CN108069998B - Synthetic method of penem drug intermediate - Google Patents
Synthetic method of penem drug intermediate Download PDFInfo
- Publication number
- CN108069998B CN108069998B CN201711488067.4A CN201711488067A CN108069998B CN 108069998 B CN108069998 B CN 108069998B CN 201711488067 A CN201711488067 A CN 201711488067A CN 108069998 B CN108069998 B CN 108069998B
- Authority
- CN
- China
- Prior art keywords
- reaction
- penem
- formula
- synthesizing
- catalyst
- 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.)
- Active
Links
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000000543 intermediate Substances 0.000 claims description 124
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- 239000007810 chemical reaction solvent Substances 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 14
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims description 7
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical group [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- -1 (R) -3-hydroxybutyric acid ester Chemical class 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- HBIHVBJJZAHVLE-UHFFFAOYSA-L dibromoruthenium Chemical group Br[Ru]Br HBIHVBJJZAHVLE-UHFFFAOYSA-L 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 4
- WHBMMWSBFZVSSR-GSVOUGTGSA-M (R)-3-hydroxybutyrate Chemical compound C[C@@H](O)CC([O-])=O WHBMMWSBFZVSSR-GSVOUGTGSA-M 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 239000012069 chiral reagent Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 230000015572 biosynthetic process Effects 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- LDLDJEAVRNAEBW-SCSAIBSYSA-N methyl (3r)-3-hydroxybutanoate Chemical group COC(=O)C[C@@H](C)O LDLDJEAVRNAEBW-SCSAIBSYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- LDLDJEAVRNAEBW-UHFFFAOYSA-N (R)-3-hydroxybutyric acid methyl ester Natural products COC(=O)CC(C)O LDLDJEAVRNAEBW-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 2
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 2
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910019891 RuCl3 Inorganic materials 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 2
- 229960003169 biapenem Drugs 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- HSJPMRKMPBAUAU-UHFFFAOYSA-N cerium(3+);trinitrate Chemical compound [Ce+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O HSJPMRKMPBAUAU-UHFFFAOYSA-N 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 2
- 229960000895 doripenem Drugs 0.000 description 2
- 229960002770 ertapenem Drugs 0.000 description 2
- 229960000379 faropenem Drugs 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 2
- 229960002182 imipenem Drugs 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960002260 meropenem Drugs 0.000 description 2
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229950011346 panipenem Drugs 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-M 3-hydroxybutyrate Chemical compound CC(O)CC([O-])=O WHBMMWSBFZVSSR-UHFFFAOYSA-M 0.000 description 1
- CYWHLOXWVAWMFO-UHFFFAOYSA-N 3-sulfanyl-1h-pyridine-2-thione Chemical compound SC1=CC=CN=C1S CYWHLOXWVAWMFO-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ANDCNBUTOQOWLW-UHFFFAOYSA-N CC1=CC=CC=C1.COC1=CC=C(C=C1)N Chemical compound CC1=CC=CC=C1.COC1=CC=C(C=C1)N ANDCNBUTOQOWLW-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- GNPBKYHFGBOEHB-UHFFFAOYSA-N acetonitrile 4-methoxyaniline Chemical compound CC#N.COc1ccc(N)cc1 GNPBKYHFGBOEHB-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- OMSUIQOIVADKIM-RXMQYKEDSA-N ethyl (R)-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](C)O OMSUIQOIVADKIM-RXMQYKEDSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VYVDNHTYCGTNAB-UHFFFAOYSA-N methanol;4-methoxyaniline Chemical compound OC.COC1=CC=C(N)C=C1 VYVDNHTYCGTNAB-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a penem drug intermediate, which takes (R) -3-hydroxybutyrate as a raw material to prepare the penem drug intermediate 4-AA, and the raw material in the route is cheap and easy to obtain and can be purchased in large quantities. The method has the advantages of simple steps, high yield of each step and simple reaction. Chiral reagents are not needed, chiral resolution is omitted, and the method has the advantages of low cost, high yield and easily obtained reaction conditions.
