US20110224425A1 - Process for producing carbapenem derivative and intermediate crystal therefor - Google Patents
Process for producing carbapenem derivative and intermediate crystal therefor Download PDFInfo
- Publication number
- US20110224425A1 US20110224425A1 US13/052,363 US201113052363A US2011224425A1 US 20110224425 A1 US20110224425 A1 US 20110224425A1 US 201113052363 A US201113052363 A US 201113052363A US 2011224425 A1 US2011224425 A1 US 2011224425A1
- Authority
- US
- United States
- Prior art keywords
- compound
- crystal
- reaction
- benzyl
- protecting group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 90
- 238000000034 method Methods 0.000 title claims abstract description 40
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 239000012453 solvate Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical group CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000003335 secondary amines Chemical class 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical group [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 24
- 239000003054 catalyst Substances 0.000 abstract description 18
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- -1 pyrrolidinylthio group Chemical group 0.000 description 48
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 0 I.I[IH]I.[1*]OC(=O)C1=C(OP(=O)(OC2=CC=CC=C2)OC2=CC=CC=C2)[C@H](C)[C@@]2([H])N1C(=O)[C@]2([H])[C@@H](C)*O.[1*]OC(=O)C1=C(S[C@H]2C[C@@H](CNS(N)(=O)=O)N([2*])C2)[C@H](C)[C@@]2([H])N1C(=O)[C@]2([H])[C@@H](C)O.[2*]N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O.[V]I Chemical compound I.I[IH]I.[1*]OC(=O)C1=C(OP(=O)(OC2=CC=CC=C2)OC2=CC=CC=C2)[C@H](C)[C@@]2([H])N1C(=O)[C@]2([H])[C@@H](C)*O.[1*]OC(=O)C1=C(S[C@H]2C[C@@H](CNS(N)(=O)=O)N([2*])C2)[C@H](C)[C@@]2([H])N1C(=O)[C@]2([H])[C@@H](C)O.[2*]N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O.[V]I 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 13
- 235000019445 benzyl alcohol Nutrition 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 11
- 125000002252 acyl group Chemical group 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical class OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 238000006482 condensation reaction Methods 0.000 description 8
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 150000004982 aromatic amines Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical class O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 229910003844 NSO2 Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- AVAACINZEOAHHE-VFZPANTDSA-N [H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CNS(N)(=O)=O)C3)[C@H](C)[C@@]21[H] Chemical compound [H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CNS(N)(=O)=O)C3)[C@H](C)[C@@]21[H] AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 229910052705 radium Inorganic materials 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229910052701 rubidium Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- XLJMOHKQRRPBDS-IENPIDJESA-N (5S)-4-pyrrolidin-1-ylsulfanyl-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical class N1(CCCC1)SC1C=CN2[C@H]1CC2=O XLJMOHKQRRPBDS-IENPIDJESA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- WYXOFORBHIOCEL-YZVGMTLCSA-N II.[H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CNS(N)(=O)=O)C3)[C@H](C)[C@@]21[H].[H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CNS(N)(=O)=O)N(C(=O)OCC=C)C3)[C@H](C)[C@@]21[H] Chemical compound II.[H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CNS(N)(=O)=O)C3)[C@H](C)[C@@]21[H].[H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CNS(N)(=O)=O)N(C(=O)OCC=C)C3)[C@H](C)[C@@]21[H] WYXOFORBHIOCEL-YZVGMTLCSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VNNBWRJJCDGJIO-KOWPAETKSA-N [H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CNS(N)(=O)=O)N(C(=O)OCC=C)C3)[C@H](C)[C@@]21[H] Chemical compound [H][C@]1([C@@H](C)O)C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CNS(N)(=O)=O)N(C(=O)OCC=C)C3)[C@H](C)[C@@]21[H] VNNBWRJJCDGJIO-KOWPAETKSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N meta-toluidine Natural products CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N ortho-methyl aniline Natural products CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
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- 150000002367 halogens Chemical class 0.000 description 1
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- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
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- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JACMPVXHEARCBO-UHFFFAOYSA-N n-pentylpentan-1-amine Chemical compound CCCCCNCCCCC JACMPVXHEARCBO-UHFFFAOYSA-N 0.000 description 1
- CATWEXRJGNBIJD-UHFFFAOYSA-N n-tert-butyl-2-methylpropan-2-amine Chemical compound CC(C)(C)NC(C)(C)C CATWEXRJGNBIJD-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- 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
- C07D207/12—Oxygen or sulfur atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Definitions
- the present invention relates to a process for producing a carbapenem derivative and an intermediate crystal therefor.
- a pyrrolidylthiocarbapenem derivative (Compound (II)) having a broad range of an antibacterial spectrum is known as a useful antibiotic (see: Patent Literature 1).
- Compound (I) of the present invention is a synthetic intermediate therefor.
- R 1 is a carboxy protecting group: R 2 is an amino protecting group
- Patent Literature 1 (Example 13, step 3) describes the following method, but a base used at a condensation reaction for introducing a 2-positional side chain is diisopropylethylamine (yield 71%).
- Patent Literature 2 (Reference Example 1) also describes the following similar reaction, but a base used at a condensation reaction is the same diisopropylethylamine (yield 54%).
- tertiary amine such as diisopropylethylamine and the like is generally used as the base at a 2-positional condensation reaction of carbapenem.
- tertiary amine is generally strongly basic, and it is thought that a side reaction hardly occurs because there is not hydrogen on the N atom.
- Patent Literature 1 Sn reagent
- Patent Literature 2 Meldrum's acid
- Patent Literature 4 a combination of amine and a Pd catalyst
- amine is used as a receptor for a lower alkenyl group
- aromatic amines such as aniline, N-methylaniline and the like.
- Compound (I) can be produced at a better yield and in a short time.
- a solvated crystal of Compound (I) which is excellent in handling is obtained.
- a method of deprotecting Compound (I) in the presence of a Pd catalyst, and a crystal of an intermediate are provided.
- R is hydrogen or a hydroxy protecting group; R 1 is a carboxy protecting group; R 2 is an amino protecting group, and Ph is phenyl
- secondary amine is used, and more preferable is secondary amine having relatively great steric hindrance.
- it is represented by NHR a R b , wherein R a and R b are independently alkyl, phenyl or the like, preferably R a and R b are the same.
- the alkyl is straight or branched C1-C10, preferably C3-C7alkyl, more preferably is branched.
- R a and R b isopropyl, t-butyl, isobutyl, amyl and phenyl are further preferably exemplified.
- diisopropylamine di-t-butylamine, diisobutylamine, diamylamine, and diphenylamine, particularly preferable is dialkylamine (e.g.: diisopropylamine).
- reaction solvent examples include acetonitrile, dimethylformamide, methylene chloride, dimethyl sulfoxide, N-dimethylacetamide and the like, preferably N-dimethylacetamide.
- a reaction temperature is usually ⁇ 40° C. to room temperature, preferable about ⁇ 20 to 0° C.
- a reaction time is usually a few tens minutes to a few tens hours, preferably 1 to 5 hours.
- Compound (III) and Compound (IV) are used at an amount of 10:1 to 1:10, preferably 1:1 to 1:5.
- Examples of the pharmaceutically acceptable salt include inorganic base salts (e.g.: alkali metal salts such as sodium salt, potassium salt etc.; alkaline earth metal salts such as calcium salt, magnesium salt etc.; ammonium salt); organic base salts (e.g.: triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt); inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate etc.; organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate etc.; salts with basic amino acids or acidic amino acids such as arginine, aspartic acid, glutamic acid etc.
- inorganic base salts e.g.: alkali metal salts such as sodium salt
- hydroxy protecting group represented by R various hydroxyl protecting groups which can be generally used in the field of ⁇ -lactam antibacterial agents can be used.
