556A1 (en) | 2015-11-12 |
US20160122350A1 (en) | 2016-05-05 |
BR112015030470B1 (pt) | 2022-08-16 |
CN105283458B (zh) | 2018-05-22 |
RU2689339C2 (ru) | 2019-05-27 |
WO2014200786A1 (en) | 2014-12-18 |
RU2015155607A (ru) | 2017-07-24 |
CN105283458A (zh) | 2016-01-27 |
MX362348B (es) | 2019-01-11 |
KR102265772B1 (ko) | 2021-06-15 |
JP2016520648A (ja) | 2016-07-14 |
EP3008069A1 (en) | 2016-04-20 |
MX2015016976A (es) | 2016-04-25 |
US9604985B2 (en) | 2017-03-28 |
BR112015030470A2 (pt) | 2017-07-25 |
PH12015502751A1 (en) | 2016-03-14 |
CA2911544A1 (en) | 2014-12-18 |
AU2014278556B2 (en) | 2018-07-19 |
EP3008069B1 (en) | 2018-01-03 |
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