Description
Technical Field
The invention relates to a synthesis method of an intermediate in the technical field of medicines, in particular to a synthesis method of a penem medicine intermediate.
Background
4-AA, namely (3R,4R) -3- [ (R) -1-tert-butyl dimethyl silica ethyl ] -4-acetoxyl-2-azetidinone, is an important intermediate of penem and carbapenem antibiotics such as synthetic imipenem (imipenem), panipenem (panipenem), meropenem (meropenem), faropenem (faropenem), ertapenem (ertapenem), biapenem (biapenem) and doripenem (doripenem), penem and carbapenem are novel atypical β -lactam antibiotics successfully developed in 20 th century in 80 th century, have broad-spectrum strong antibacterial action on gram negative and positive bacteria, aerobic bacteria and anaerobic bacteria, are stable to β -lactamase, have good antibacterial action on cephalosporin drug-resistant bacteria, are the first-choice drugs for treating severe infections and multiple infections, and are one of hot spots of antibacterial drugs.
The 4-AA has 3 chiral carbon atoms in the structure, so 8 stereoisomers exist, and how to stereoselectively construct β -lactam ring is the key and difficult point of synthesis.
At present, the main total synthesis route of 4-AA can be summarized into the following five main production routes by classifying different raw materials:
the first method uses 6-aminopenicillanic acid (6-APA) as a raw material, but the route is not suitable for industrial production due to too high raw material cost and too low total yield.
The second method uses 3-hydroxybutyrate as a starting material, but the total yield of the route is low, and the cost is high.
The third method uses methyl acetoacetate as a starting material and uses (R) -BINAP-Ru as a chiral catalyst, and has relatively high price because a noble metal catalyst is used.
The fourth method takes chiral 1, 3-butanediol as a starting material, and is a better industrial route which is mainly adopted by Japanese enterprises, but the raw material is not produced at home and is not suitable for industrial mass production at home.
And the fifth method takes the L-threonine as a starting material, the raw materials of the route are convenient and easy to obtain, the reaction conditions are easy, and the method is suitable for industrial production, but the preparation, separation and purification of intermediates are difficult, and a large amount of lead tetraoxide and cerium nitrate are used as oxidants, so that the defects of heavy metal pollution and the like are caused.
Therefore, in order to solve the problems in the prior art, a synthetic route which is low in cost, environment-friendly and suitable for large-scale production is urgently needed to be found.
Disclosure of Invention
In order to overcome the defects, especially the defects of heavy metal pollution and low yield, the invention provides a synthetic method of a penem drug intermediate, and compared with other routes, the synthetic route has the advantages of easily obtained raw materials, stable and mild reaction conditions in each step, and avoids the use of chiral reagents.
The technical scheme adopted by the invention is as follows:
a synthetic method of a penem drug intermediate comprises the following steps:
(1) taking (R) -3-hydroxybutyric acid ester as a raw material, and reacting with N, N-dimethylformamide dimethyl acetal to obtain an intermediate A shown in a formula (I);
(2) carrying out substitution reaction on the intermediate A and p-anisidine to obtain an intermediate B shown as a formula (II);
(3) under the action of a catalyst, carrying out chiral hydrogenation reduction reaction on the intermediate B and hydrogen to obtain an intermediate C shown in a formula (III);
(4) hydrolyzing the intermediate D shown in the formula (IV) by the intermediate C;
(5) under the alkaline reagent, the intermediate D carries out ring closing reaction to obtain an intermediate E shown in a formula (VI);
(6) under the action of an acid binding agent, reacting the intermediate E with tert-butyldimethylsilyl chloride to obtain an intermediate F shown in a formula (VI);
(7) removing a protecting group on nitrogen from the intermediate F under the action of an oxidant to obtain an intermediate G shown as a formula (VII);
(8) under the catalysis of ruthenium trichloride, reacting the intermediate G with peroxyacetic acid to obtain 4-AA shown in a formula (VIII);
wherein R is methyl or ethyl.
The synthetic route of the invention is as follows:
the (R) -3-hydroxybutyrate is (R) -3-hydroxybutyrate methyl ester or (R) -3-hydroxybutyrate ethyl ester.