- specific examples include trialkylsilyl (the alkyl is preferably C1-C6, e.g.: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl), optionally substituted benzyl (example of substituent: nitro, lower alkoxy), lower alkoxycarbonyl group (e.g.: methoxycarbonyl, ethoxycarbonyl), halogeno lower alkoxycarbonyl group, optionally substituted benzyloxycarbonyl (example of substituent: nitro, lower alkoxy), acyl (e.g.: acetyl, benzoyl), aralkyl (e.g.: triphen
- hydroxy protecting groups can be optionally deprotected by methods well-known to a person skilled in the art after a reaction.
- those protecting groups may be protecting groups which are automatically eliminated during a coupling reaction or at a post-treatment (e.g.: extraction, washing) step. For example, trimethylsilyl or the like is eliminated with an acid in an extraction procedure after a reaction.
- Examples of the carboxy protecting group represented by R 1 include lower alkyl (e.g.: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl), lower alkanoyloxy (lower)alkyl (e.g.: acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl), lower alkanesulfonyloxy (lower)alkyl (e.g.: 2-mesylethyl), mono (or di or tri) halo (lower)alkyl (e.g.: 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarbonyloxy (lower)alkyl (e.g.: methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbon
- R 1 is preferably lower alkyl, lower alkenyl (e.g.: vinyl, allyl), lower alkynyl, (substituted) aryl(lower)alkyl, or (substituted) aryl since there is a great advantage of utilization of the present process in the case of a relatively electron donating protecting group.
- a protecting group which is hardly eliminated during a coupling reaction and particularly preferable is allyl (—CH 2 CH ⁇ CH 2 ).
- Examples of the amino protecting group represented by R 2 include aliphatic acyl groups derived from carboxylic acid, carbonic acid, sulfonic acid and carbamic acid, and aliphatic acyl groups substituted with an aromatic group.
- aliphatic acyl group examples include saturated or unsaturated alicyclic or cyclic acyl groups, for example, alkanoyl groups such as lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, alkylsulfonyl groups such as lower alkylsulfonyl groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like, carbamoyl groups, for example, N-alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamo
- aliphatic acyl group substituted with an aromatic group examples include aralkoxycabonyl groups such as phenyl(lower)alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl and the like.
- acyl groups may be further substituted with one or more suitable substituents such as a nitro group, and examples of such the preferable acyl group having a substituent include nitroaralkoxycarbonyl groups such as nitrobenzyloxycarbonyl and the like.
- the amino protecting group is preferably a protecting group which is hardly eliminated during a coupling reaction, particularly preferably an alkenyloxycarbonyl group (e.g.: —COOCH 2 CH ⁇ CH 2 ).
- Compound (I-a) can be crystallized from an alcohol solvent.
- the alcohol is preferably optionally substituted benzyl alcohol, and the alcoholated crystal is obtained.
- a substituent of optionally substituted benzyl alcohol include lower alkyl, preferably C1-C4 alkyl (e.g.: methyl, ethyl, propyl), lower alkoxy (e.g.: methoxy, ethoxy, propoxy), halogen (e.g.: F, Cl, Br), optionally substituted amino (example of substituent: lower alkyl), nitro, cyano, OH and the like, and a substitution position may be any of ortho, meta and para.
- the optionally substituted benzyl alcoholated crystal is preferably a benzyl alcoholated crystal.
- a content of benzyl alcohol in the benzyl alcoholated crystal is 0.1 to 5 mole equivalent, preferably 0.5 to 2 mole equivalent, more preferably 1 mole equivalent relative to Compound (I-a).
- the benzyl alcoholated crystal preferably exhibits a pattern of FIG. 1 in powder X-ray diffraction.
- the aforementioned spacing d value is such that, among X-ray peaks, main peaks having a strong relative intensity are selected, but a crystal structure is not particularly limited only by these values. That is, peaks other than these peaks may be contained.
- peaks may generate a slight measurement error, depending on a measuring instrument, measuring condition, the presence of an attached solvent or the like. For example, a measurement error of around ⁇ 0.2 as expressed by a value of spacing d may be generated in some cases and, even when a very precise facility is used, a measurement error of around ⁇ 0.01 to ⁇ 0.1 may be generated in some cases. Therefore, upon identification of a crystal structure, slight error may be taken into consideration, and all of crystals which are characterized by substantially the same X-ray pattern as that described above are within the scope of the present invention.
- the compound is obtained by dissolving Compound (I-a) or a solvate thereof in a soluble solvent, adding benzyl alcohol, stirring this at room temperature for a few hours and, optionally allowing to stand this at 0° C. to room temperature for a few hours to a few days, followed by filtering and drying according to a conventional method.
- a solvent is once distilled off to obtain a concentrate, to this are added benzyl alcohol and, optionally, other organic solvent, and stirring, filtration, drying and the like may be performed as described above.
- solvent As the solvent, following soluble solvents, insoluble solvents and a mixture thereof are exemplified.
- alcohols such as methanol, ethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol
- ethers such as dioxane, tetrahydrofuran, and dimethoxyethane
- ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone
- esters such as methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, and ethyl propionate
- organic halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, chlorobenzene, dichlorobenzene, nitriles such as acetonitrile, and propionitrile, dimethylformamide, di
- alcohols such as 2-propanol, 2-pentanol, 1-pentanol, t-amyl alcohol, 1-propanol, n-propanol, t-propanol, isobutanol, n-butanol, cyclohexanol, and benzyl alcohol
- ethers such as diethyl ether, isopropyl ether, dibutyl ether, ethyl isoamyl ether, and ethyl phenyl ether
- hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, methylcyclohexane, toluene, benzene, ethylbenzene, cumene, cymene, and xylene
- solvents may be used alone, or
- a ratio of the soluble solvent and the insoluble solvent to be used is usually 1:0 to 1:1000, preferably 1:0.1 to 1:100, particularly preferably 1:1 to 1:50, or usually 0:1 to 1000:1, preferably 0.1:1 to 100:1, particularly preferably 1:1 to 50:1 by weight.
- ethyl acetate and benzyl alcohol are used at a ratio of 1:1 to 5.
- a benzyl alcoholated crystal of Compound (I-a) has excellent crystallizability as apparent from its clear X-ray peaks. Therefore, when Compound (I-a) is synthesized by a 2-positional condensation reaction, and is isolated as a benzyl alcoholated crystal, an objective substance is obtained at a better yield and a high purity. In addition, handling property is better, and storage stability is high. Therefore, this is very useful as a synthetic intermediate for Compound (II) which is a carbapenem antibacterial agent.
- the compound when Compound (I-a) is isolated as a benzyl alcoholated crystal from a reaction solution after a 2-positional condensation reaction, preferably, the compound may be crystallized by washing the reaction extract, distilling a solvent off, drying this, dissolving the material in a soluble solvent as described above, and adding benzyl alcohol and, optionally, other insoluble solvent.
- benzyl alcohol optionally, a separately prepared benzyl alcoholated crystal of Compound (I-a) may be added as a seed crystal.
- Compound (I) By subjecting Compound (I), a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof, preferably a benzyl alcoholated crystal of Compound (I-a) to a deprotecting reaction, Compound (II) which is an antibacterial agent disclosed in JP-A No. 05-294970, or a pharmaceutically acceptably salt, or a solvate thereof, or a crystal thereof is obtained.
- the deprotecting reaction is performed according to the method well-known to a person skilled in the art.
- a nickel catalyst, a cobalt catalyst, an iron catalyst, a copper catalyst and a noble metal catalyst such as a platinum catalyst and a palladium catalyst are used.
- the palladium catalyst and the nickel catalyst are used, and more preferably, tetrakis(triphenylphosphine)palladium, (triphenylphosphine)palladium acetate and (triethylphosphite)palladium acetate are used.
- An additive preferably triphenylphosphine etc.
- a reducing agent for reduction-removing a protecting group or a nucleophile (trapping agent for aryl group) is added to the palladium catalyst.
- the reducing agent is hydrogen, metal hydride or the like, preferably tri-n-butyltin hydride or the like.
- the nucleophile include carboxylate (e.g. sodium 2-ethylhexanoate etc.), 1,3-dicarbonyl compound (e.g. Meldrum's acid, dimedone and malonic acid ester etc.), secondary amine (e.g. diethylamine etc.), and aromatic amine.
- a deprotecting reagent is more preferably a combination of a palladium catalyst (e.g.: tetrakis(triphenylphosphine)palladium) and aromatic amine (e.g.: aniline derivative).
- a palladium catalyst e.g.: tetrakis(triphenylphosphine)palladium
- aromatic amine e.g.: aniline derivative
- aniline derivative include aniline, N-methylaniline, N-ethylaniline, N,N-dimethylaniline, and electron donating group-substituted anilines such as o-, m- or p-toluidine, o-, m- or p-anisidine and the like, particularly preferably N-ethylaniline.
- N-ethylaniline By using N-ethylaniline, even when an amount of the Pd reagent to be used is considerably reduced (e.g.: not more than 0.01 mole equivalent, preferably not more than 0.005 mole equivalent, more preferably 0.003 to 0.001 mole equivalent relative to Compound (I)), a deprotecting reaction proceeds at a high yield. In addition, a production rate of byproduct which is derived from a protecting group and aniline reagent is low and, further, handling procedure of Compound (II) precipitated after deprotection is better, being suitable as a large scale production method.
- an amount of the Pd reagent to be used is considerably reduced (e.g.: not more than 0.01 mole equivalent, preferably not more than 0.005 mole equivalent, more preferably 0.003 to 0.001 mole equivalent relative to Compound (I))
- a deprotecting reaction proceeds at a high yield.
- An amount of aromatic amine (e.g.: aniline derivative) to be used is 1 to 20 mole equivalent, preferably 5 to 15 mole equivalent relative to Compound (I).
- any solvent may be used as far as it is used in a normal reaction.
- acetone acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol and water.
- solvents may be used alone, or two or more kinds may be used by mixing them.
- Compound (I), or a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof, and a nucleophile are added to a solvent, and a reaction system (e.g. a reaction mixed solution and a vessel) is preferably filled with nitrogen.
- a reaction system e.g. a reaction mixed solution and a vessel
- a reaction temperature is in a range of about ⁇ 20 to 50° C., preferably 0 to 30° C.
- a reaction time is usually a few minutes to a few tens hours, preferably in a range of 1 to 3 hours.
- the present invention further provides each crystal of Compound (IV-a) and (V-a) which are a synthetic intermediate for Compound (I-a).
- a crystal of Compound (IV-a) may be a solvate (e.g.: hydrate, alcoholate).
- a crystal of Compound (V-a) may be a solvate (e.g.: hydrate, alcoholate).
- a crystal of Compound (IV-a), as shown in Example later, can be crystallized with an organic solvent (preferably ethyl acetate-toluene system) after a crystal of Compound (V-a) is deprotected with preferably an acid, more preferably an inorganic acid (e.g.: hydrochloric acid), a pH of the reaction is adjusted with an alkali (preferably pH 2 to 3) to precipitate the compound, and dried and concentrated by a conventional method.
- an organic solvent preferably ethyl acetate-toluene system
- an organic solvent preferably ethyl acetate-toluene system
- a pH of the reaction is adjusted with an alkali (preferably pH 2 to 3) to precipitate the compound, and dried and concentrated by a conventional method.
- an alkali preferably pH 2 to 3
- a radical trapping agent may be used jointly. Examples of the radical trapping agent include dibutylhydroxytoluene.
- the present process by using the above-obtained Compound (I), a pharmaceutically acceptable salt, a solvate thereof or a crystal thereof, having a high purity, it has become possible to prepare an aqueous solution in which an objective Compound (II) is dissolved at a high concentration, in an impurity extraction procedure using water and an organic solvent, preferably dichlohomethane after a deprotecting reaction.
- concentration and column chromatography treatment which have previously been essential in a post-treatment step become not an essential procedure, and it has become possible to easily isolate an objective pyrrolidylthiocarbapenem derivative (II), or a pharmaceutically acceptable salt, or a solvate or a crystal thereof. Therefore, the present process is useful also as an industrial process.
- 2-Propanolated crystal (3.340 g, corresponding to 3.137 g in terms of non-solvent) of Compound (I-a) described in WO 2004/72073 was dissolved in ethyl acetate (67 ml), and ethyl acetate and isopropanol were distilled off to obtain an ethyl acetate concentrate (4.551 g). To this were added ethyl acetate (3.14 ml), benzyl alcohol (3.14 ml), and toluene (12.55 ml), and the mixture was stirred at room temperature for 2 hours, and at 5° C. for 1 hour.
- Powder X-ray diffraction a chart is shown in FIG. 1 and peak values are shown in FIG. 2 .
- Amorphous powdery Compound (I-a) (100 mg) was dissolved in ethyl acetate (0.1 ml), benzyl alcohol (0.3 ml) was added, and the mixture was stirred at room temperature for 1 hour, and allowed to stand at 5° C. for 2 days. A precipitated crystal was filtered, and air-dried to obtain a benzyl alcoholated crystal of Compound (I-a) (79 mg) exhibiting substantially the same powder X-ray pattern as that of Example 1.
- the organic layer was sequentially washed with water, a 5% aqueous sodium bicarbonate solution, and water, and dried with sodium sulfate, and a solvent was distilled off.
- the residue was dissolved in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol, and a crystal obtained in Example 2 as a seed crystal were added, and the mixture was stirred at room temperature for 2 hours.
- Toluene (5 ml) was slowly added, and the mixture was further stirred at room temperature for 2 hours, and cooled to 5° C. After filtration and drying, 554 mg (85%) of a benzyl alcoholated crystal of Compound (I-a) exhibiting substantially the same powder X-ray pattern as that of Example 1 was obtained.
- the organic layer was sequentially washed with water, a 5% aqueous sodium bicarbonate solution, and water, and dried with sodium sulfate, and a solvent was distilled off.
- the residue was diluted in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol and a crystal obtained in Example 2 as a seed crystal were added, and the mixture was stirred at room temperature for 2 hours.
- Toluene (5 ml) was slowly added, and the mixture was further stirred at room temperature for 2 hours, and cooled to 5° C. After filtration and drying, 548 mg (84%) of a benzyl alcoholated crystal of Compound (I-a) exhibiting substantially the same powder X-ray pattern as that of Example 1 was obtained.
- Example 5 The similar reaction to that of Example 5 was performed by reducing an amount of the Pd catalyst to be used.
- Compound (I-a) (provided that an isopropyl alcoholated crystal was used) (500 mg) was dissolved in 2 ml of tetrahydrofuran (THF), 10 equivalent of N-ethylaniline, 2 ml of THF, and 1 ml of H 2 O were sequentially added, and degassing under reduced pressure and nitrogen replacement of a charging solution were repeated three times. Further, 0.002 equivalent of Pd(PPh 3 ) 4 and 2 ml of THF were sequentially added, and degassing under reduced pressure and nitrogen replacement of a charging solution were further repeated three times.
- THF tetrahydrofuran
- Example 6 The reaction of Example 6 was performed using N-methylaniline in place of N-ethylaniline, and a generation rate of Compound (II) was found to be 89%. In addition, a nature of precipitated Compound (II) was viscous as compared with the case of use of N-ethylaniline, and was partially massy, and a part of the compound was adhered to a wall of a reaction vessel.
- Example 6 The reaction of Example 6 was performed similarly using aniline in place of N-ethylaniline (provided that, as a solvent, THF (12V) -water (2V) was used). As shown below, when an amount of the Pd catalyst to be used was reduced, a large amount of a byproduct was generated, and a generation rate of Compound (II) was remarkably reduced.
- DIAD diethyl azodicarboxylate
- Powder X-ray diffraction data is shown in FIG. 4 .
- a peak of peak No. 23 is a peak derived from aluminum used at measurement.