In the step (1), performing condensation reaction on (R) -3-hydroxybutyrate, N-dimethylformamide dimethyl acetal and a reaction solvent at the temperature of 30-150 ℃ for 1-5 h, washing, separating liquid, and concentrating to obtain an intermediate A, wherein the intermediate A is directly used for the next reaction without further treatment;
wherein the molar ratio of (R) -3-hydroxybutyrate to N, N-dimethylformamide dimethyl acetal (DMF-DMA) is 1: 0.5 to 2, preferably, the molar ratio of (R) -3-hydroxybutyrate to DMF-DMA is 1: 1.5;
in the step (1), the reaction solvent is one or a mixture of methyltetrahydrofuran, toluene, benzene, dichloromethane and acetonitrile in any proportion, preferably, the reaction solvent is methyltetrahydrofuran, the solubility of the raw material (R) -3-hydroxybutyrate in the methyltetrahydrofuran is better, and a higher-concentration (R) -3-hydroxybutyrate solution is beneficial to forward reaction;
preferably, in the step (1), the reaction temperature is 70-120 ℃, and the reaction time is 1-3 h.
In the step (2), mixing the intermediate A with a reaction solvent, dropwise adding a p-anisidine solution, reacting for 2-5 hours at 30-120 ℃, heating to recover a byproduct, filtering, washing, and drying to obtain an intermediate C;
wherein the p-anisidine solution is prepared from p-anisidine and a corresponding reaction solvent, and the concentration is 0.3-1.0 mol/L;
the molar ratio of the intermediate A to the p-anisidine is 0.5-2: preferably, the molar ratio of the intermediate A to the p-anisidine is 0.5-1: 1;
in the step (2), the reaction solvent is one of toluene, methanol, acetonitrile, benzene, dichloromethane and tetrahydrofuran or a mixture thereof in any proportion, preferably, the reaction solvent is toluene;
preferably, in the step (2), the reaction temperature is 80-110 ℃, the reaction time is 2-5 h, and the yield is highest under the condition.
In the step (3), mixing a catalyst, an intermediate B and a reaction solvent, filling 1-6 MPa of hydrogen into each mol of the intermediate B, and carrying out a manual hydrogenation reduction reaction at 30-100 ℃ for 3-10 h to obtain an intermediate C;
the catalyst is ruthenium-based catalyst, such as RuBr2[(R)-BINAP]，RuCl2[(R)-BINAP]2·N(C2H5)3，[RuCl(C6H6)((R)-BINAP)]Cl, etc., preferably, the catalyst is RuCl2[(R)-BINAP]2·N(C2H5)3RuCl, in contrast to other ruthenium-based catalysts2[(R)-BINAP]2·N(C2H5)3N (C) in (1)2H5)3The affinity with the intermediate B at a chiral position is strong, the activation energy can be effectively reduced in the reaction, and the optical selectivity can be well improved by utilizing the structural selectivity of the catalyst at the chiral site;
the using amount of the catalyst is 3-10% of the molar amount of the intermediate B; preferably, the amount of the catalyst is 5-8% of the molar amount of the intermediate B;
in the step (3), the reaction solvent is one of methanol, ethanol, dichloromethane, acetonitrile, toluene and chloroform or a mixture thereof in any proportion, preferably, the reaction solvent is dichloromethane;
preferably, in the step (3), the reaction temperature is 30-60 ℃ and the reaction time is 3-6 h.
In the step (4), the intermediate C, alkali and a reaction solvent are subjected to hydrolysis reaction at 30-100 ℃, and are acidified, filtered and dried after reacting for 1-3 hours to obtain an intermediate D;
wherein the molar ratio of the intermediate C to the alkali is 0.5-2: 1;
the alkali is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or sodium ethoxide, the alkali strength of the alkali can obviously influence the reaction, the influence on the hydrolysis degree of the raw materials is great, and the hydrolysis reaction can be smoothly carried out only by selecting proper alkali; preferably, the alkali is sodium carbonate, and the alkalinity of the sodium carbonate is moderate, so that the hydrolysis reaction of the intermediate C is facilitated.
In the step (4), the reaction solvent is one or a mixture of DMF, DMAC and pyridine in any proportion;
preferably, in the step (4), the reaction temperature is 70-100 ℃, and the reaction time is 1-3 h.
In the step (5), the alkaline reagent is a mixture of triphenylphosphine and 2, 2' -dipyridyl disulfide or triethylamine, preferably, the alkaline reagent is triethylamine;
in the step (5), the intermediate E and an alkaline reagent are mixed, a reaction solvent is added, the mixture reacts for 10-24 hours at the temperature of 30-120 ℃, and the intermediate E is obtained through post-treatment. Wherein the reaction solvent is one of methyl tetrahydrofuran and acetonitrile or a mixture of methyl tetrahydrofuran and acetonitrile in any proportion; preferably, the reaction solvent is acetonitrile.
In the step (6), the acid-binding agent is triethylamine, imidazole or 4-N, N-dimethylaminopyridine, and the reaction is carried out in a reaction solvent at the temperature of 30-100 ℃ for 8-15 h, wherein the reaction solvent is one of N, N-Dimethylformamide (DMF), dichloromethane and chloroform or a mixture of the DMF and the dichloromethane in any proportion.
In the step (7), the oxidant is ozone or ammonium ceric nitrate, and the reaction is carried out in a reaction solvent, wherein the reaction solvent is one of methanol, acetonitrile and acetone or a mixture of methanol, acetonitrile and acetone in any proportion.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention provides a new 4-AA synthetic route, and the raw materials of the route are cheap and easy to obtain and can be purchased in large quantities.
(2) The method has the advantages of simple steps, high yield of each step and simple reaction.
(3) Chiral reagents are not needed, chiral resolution is omitted, and the method has the advantages of low cost, high yield and easily obtained reaction conditions.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the invention is not limited to the examples.
Example 1
A new synthesis method of a penem drug intermediate (3R,4R) -3- (R) -1-tert-butyl dimethyl silica ethyl ] -4-acetoxyl-2-azetidinone (short for 4-AA) comprises the following steps:
(1) synthesis of intermediate A
5.9kg of (R) -3-hydroxybutyric acid methyl ester, 7.1L of DMF-DMA and 10L of Methyltetrahydrofuran (MTHF) were charged in a reaction vessel, stirred, and reacted at 90 ℃ under reflux for 3 hours, after which the reaction vessel was cooled to room temperature. 10L of distilled water was added and the mixture was washed 3 times. And (3) separating, namely recovering MTHF from the upper organic layer at 70 ℃ under reduced pressure, wherein the recovered MTHF can be recycled, and the obtained foam is the intermediate A which is not required to be treated and is directly used in the next step. The reaction yield in this step was 95%.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR:1.18(m,3H,CH3),3.25(m,6H,N(CH3)2),3.31(q,J＝2.4,1H,CH),3.71(s,3H,CH3),4.90(m,lH,OC-CH＝),5.14(m,1H,OH),7.62(m,1H,C＝CH-N).13C-NMR:171.54,153.81,155.25,140.90,114.21,62.65,61.94,52.08,44.25,21.83.IR(KBr):v 3415,2974,2849,2621,1741,1703,1652,1366,1332,1301,1244,1186,1129,1081,1023,981,921,829,805cm-1。
(2) synthesis of intermediate B