- DIAD (22.80 g; 1.2 eq) was added dropwise to a solution of 26.48 g (0.1 mol, 94% purity) of Compound 6, 24.89 g (1.35 eq) of H 2 NSO 2 NHBoc, and 29.57 g (1.2 eq) of PPh 3 in 244 ml of ethyl acetate at room temperature for 30 minute. After stirred at the same temperature for 16 hours, ethyl acetate was distilled off under reduced pressure, and the residue was dissolved in 260 ml of methanol. Methanesulfonic acid (3.8 ml; 1.0 eq) was added, and the mixture was stirred at 65 to 70° C. for 4 hours.
- Powder X-ray diffraction data is shown in FIG. 3 .
- a peak of peak No. 20 is a peak derived from aluminum used at measurement.
- FIG. 1 is a chart of a powder X-ray diffraction pattern of a benzyl alcoholated crystal of Compound (I-a) obtained in Example 1.
- FIG. 2 shows peak values of a powder X-ray diffraction pattern of a benzyl alcoholated crystal of Compound (I-a) obtained in Example 1.
- FIG. 3 is a chart of a powder X-ray diffraction pattern of a crystal of Compound (IV-a) obtained in Example 7.
- FIG. 4 is a chart of a powder X-ray diffraction pattern of a crystal of Compound (V-a) obtained in Example 7.
Abstract
An object of the present invention is to provide a carbapenem synthetic intermediate which is advantageous in an industrial process. There are provided a process for producing Compound (I), or a pharmaceutically acceptable salt, or a solvate, or a crystal thereof, comprising reacting Compound (III) and Compound (IV) in the presence of the secondary amine, and a benzyl alcoholated crystal of Compound (I). There are further provided a method of deprotecting Compound (I) with a Pd catalyst, and a crystal of Compound (IV).
Description
- The present invention relates to a process for producing a carbapenem derivative and an intermediate crystal therefor.
- A pyrrolidylthiocarbapenem derivative (Compound (II)) having a broad range of an antibacterial spectrum is known as a useful antibiotic (see: Patent Literature 1). Compound (I) of the present invention is a synthetic intermediate therefor.
- (wherein R1 is a carboxy protecting group: R2 is an amino protecting group)
- As an example of production of Compound (I), Patent Literature 1 (Example 13, step 3) describes the following method, but a base used at a condensation reaction for introducing a 2-positional side chain is diisopropylethylamine (yield 71%).
- In addition, Patent Literature 2 (Reference Example 1) also describes the following similar reaction, but a base used at a condensation reaction is the same diisopropylethylamine (yield 54%).
- Further, a method of synthesizing a carbapenem derivative having a pyrrolidinylthio group of another structure at a 2-position is known, but as a base at a condensation reaction at a 2-position, diisopropylethylamine is also used (see:
Patent Literature 3, Examples 1, 7 etc.). - Like this, as the base at a 2-positional condensation reaction of carbapenem, tertiary amine such as diisopropylethylamine and the like is generally used. The reason is presumed as follows: tertiary amine is generally strongly basic, and it is thought that a side reaction hardly occurs because there is not hydrogen on the N atom.
- In addition, regarding crystallization of the Compound (I-a), various alcoholated crystals (example: 2-propanol, 2-pentanol, 1-pentanol, t-amyl alcohol, 1-propanol) are known (see: Patent Literature 2).
- In addition, the Compound (IV-a) which is a synthetic intermediate for Compound (I-a) is described in Patent Literature 1 (see: Preparation Example 8), but a crystal thereof is not isolated.
- Further, as a method of deprotecting Compound (I-a), a Sn reagent (see: Patent Literature 1) and Meldrum's acid (see: Patent Literature 2) were used, but from a viewpoint of loading on the environment and stability of a reagent itself, they were not preferable for industrial implementation. On the other hand, as other reagent for deprotecting a carbapenem derivative, a combination of amine and a Pd catalyst is known (see: Patent Literature 4). In
Patent Literature 4, amine is used as a receptor for a lower alkenyl group, and as preferable amine, there is exemplified aromatic amines such as aniline, N-methylaniline and the like. -
- Japanese Patent Application Laid-Open (JP-A) No. 05-294970
-
- WO/2004/72073
-
- JP-A No. 2-15080
-
- JP-A No. 64-79180
- Development of a further preferable industrial process for producing Compound (I) which is an intermediate of a carbapenem derivative is desired. In addition, development of a further preferable crystal of Compound (I) is desired. Further, development of an industrially preferable method of deprotecting Compound (I), and a crystal of Compound (IV-a) or the like which is an intermediate of Compound (I) is desired.
- In view of the above problems, the present inventors intensively continued to study and, as a result, found out that, when a particular base, preferably secondary amine is used at a 2-positional condensation reaction of carbapenem, a reaction yield is improved, a reaction time is shortened, and Compound (I) can be effectively produced. In addition, it was also found out that, when Compound (I) is crystallized from benzyl alcohol or the like, a crystal which is excellent in handling as an intermediate is obtained. Further, a method of deprotecting Compound (I) in the presence of a Pd catalyst and particular amine, and a crystal of Compound (IV-a) or the like were found out, resulting in completion of the following present invention.
- (1) A process for producing Compound (I) represented by the formula:
- (wherein R1 and R2 are as defined below),
- or a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof, comprising:
- reacting Compound (III) represented by the formula:
- (wherein R is hydrogen or a hydroxyl protecting group; R1 is a carboxy protecting group; Ph is phenyl)
- with Compound (IV) represented by the formula:
- (wherein R2 is an amino protecting group),
- or a pharmaceutically acceptable salt thereof in the presence of secondary amine and, optionally, deprotecting the hydroxyl protecting group.
- (2) The process according to (1), wherein the secondary amine is diisopropylamine.
- (3) The process according to (1) or (2), wherein R1 is CH2CH═CH2; R2 is COOCH2CH═CH2.
- (4) A process for producing Compound (II) represented by the formula:
- or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising:
- obtaining Compound (I), or a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof by a method as defined in any one of (1) to (3), and subjecting this to a deprotecting reaction.
- (5) A solvated crystal (provided that the solvent is optionally substituted benzyl alcohol) of Compound (I-a) represented by the formula:
- (6) The crystal according to (5), which is a benzyl alcoholated crystal.
- (7) The crystal according to (3), wherein a content of benzyl alcohol is 1 to 10 mole equivalent relative to Compound (I).
- (8) The crystal according to (6) or (7), wherein a main peak is present at a diffraction angle 2θ=around 7.6, 17.7, 18.5, 19.5, 19.9, 21.3, 23.8 (unit: degree) in a powder X-ray diffraction pattern.
- (9) A process for producing Compound (II) represented by the formula:
- or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising:
- deprotecting a crystal as defined in any one of (5) to (8).
- (10) The process for producing Compound (II), or a pharmaceutically acceptable salt thereof, or a solvate thereof according to (9), comprising obtaining Compound (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof by the method as defined in any one of (1) to (3), crystallizing this in optionally substituted benzyl alcohol to obtain an optionally substituted benzyl alcoholated crystal of Compound (I), and deprotecting this.
- (11) A process for producing Compound (II) represented by the formula:
- or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising:
- deprotecting a compound represented by the formula:
- (wherein R1 is a carboxy protecting group; R2 is an amino protecting group),
- or a solvate thereof or a crystal thereof in the presence of a Pd catalyst and N-ethylaniline.
- (12) The process according to (11), wherein R1 is CH2CH═CH2; R2 is COOCH2CH═CH2.
- (13) The process according to (11), wherein an amount of the Pd catalyst to be used is 0.01 mole equivalent or less relative to Compound (I).
- (14) The process according to (11), wherein an amount of the Pd catalyst to be used is 0.005 mole equivalent or less relative to Compound (I).
- (15) A crystal of a compound represented by the formula:
- (16) The crystal according to (15), wherein a main peak is present at a diffraction angle 2θ=around 6.26, 12.50, 18.24, 18.80, 23.90, and 26.86 (unit: degree) in a powder X-ray diffraction pattern.
- (17) A crystal of a compound represented by the formula:
- (wherein Ac is acetyl; Boc is t-butoxycarbonyl).