Adding 3kg of the intermediate A into a reaction kettle, adding 5L of toluene serving as a solvent, dropwise adding 2L of p-anisidine toluene solution with the concentration of 0.5mol/L at room temperature, stirring and heating to 60 ℃, and carrying out heat preservation reaction for 4 hours after dropwise adding is finished for 1 hour. After the reaction is finished, cooling to 0 ℃, performing suction filtration, leaching the filter cake with cold methanol, and drying to obtain white crystals with the yield of 90.8%.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR:1.18(m,3H,CH3),3.31(q,J＝2.4,1H,CH),3.71(s,3H,CH3),3.85(s,2H，CH2-N),4.90(m,lH,OC-CH＝),5.14(m,1H，OH),6.91(m,2H,CH),7.15(m,2H,CH),7.62(m,1H,C＝CH-N).13C-NMR:170.42,161.84,153.25,139.03,130.90,114.21,65.65,53.26,55.81,21.83.(KBr):v 3409,2976,2844,2621,1744,1713,1650,1589,1509,1455,1365,1339,1301,1249,1188,1131,1086,1021,979,913,835,801cm-1。
(3) synthesis of intermediate C
3kg of intermediate B, 7L of dichloromethane were added to the reaction kettle, and 100g of RoCl was added2[(R)-BINAP]2·N(C2H5)3And carrying out asymmetric chiral hydrogenation reduction reaction with hydrogen at 50 ℃, wherein the pressure of the hydrogen is 4 MPa. The reaction was carried out for 5 hours, after which the temperature was lowered to 0 ℃ and the mixture was filtered and the resulting clear liquid was distilled under reduced pressure leaving a white solid as the desired intermediate C. The yield was 93%, and the ee value was 96.1%.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR:1.19(m,3H,CH3),3.31(q,J＝2.4,1H，CH),3.71(s,3H，CH3),3.85(s,2H，CH2-N),3.94(s,3H，CH3),4.14(m,1H,OH),4.50(m,lH,OC-CH),6.95(m,2H,CH),7.04(s,lH,NH),7.15(m,2H,CH).13C-NMR:178.54,155.25,135.90,117.16,114.21,75.65,62.94,55.25,52.08,21.83.(KBr):v 3410,2966,2848,2625,2523,1741,1709,1589,1511,1452,1361,1348,1305,1246,1190,1133,1080,1022,966,923,831,799cm-1。
(4) synthesis of intermediate D
1.75kg of intermediate C and 6kg of Na were added to the reaction kettle2CO3And 5L of DMF, stirring, heating to 80 ℃, and keeping the temperature for reaction for 2 hours. Hot filtration, cooling the filtrate to 5 ℃, adding hydrochloric acid to acidify to pH 5 to give a white solid, filtration, and drying of the filter cake to give 1.57kg of white solid as intermediate D. The yield thereof was found to be 95.4%.
Obtained intermediate D for1H-NMR,13C-NMR and FT-IR measurements gave the following data:1H-NMR:1.17(m,3H,CH3),3.31(q,J＝2.4,1H,CH),3.61(s,3H,CH3),3.85(s,2H，CH2-N),4.14(m,1H，OH),4.50(m,1H,OC-CH),5.14(m,1H，OH),6.91(m,2H，CH),7.07(m,2H，CH).13C-NMR:175.54,153.25,130.90,115.16,114.21,75.65,62.94,55.25,55.08,21.83.(KBr):v 3425,2936,2858,2615,1743,1712,1589,1514,1448,1365,1342,1300,1246,1200,1138,1079,1024,968,927,835,802cm-1。
(5) synthesis of intermediate E
1kg of intermediate D was added to the reaction vessel, an equimolar amount of triethylamine was added, 20L of acetonitrile was added, the mixture was dissolved, the mixture was heated to 80 ℃ and reacted with stirring for 15 hours, and the result was monitored by TLC. After the reaction was completed, it was cooled to room temperature. The solvent was recovered by distillation under reduced pressure at 60 ℃ and the residual oil was purified by recrystallization to give intermediate E in 92% yield and 97% purity by HPLC.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR:1.21(m,3H,CH3),3.35(q,J＝2.4,1H,CH),3.71(s,3H,CH3),4.05(s,2H,CH2-N),4.14(m,1H,OH),4.50(m,1H,OC-CH),6.91(m,2H,CH),7.15(m,2H,CH).13C-NMR:173.54,163.87,135.90,118.16,114.21,69.05,61.54,54.25,52.28,21.53.(KBr):v 3405,2956,2846,2610,1733,1711,1592,1514,1445,1363,1337,1300,1256,1193,1128,1075,1014,958,925,867,833,795cm-1。