- (18) The crystal according to (17), wherein a main peak is present at a diffraction angle 2θ=around 10.24, 12.26, 13.34, 17.32, 20.84, 21.22, 21.72 and 22.28 (unit: degree) in a powder X-ray diffraction pattern.
- According to the present process, Compound (I) can be produced at a better yield and in a short time. In addition, a solvated crystal of Compound (I) which is excellent in handling is obtained. In addition, a method of deprotecting Compound (I) in the presence of a Pd catalyst, and a crystal of an intermediate are provided. By utilizing these processes, and crystals, Compound (II) which is a carbapenem antibacterial agent, or a solvate thereof, or a crystal thereof can be effectively produced.
-
- (wherein R is hydrogen or a hydroxy protecting group; R1 is a carboxy protecting group; R2 is an amino protecting group, and Ph is phenyl)
- By reacting Compound (III) with Compound (IV) or a pharmaceutically acceptable salt thereof in the presence of a base and, optionally, deprotecting the hydroxy protecting group, Compound (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof or a crystal thereof is obtained.
- As the base, secondary amine is used, and more preferable is secondary amine having relatively great steric hindrance. Specifically, it is represented by NHRaRb, wherein Ra and Rb are independently alkyl, phenyl or the like, preferably Ra and Rb are the same. The alkyl is straight or branched C1-C10, preferably C3-C7alkyl, more preferably is branched. As Ra and Rb, isopropyl, t-butyl, isobutyl, amyl and phenyl are further preferably exemplified. As secondary amine, more preferable are diisopropylamine, di-t-butylamine, diisobutylamine, diamylamine, and diphenylamine, particularly preferable is dialkylamine (e.g.: diisopropylamine).
- Examples of a reaction solvent include acetonitrile, dimethylformamide, methylene chloride, dimethyl sulfoxide, N-dimethylacetamide and the like, preferably N-dimethylacetamide.
- A reaction temperature is usually −40° C. to room temperature, preferable about −20 to 0° C.
- A reaction time is usually a few tens minutes to a few tens hours, preferably 1 to 5 hours.
- Compound (III) and Compound (IV) are used at an amount of 10:1 to 1:10, preferably 1:1 to 1:5.
- Examples of the pharmaceutically acceptable salt include inorganic base salts (e.g.: alkali metal salts such as sodium salt, potassium salt etc.; alkaline earth metal salts such as calcium salt, magnesium salt etc.; ammonium salt); organic base salts (e.g.: triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt); inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate etc.; organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate etc.; salts with basic amino acids or acidic amino acids such as arginine, aspartic acid, glutamic acid etc.
- As the hydroxy protecting group represented by R, various hydroxyl protecting groups which can be generally used in the field of β-lactam antibacterial agents can be used. Specific examples include trialkylsilyl (the alkyl is preferably C1-C6, e.g.: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl), optionally substituted benzyl (example of substituent: nitro, lower alkoxy), lower alkoxycarbonyl group (e.g.: methoxycarbonyl, ethoxycarbonyl), halogeno lower alkoxycarbonyl group, optionally substituted benzyloxycarbonyl (example of substituent: nitro, lower alkoxy), acyl (e.g.: acetyl, benzoyl), aralkyl (e.g.: triphenylmethyl), tetrahydropyranyl and the like. Preferable is trialkylsilyl, particularly preferable is trimethylsilyl and t-butyldimethylsilyl.
- These hydroxy protecting groups can be optionally deprotected by methods well-known to a person skilled in the art after a reaction. Alternatively, those protecting groups may be protecting groups which are automatically eliminated during a coupling reaction or at a post-treatment (e.g.: extraction, washing) step. For example, trimethylsilyl or the like is eliminated with an acid in an extraction procedure after a reaction.
- Examples of the carboxy protecting group represented by R1 include lower alkyl (e.g.: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl), lower alkanoyloxy (lower)alkyl (e.g.: acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl), lower alkanesulfonyloxy (lower)alkyl (e.g.: 2-mesylethyl), mono (or di or tri) halo (lower)alkyl (e.g.: 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarbonyloxy (lower)alkyl (e.g.: methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, tertiary butoxycarbonyloxymethyl, 1- (or 2-)methoxycarbonyloxyethyl, 1- (or 2-)ethoxycarbonyloxyethyl, 1- (or 2-)isopropoxycarbonyloxyethyl), lower alkenyl (e.g.: vinyl, allyl), lower alkynyl (e.g.: ethynyl, propynyl), (substituted) aryl (lower)alkyl (e.g.: benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, benzhydryl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tertiary butylbenzyl), (substituted) aryl (e.g.: phenyl, 4-chlorophenyl, tolyl, tertiary butylphenyl, xylyl). Among them, R1 is preferably lower alkyl, lower alkenyl (e.g.: vinyl, allyl), lower alkynyl, (substituted) aryl(lower)alkyl, or (substituted) aryl since there is a great advantage of utilization of the present process in the case of a relatively electron donating protecting group. Further preferable is a protecting group which is hardly eliminated during a coupling reaction, and particularly preferable is allyl (—CH2CH═CH2).
- Examples of the amino protecting group represented by R2 include aliphatic acyl groups derived from carboxylic acid, carbonic acid, sulfonic acid and carbamic acid, and aliphatic acyl groups substituted with an aromatic group.
- Examples of the aliphatic acyl group include saturated or unsaturated alicyclic or cyclic acyl groups, for example, alkanoyl groups such as lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, alkylsulfonyl groups such as lower alkylsulfonyl groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like, carbamoyl groups, for example, N-alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl and the like, alkoxycarbonyl groups such as lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like, alkenyloxycarbonyl groups such as lower alkenyloxycarbonyl groups such as vinyloxycarbonyl, allyloxycarbonyl and the like, alkenoyl groups such as lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl and the like, and cycloalkanecarbonyl groups such as cyclo(lower)alkanecarbonyl groups such as cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl and the like.
- Examples of the aliphatic acyl group substituted with an aromatic group include aralkoxycabonyl groups such as phenyl(lower)alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl and the like.
- These acyl groups may be further substituted with one or more suitable substituents such as a nitro group, and examples of such the preferable acyl group having a substituent include nitroaralkoxycarbonyl groups such as nitrobenzyloxycarbonyl and the like.
- The amino protecting group is preferably a protecting group which is hardly eliminated during a coupling reaction, particularly preferably an alkenyloxycarbonyl group (e.g.: —COOCH2CH═CH2).
- Compound (I-a) can be crystallized from an alcohol solvent. The alcohol is preferably optionally substituted benzyl alcohol, and the alcoholated crystal is obtained. Examples of a substituent of optionally substituted benzyl alcohol include lower alkyl, preferably C1-C4 alkyl (e.g.: methyl, ethyl, propyl), lower alkoxy (e.g.: methoxy, ethoxy, propoxy), halogen (e.g.: F, Cl, Br), optionally substituted amino (example of substituent: lower alkyl), nitro, cyano, OH and the like, and a substitution position may be any of ortho, meta and para.
- The optionally substituted benzyl alcoholated crystal is preferably a benzyl alcoholated crystal. A content of benzyl alcohol in the benzyl alcoholated crystal is 0.1 to 5 mole equivalent, preferably 0.5 to 2 mole equivalent, more preferably 1 mole equivalent relative to Compound (I-a). The benzyl alcoholated crystal preferably exhibits a pattern of
FIG. 1 in powder X-ray diffraction. - The benzyl alcoholated crystal preferably has a main peak around on at least following positions indicated below in a powder X-ray diffraction pattern. 2θ=7.6, 17.7, 18.5, 19.5, 19.9, 21.3, 23.8 (unit: degree) (X-ray diffraction measuring condition: tubular lamp CuKα ray, tubular voltage 30 Kv, tubular current 15 mA, d sin θ=nλ (n is integer, θ is diffraction angle))
- The aforementioned spacing d value is such that, among X-ray peaks, main peaks having a strong relative intensity are selected, but a crystal structure is not particularly limited only by these values. That is, peaks other than these peaks may be contained. In addition, generally, when a crystal is measured by X-ray analysis, peaks may generate a slight measurement error, depending on a measuring instrument, measuring condition, the presence of an attached solvent or the like. For example, a measurement error of around ±0.2 as expressed by a value of spacing d may be generated in some cases and, even when a very precise facility is used, a measurement error of around ±0.01 to ±0.1 may be generated in some cases. Therefore, upon identification of a crystal structure, slight error may be taken into consideration, and all of crystals which are characterized by substantially the same X-ray pattern as that described above are within the scope of the present invention.