(6) synthesis of intermediate F
3L of DMF and 0.5kg of intermediate E are sequentially added into a reaction kettle, stirred uniformly and cooled to the temperature of minus 8 ℃. Slowly dripping 0.25kg of imidazole and 0.25kg of tert-butyldimethylsilyl chloride again, keeping the temperature for reacting for 45min after finishing dripping 45min, heating to 80 ℃, and reacting for 10h at the temperature. The extent of reaction of the compounds was monitored by TLC during this period. After the reaction was completed, 3L of water was added under stirring, and extracted three times with 500mL of chloroform, and the organic phases were combined. The organic phase is washed three times by 1L saturated saline solution, and is dried for 24 hours under reduced pressure to obtain a crude product. Recrystallization from methanol-water solution gave F as a gray solid with a yield of 91%.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR 0.06(s,3H,CH3),0.07(s,3H,CH3),0.76(s,9H,C(CH3)3),1.27(d,J＝6.0Hz,3H,CH3),3.40(s,1H,CH),3.77(s,3H,CH3),3.11(t,J＝2.4,lH，CH)，3.76(s,2H,CH2-N),6.83(d,J＝9.2,2H,CH),7.25(d,J＝9.2,2H,CH).13C-NMR:175.13,164.20,156.17,130.47,117.87,114.20,64.16,62.82,55.43,51.99,25.58,22.39,17.78,-4.20,-5.02.(KBr):v 2954,2936,2855,1751,1586,1502,1434,1384,1365,1337,1289,1256,1209,1155,1138,1071,1024,968,925,823cm-1.
(7) synthesis of intermediate G
Adding 4L of methanol and 1.50kg of intermediate F into a reaction kettle, introducing ozone (the mass concentration of the ozone is 25-26 mg/L), starting to add 1.35kg of sodium thiosulfate and 8kg of water, controlling the temperature below 5 ℃, and then adding 0.45kg of thiourea (after 1 hour of addition is finished). After the reaction is finished, the material is pumped into a concentration kettle to begin vacuum distillation to recover methanol, after the distillation is finished, 10kg of water is added, and the mixture is cooled, crystallized and dried to obtain 0.95kg of intermediate G with the yield of 93.1%.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR:0.07-0.06(d,J＝6.0,6H,Si(CH3)2),0.86(s,9H,C(CH3)3),1.19(d,J＝6.4,3H,CH3),2.04(s,3H,CH3),3.11(t,J＝2.4,lH,CH),3.53(s,2H,CH2-N),7.04(s,lH,NH).13C-NMR:170.7,166.4,74.9,64.8,63.7,25.6,20.8,20.5,17.8,-4.4,-5.1.IR(KBr):v 3203,2955,2929,2856,1782,1745,1387,1365,1339,1290,1251,1214,1143,1107,1074,1029,978,900,822,790cm-1.
(8) synthesis of 4-AA
Dissolving 0.78kg of the intermediate G obtained in the previous step in a mixed solvent composed of 2L of dichloromethane, 1L of acetic acid and 1L of acetonitrile, and adding 42G of RuCl3As a catalyst. Controlling the temperature at 0 ℃, continuously dropwise adding 2.5L of acetic acid solution of peroxyacetic acid with the concentration of 1mol/L under stirring, monitoring the reaction process by TLC, after the reaction is finished, distilling and concentrating the product under reduced pressure at 30 ℃, adding saturated salt water to wash for 3 times after the reaction is finished, distilling and concentrating under reduced pressure, recrystallizing to obtain white crystals, and passing through a silica gel column to obtain 0.87kg of 4-AA with the yield of 93.3%. HPLC purity 99.34%, melting point 105-.