- When the benzyl alcoholated crystal is prepared from Compound (I-a), preferably, the compound is obtained by dissolving Compound (I-a) or a solvate thereof in a soluble solvent, adding benzyl alcohol, stirring this at room temperature for a few hours and, optionally allowing to stand this at 0° C. to room temperature for a few hours to a few days, followed by filtering and drying according to a conventional method. Alternatively, after Compound (I-a) or a solvate thereof is dissolved in a large amount of a solvent, a solvent is once distilled off to obtain a concentrate, to this are added benzyl alcohol and, optionally, other organic solvent, and stirring, filtration, drying and the like may be performed as described above.
- As the solvent, following soluble solvents, insoluble solvents and a mixture thereof are exemplified.
- As the soluble solvent, alcohols such as methanol, ethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol, ethers such as dioxane, tetrahydrofuran, and dimethoxyethane, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, esters such as methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, and ethyl propionate, organic halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, chlorobenzene, dichlorobenzene, nitriles such as acetonitrile, and propionitrile, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, quinoline, pyridines, and triethylamine can be used. These solvents may be used alone, or two or more kinds may be used by mixing them. Alternatively, they may be used by mixing with water. Preferable is ethyl acetate.
- As the insoluble solvent, alcohols such as 2-propanol, 2-pentanol, 1-pentanol, t-amyl alcohol, 1-propanol, n-propanol, t-propanol, isobutanol, n-butanol, cyclohexanol, and benzyl alcohol, ethers such as diethyl ether, isopropyl ether, dibutyl ether, ethyl isoamyl ether, and ethyl phenyl ether, and hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, methylcyclohexane, toluene, benzene, ethylbenzene, cumene, cymene, and xylene can be used. These solvents may be used alone, or two or more kinds may be used by mixing them.
- A ratio of the soluble solvent and the insoluble solvent to be used is usually 1:0 to 1:1000, preferably 1:0.1 to 1:100, particularly preferably 1:1 to 1:50, or usually 0:1 to 1000:1, preferably 0.1:1 to 100:1, particularly preferably 1:1 to 50:1 by weight. Preferably, ethyl acetate and benzyl alcohol are used at a ratio of 1:1 to 5.
- A benzyl alcoholated crystal of Compound (I-a) has excellent crystallizability as apparent from its clear X-ray peaks. Therefore, when Compound (I-a) is synthesized by a 2-positional condensation reaction, and is isolated as a benzyl alcoholated crystal, an objective substance is obtained at a better yield and a high purity. In addition, handling property is better, and storage stability is high. Therefore, this is very useful as a synthetic intermediate for Compound (II) which is a carbapenem antibacterial agent. Alternatively, when Compound (I-a) is isolated as a benzyl alcoholated crystal from a reaction solution after a 2-positional condensation reaction, preferably, the compound may be crystallized by washing the reaction extract, distilling a solvent off, drying this, dissolving the material in a soluble solvent as described above, and adding benzyl alcohol and, optionally, other insoluble solvent. Alternatively, in adding benzyl alcohol, optionally, a separately prepared benzyl alcoholated crystal of Compound (I-a) may be added as a seed crystal.
- (3) Step of Deprotecting Compound (I), or a Solvate or a Crystal thereof
- By subjecting Compound (I), a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof, preferably a benzyl alcoholated crystal of Compound (I-a) to a deprotecting reaction, Compound (II) which is an antibacterial agent disclosed in JP-A No. 05-294970, or a pharmaceutically acceptably salt, or a solvate thereof, or a crystal thereof is obtained.
- The deprotecting reaction is performed according to the method well-known to a person skilled in the art. In the present reaction, a nickel catalyst, a cobalt catalyst, an iron catalyst, a copper catalyst and a noble metal catalyst such as a platinum catalyst and a palladium catalyst are used. Preferably, the palladium catalyst and the nickel catalyst are used, and more preferably, tetrakis(triphenylphosphine)palladium, (triphenylphosphine)palladium acetate and (triethylphosphite)palladium acetate are used. An additive (preferably triphenylphosphine etc.) may be added to a mixed solution to which palladium has been added. Further preferably, a reducing agent for reduction-removing a protecting group or a nucleophile (trapping agent for aryl group) is added to the palladium catalyst. The reducing agent is hydrogen, metal hydride or the like, preferably tri-n-butyltin hydride or the like. Examples of the nucleophile include carboxylate (e.g. sodium 2-ethylhexanoate etc.), 1,3-dicarbonyl compound (e.g. Meldrum's acid, dimedone and malonic acid ester etc.), secondary amine (e.g. diethylamine etc.), and aromatic amine.
- When the environmental aspect and a reaction yield are taken into consideration, a deprotecting reagent is more preferably a combination of a palladium catalyst (e.g.: tetrakis(triphenylphosphine)palladium) and aromatic amine (e.g.: aniline derivative). Examples of the aniline derivative include aniline, N-methylaniline, N-ethylaniline, N,N-dimethylaniline, and electron donating group-substituted anilines such as o-, m- or p-toluidine, o-, m- or p-anisidine and the like, particularly preferably N-ethylaniline. By using N-ethylaniline, even when an amount of the Pd reagent to be used is considerably reduced (e.g.: not more than 0.01 mole equivalent, preferably not more than 0.005 mole equivalent, more preferably 0.003 to 0.001 mole equivalent relative to Compound (I)), a deprotecting reaction proceeds at a high yield. In addition, a production rate of byproduct which is derived from a protecting group and aniline reagent is low and, further, handling procedure of Compound (II) precipitated after deprotection is better, being suitable as a large scale production method.
- An amount of aromatic amine (e.g.: aniline derivative) to be used is 1 to 20 mole equivalent, preferably 5 to 15 mole equivalent relative to Compound (I).
- As a solvent used in the deprotecting reaction, any solvent may be used as far as it is used in a normal reaction. Preferable are acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol and water. These solvents may be used alone, or two or more kinds may be used by mixing them. Particularly preferable is a combination of tetrahydrofuran and water, and the combination is preferably used at a ratio of tetrahydrofuran:water=1:1 to 10:1.
- Compound (I), or a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof, and a nucleophile are added to a solvent, and a reaction system (e.g. a reaction mixed solution and a vessel) is preferably filled with nitrogen.
- A reaction temperature is in a range of about −20 to 50° C., preferably 0 to 30° C.
- A reaction time is usually a few minutes to a few tens hours, preferably in a range of 1 to 3 hours.
- The present invention further provides each crystal of Compound (IV-a) and (V-a) which are a synthetic intermediate for Compound (I-a).
- (Ac=acetyl; Boc=t-butoxycarbonyl)
- The present crystal has main peaks around diffraction angle 2θ=at least 6.26, 12.50, 18.24, 18.80, 23.90, and 26.86 (unit: degree) in a powder X-ray diffraction pattern. More particularly, a pattern in
FIG. 3 is shown. A crystal of Compound (IV-a) may be a solvate (e.g.: hydrate, alcoholate). - The present crystal has main peaks around diffraction angle 2θ=at least 10.24, 12.26, 13.34, 17.32, 20.84, 21.22, 21.72 and 22.28 (unit: degree) in a powder X-ray diffraction pattern. More particularly, a pattern in
FIG. 4 is shown. A crystal of Compound (V-a) may be a solvate (e.g.: hydrate, alcoholate). - A crystal of Compound (IV-a), as shown in Example later, can be crystallized with an organic solvent (preferably ethyl acetate-toluene system) after a crystal of Compound (V-a) is deprotected with preferably an acid, more preferably an inorganic acid (e.g.: hydrochloric acid), a pH of the reaction is adjusted with an alkali (preferably pH 2 to 3) to precipitate the compound, and dried and concentrated by a conventional method. Alternatively, after Compound (VI-a) is reacted with H2NSO2NHBoc to produce Compound (V-a), this may be subsequently subjected to a deprotecting reaction without isolation as described above. When there is a possibility that a byproduct derived from an amino-protecting group is generated at a deprotecting reaction, preferably, a radical trapping agent may be used jointly. Examples of the radical trapping agent include dibutylhydroxytoluene.
- In the present process, by using the above-obtained Compound (I), a pharmaceutically acceptable salt, a solvate thereof or a crystal thereof, having a high purity, it has become possible to prepare an aqueous solution in which an objective Compound (II) is dissolved at a high concentration, in an impurity extraction procedure using water and an organic solvent, preferably dichlohomethane after a deprotecting reaction. As a result, concentration and column chromatography treatment which have previously been essential in a post-treatment step become not an essential procedure, and it has become possible to easily isolate an objective pyrrolidylthiocarbapenem derivative (II), or a pharmaceutically acceptable salt, or a solvate or a crystal thereof. Therefore, the present process is useful also as an industrial process.
- Examples will be shown below.
-
- 2-Propanolated crystal (3.340 g, corresponding to 3.137 g in terms of non-solvent) of Compound (I-a) described in WO 2004/72073 was dissolved in ethyl acetate (67 ml), and ethyl acetate and isopropanol were distilled off to obtain an ethyl acetate concentrate (4.551 g). To this were added ethyl acetate (3.14 ml), benzyl alcohol (3.14 ml), and toluene (12.55 ml), and the mixture was stirred at room temperature for 2 hours, and at 5° C. for 1 hour. The precipitated crystal was filtered, washed with toluene (6.26 ml), and air-dried to obtain a benzyl alcoholated crystal of Compound (I-a) (3.668 g, corresponding to 3.037 g in terms of non-solvent, containing benzyl alcohol (1.0 mol)). Yield: 96.8%
- Mp. 74.9° C.
- Elementary Analysis for C22H31N4O8S2.1.0C7H8O.0.2H2O
- Calcd: C: 53.15; H: 6.06; N: 8.55; S: 9.79. Found: C: 53.19; H: 6.12; N: 8.65; S: 9.85.
- Powder X-ray diffraction: a chart is shown in
FIG. 1 and peak values are shown inFIG. 2 . - Regarding other alcohol solvate crystals of Compound (I-a) (solvent example: 2-propanol, 2-pentanol, 1-pentanol, t-amyl alcohol, 1-propanol), when stored under the general environment of 25° C. and 1 atom, phenomenon was recognized, in which the crystal was effloresced with time, and an amount of a contained solvent was reduced. However, regarding a benzyl alcoholated crystal, such the phenomenon was not recognized in handling for a few days, and it was seen that the crystal has high stability.
- Amorphous powdery Compound (I-a) (100 mg) was dissolved in ethyl acetate (0.1 ml), benzyl alcohol (0.3 ml) was added, and the mixture was stirred at room temperature for 1 hour, and allowed to stand at 5° C. for 2 days. A precipitated crystal was filtered, and air-dried to obtain a benzyl alcoholated crystal of Compound (I-a) (79 mg) exhibiting substantially the same powder X-ray pattern as that of Example 1.
-
- (wherein Me=methyl; Ph=phenyl)
- Diisopropylamine (0.168 ml; 1.2 mmol) was added dropwise to a solution of 595 mg (1 mmol) of enolphosphate (III-a) in which hydroxy on a 6-positional side chain was protected, and 345 mg (1.1 mmol) of thiol (IV-a) in 2 ml of N-dimethylacetamide at −12 to −8° C., and the mixture was stirred at the same temperature for 1 hour and 30 minutes. At this time point, it was confirmed by HPLC that a condensation reaction proceeded 92%. The reaction solution was poured into dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water, a 5% aqueous sodium bicarbonate solution, and water, and dried with sodium sulfate, and a solvent was distilled off. The residue was dissolved in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol, and a crystal obtained in Example 2 as a seed crystal were added, and the mixture was stirred at room temperature for 2 hours. Toluene (5 ml) was slowly added, and the mixture was further stirred at room temperature for 2 hours, and cooled to 5° C. After filtration and drying, 554 mg (85%) of a benzyl alcoholated crystal of Compound (I-a) exhibiting substantially the same powder X-ray pattern as that of Example 1 was obtained.
-
- Diisopropylamine (0.168 ml; 1.2 mmol) was added dropwise to a solution of 500 mg (1 mmol) of enolphosphate (III-b) and 345 mg (1.1 mmol) of thiol (IV-a) in 2 ml of N-dimethylacetamide at −15° C., and the mixture was stirred at the same temperature for 3 hours. At this time point, production of Compound (I-a) was confirmed (HPLC quantitation: 92%). The reaction solution was poured into dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water, a 5% aqueous sodium bicarbonate solution, and water, and dried with sodium sulfate, and a solvent was distilled off. The residue was diluted in 2 ml of ethyl acetate, 0.5 ml of benzyl alcohol and a crystal obtained in Example 2 as a seed crystal were added, and the mixture was stirred at room temperature for 2 hours. Toluene (5 ml) was slowly added, and the mixture was further stirred at room temperature for 2 hours, and cooled to 5° C. After filtration and drying, 548 mg (84%) of a benzyl alcoholated crystal of Compound (I-a) exhibiting substantially the same powder X-ray pattern as that of Example 1 was obtained.
-
- A benzyl alcoholated crystal (2.0 g; 3.06 mmol) of Compound (I-a) was dissolved in 12 ml of tetrahydrofuran, 1 ml of isopropanol, 3.71 ml (30.62 mmol) of N-ethylaniline, 4 ml of water, and 7.1 mg (0.2 eq) of Pd (PPh3)4 (Ph=phenyl) were sequentially added, and the mixture was stirred at 25° C. for 3 hours under a nitrogen stream. Then, after allowing to stand at the same temperature for 1.5 hours, and at 5° C. for 16 hours, a precipitate was filtered and dried to obtain 1.26 g (94%) of an objective material (11).
-
- The similar reaction to that of Example 5 was performed by reducing an amount of the Pd catalyst to be used.
- Compound (I-a) (provided that an isopropyl alcoholated crystal was used) (500 mg) was dissolved in 2 ml of tetrahydrofuran (THF), 10 equivalent of N-ethylaniline, 2 ml of THF, and 1 ml of H2O were sequentially added, and degassing under reduced pressure and nitrogen replacement of a charging solution were repeated three times. Further, 0.002 equivalent of Pd(PPh3)4 and 2 ml of THF were sequentially added, and degassing under reduced pressure and nitrogen replacement of a charging solution were further repeated three times. Under the condition of room temperature, nitrogen atmosphere and stirring with a stirrer, a reaction was performed for about 1.5 hours, and Compound (II) was initiated to be crystallized. Disappearance of raw materials, and a reaction intermediate was confirmed by HPLC, thereafter, three hours after initiation of a reaction, dimethylformamide (DMF) was added to uniformize the reaction solution. A generation rate of Compound (II) calculated from this reaction solution was 92%.
- The reaction of Example 6 was performed using N-methylaniline in place of N-ethylaniline, and a generation rate of Compound (II) was found to be 89%. In addition, a nature of precipitated Compound (II) was viscous as compared with the case of use of N-ethylaniline, and was partially massy, and a part of the compound was adhered to a wall of a reaction vessel.
- Further, the similar reaction was performed using other electron donating group-substituted anilines (e.g.: N,N-dimethylaniline, toluidine, anisidine) in place of N-ethylaniline, and a generation rate of Compound (II) was lower (
yield 0 to 86%) in any case as compared with the case of use of N-ethylaniline. - The reaction of Example 6 was performed similarly using aniline in place of N-ethylaniline (provided that, as a solvent, THF (12V) -water (2V) was used). As shown below, when an amount of the Pd catalyst to be used was reduced, a large amount of a byproduct was generated, and a generation rate of Compound (II) was remarkably reduced.
-
TABLE 1 Reaction Generation rate Pd(PPh3)4 time of Compound (II) (eq) (h) (%) 0.0200 0.5 86 0.0100 0.5 84 0.0050 1.5 83 0.0025 5.0 70 -
- DIAD (diethyl azodicarboxylate) (23.63 g; 1.2 eq) was added dropwise to a solution containing 26.7 g (0.1 mol, 97.1% purity) of Compound 6 synthesized by the method described in JPA (Kokai) No. 5-294970 or the above route, 26.49 g (1.35 eq) of H2NSO2NHBoc (Boc=t-butoxycarbonyl), and 32 g (1.22 eq) of PPh3 (triphenylphosphine) in 400 ml of ethyl acetate at room temperature for 30 minutes. After stirred at the same temperature for 16 hours, ethyl acetate was distilled off under reduced pressure, and the solvent was replaced with 100 ml of toluene. A precipitated reduced entity of DIAD was filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and an elution portion at n-hexane-ethyl acetate=2:1 was concentrated to obtain 48.5 g of an objective substance 7. Crystallization from ethyl ether afforded 27.12 g (62%) of a crystal.
- Mp. 115° C.
- Anal for C16H27N3O7S2 (FW 437.53), Calcd.; C, 43.92; H, 6.22; N, 9.60; S, 14.66. Found; C, 43.87; H, 6.20; N, 9.67; S, 14.37.
- 1H NMR (CDCl3): δ 1.51 (s, 9H), 2.34 (s, 3H), 2.53-2.63 (m, 1H), 3.19-3.25 (m, 1H), 3.57-3.63 (m, 1H), 3.90-4.04 (m, 2H), 4.20-4.27 (m, 3H), 4.52-4.54 (m, 3H), 5.21-5.32 (m, 3H), 5.82-5.96 (m, 4H)
- λmax MeOH ε(nm); 4,310 (231)
- νmax Nujol 3374, 3195, 1721, 1678 cm−1
- [α]365 22°+4.6±0.5°, [α]436 22°+1.2±0.4° (MeOH, C=1.00%)
- Powder X-ray diffraction data is shown in
FIG. 4 . A peak of peak No. 23 is a peak derived from aluminum used at measurement. - (2) Synthesis of 8 from 6 (Crystal of Compound (VI-a))
- DIAD (22.80 g; 1.2 eq) was added dropwise to a solution of 26.48 g (0.1 mol, 94% purity) of Compound 6, 24.89 g (1.35 eq) of H2NSO2NHBoc, and 29.57 g (1.2 eq) of PPh3 in 244 ml of ethyl acetate at room temperature for 30 minute. After stirred at the same temperature for 16 hours, ethyl acetate was distilled off under reduced pressure, and the residue was dissolved in 260 ml of methanol. Methanesulfonic acid (3.8 ml; 1.0 eq) was added, and the mixture was stirred at 65 to 70° C. for 4 hours. After cooling, a solvent was distilled off, and the residue was added to 260 ml (2.2 eq) of a 0.5N NaOH solution, and washed with 260 ml of ethyl acetate two times. Each ethyl acetate layer was back-extracted with 234 ml (2 eq) of a 0.5N NaOH solution. The aqueous layers were combined, made acidic with hydrochloric acid, and extracted with 260 ml of ethyl acetate two times. The extracts were washed with 130 ml of water, combined, and dried with Na2SO4, and a solvent was concentrated under reduced pressure to obtain 6.61 g (66.1%) of a crystal of 8.
- When hydrochloric acid or hydrochloric acid/methanol solution was used in place of methanesulfonic acid, the similar result was obtained.
- Mp. 107-109° C.
- Anal for C9H17N3O4S2 (FW 295.38), Calcd.; C, 36.60;H, 5.80; N, 14.23; S, 21.71. Found; C, 36.58; H, 5.75l N, 14.14l S, 21.82.
- 1H NMR (CDCl3) δ 1.72-1.74 (m, 2H), 2.55-2.64 (m, 1H), 3.11-3.22 (m, 1H), 3.24-3.35 (m, 2H), 3.41-3.49 (m, 1H), 4.02-4.09 (m, 2H), 4.58-4.60 (m, 2H), 4.71 (3, 2H), 5.24-5.35 (m, 2H), 5.87-6.00 (m, 2H)
- [α]D 23°−49.7±0.9° (MeOH, C=1.004%)
- Powder X-ray diffraction data is shown in
FIG. 3 . A peak of peak No. 20 is a peak derived from aluminum used at measurement. - (3) Synthesis of 8 from 7
- A 2.26N HCl/methanol solution (30.34 ml; 4 eq) was added to a solution of 7.5 g (17.14 mol) of a crystal 7 in 15 ml of methanol at room temperature, and the mixture was stirred at 40° C. for 4.5 hours. After cooling, salting out was performed by adjusting a pH at 2.5 with a 10% NaOH aqueous solution, followed by extraction with 50 ml of ethyl acetate three times. Each ethyl acetate layer was washed with 38 ml of a 6% aqueous sodium chloride solution three times. Ethyl acetate layers were combined, and dried with Na2SO4, a solvent was concentrated, and this was crystallized from ethyl acetate-toluene system to obtain 8 4.77 g (94.2%).
-
FIG. 1 is a chart of a powder X-ray diffraction pattern of a benzyl alcoholated crystal of Compound (I-a) obtained in Example 1. -
FIG. 2 shows peak values of a powder X-ray diffraction pattern of a benzyl alcoholated crystal of Compound (I-a) obtained in Example 1. -
FIG. 3 is a chart of a powder X-ray diffraction pattern of a crystal of Compound (IV-a) obtained in Example 7. -
FIG. 4 is a chart of a powder X-ray diffraction pattern of a crystal of Compound (V-a) obtained in Example 7.
Claims (5)
1. A process for producing Compound (I) represented by the formula:
(wherein R1 and R2 are as defined below),
or a pharmaceutically acceptable salt thereof, or a solvate or a crystal thereof, comprising:
reacting Compound (III) represented by the formula:
(wherein R is hydrogen or a hydroxyl protecting group; R1 is a carboxy protecting group; Ph is phenyl)
with Compound (IV) represented by the formula:
2. The process according to claim 1 , wherein the secondary amine is diisopropylamine.
3. The process according to claim 1 , wherein R1 is CH2CH═CH2; R2 is COOCH2CH═CH2.
4-18. (canceled)
19. The process according to claim 2 , wherein R1 is CH2CH═CH2; R2 is COOCH2CH═CH2.
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US88419507A | 2007-08-13 | 2007-08-13 | |
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US20060229285A1 (en) * | 2003-02-14 | 2006-10-12 | Shionogi & Co., Ltd. | Crystal of intermediate for carbapenem |
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JP2522671B2 (en) | 1986-07-30 | 1996-08-07 | 住友製薬 株式会社 | Crystalline carbapenem compound, method for producing the same and injectable antibacterial agent containing the compound |
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JP4274739B2 (en) | 2001-05-10 | 2009-06-10 | 塩野義製薬株式会社 | Method for producing acetylthiopyrrolidine derivatives |
WO2006117763A2 (en) | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | A process for the preparation of doripenem |
JP2008303143A (en) * | 2005-08-19 | 2008-12-18 | Shionogi & Co Ltd | Method for producing carbapenem derivative by continuous reaction |
-
2006
- 2006-02-14 US US11/884,195 patent/US7932381B2/en not_active Expired - Fee Related
-
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US4720490A (en) * | 1982-07-26 | 1988-01-19 | Sandoz Ltd. | Fluoralkylatedcarbapenem derivatives |
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US6642377B1 (en) * | 1999-07-30 | 2003-11-04 | Eisai Co., Ltd. | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
US20060229285A1 (en) * | 2003-02-14 | 2006-10-12 | Shionogi & Co., Ltd. | Crystal of intermediate for carbapenem |
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