By using1H-NMR，13C-NMR, FT-IR detection, data as follows:1H-NMR:0.07-0.06(d,J＝6.0,6H,N(CH3)2),0.86(s,9H,C(CH3)3),1.19(d,J＝6.4,3H,CH3),2.04(s,3H,CH3),3.11(t,J＝2.4,lH,CH),4.23-4.21(m,lH，OCH-),5.83(s,lH,OCH-N),7.04(s,lH，NH).13C-NMR:171.6,166.4,74.9,64.8,63.7,25.6,20.8,20.5,17.8,-4.4,-5.1.IR(KBr):v 3205,2963,2934,2893,2852,1772,1755,1463,1379,1359,1340,1250,1231,1165,1107,1074,1036,978,944,889,868cm-1。
example 2
A new synthesis method of a penem drug intermediate (3R,4R) -3- (R) -1-tert-butyl dimethyl silica ethyl ] -4-acetoxyl-2-azetidinone (short for 4-AA) comprises the following steps:
(1) synthesis of intermediate A
5.9kg of (R) -3-hydroxybutyric acid methyl ester, 8L of DMF-DMA and 8kg of toluene were added to the reaction vessel, stirred, and reacted at 110 ℃ under reflux for 3 hours, after which the reaction vessel was cooled to room temperature. The obtained mixture was concentrated under reduced pressure at 70 ℃ to recover toluene, and the obtained concentrated solution was purified by silica gel column chromatography using methanol/petroleum ether (20:80) as a mobile phase to obtain intermediate a, which was 85% in reaction yield.
(2) Synthesis of intermediate B
Adding 3kg of the intermediate A into a reaction kettle, adding 5L of acetonitrile serving as a solvent, dropwise adding 2L of p-anisidine acetonitrile solution with the concentration of 0.5mol/L at room temperature, stirring and heating to 60 ℃ after dropwise adding is finished for 1 hour, keeping the temperature and reacting for 5 hours, heating to 80 ℃ after the reaction is finished, recovering acetonitrile, cooling a crude product to 0 ℃, performing suction filtration, leaching a filter cake with cold methanol, and drying to obtain white crystals with the yield of 86.2%.
(3) Synthesis of intermediate C
3kg of intermediate B, 7L of toluene and 100g of RoCl were added to the reactor2[(R)-BINAP]2·N(C2H5)3And the catalyst and hydrogen are subjected to asymmetric hydrogenation reaction at 50 ℃, and the pressure of the hydrogen is 3 MPa. The reaction was carried out for 5 hours, after which the temperature was lowered to 0 ℃ and the mixture was filtered and the resulting clear liquid was distilled under reduced pressure leaving a white solid as the desired intermediate C. The yield was 84% and the ee value was 95.5%.
(4) Synthesis of intermediate D
1.75kg of intermediate C and 5kg of Na are added into a reaction kettle2CO3And 5L of DMAC, stirring and heating to 100 ℃, and carrying out heat preservation reaction for 1 h. Hot filtration, cooling the filtrate to 5 ℃, adding hydrochloric acid to acidify to pH 5 to give a white solid, filtration, and drying of the filter cake to give a white solid as intermediate D in 90.7% yield.
(5) Synthesis of intermediate E
1kg of intermediate D was charged into the reaction vessel, and an equal mass of triphenylphosphine and 0.25kg of dithiopyridine were added, and 5L of acetonitrile was added to dissolve the mixture, and the mixture was heated to a temperature of 80 ℃ and reacted with stirring for 15 hours, and the result was monitored by TLC. After the reaction was completed, it was cooled to room temperature. The solvent was recovered by distillation under reduced pressure at 65 ℃ and the residual oil was purified by recrystallization to give intermediate E in 89% yield and 97% purity by HPLC.
(6) Synthesis of intermediate F
Sequentially adding 3L of DMF and 0.5kg of intermediate E into a reaction kettle, uniformly stirring, adding 0.50kg of triethylamine and 0.25kg of tert-butyldimethylsilyl chloride, heating to 30-35 ℃, and keeping the temperature for 12-16 h. The extent of reaction of the compounds was monitored by TLC during this period. After the reaction was complete, 3L of water was added with stirring, cooled to 5 ℃ and extracted three times with 500mL of chloroform, and the organic phases were combined. The organic phase is washed three times by 1L saturated saline solution, and is dried for 24 hours under reduced pressure to obtain a crude product. Recrystallization from methanol-water solution gave F as a gray solid in 85% yield.
(7) Synthesis of intermediate G
Adding 4L of methanol and 1.50kg of intermediate F into a reaction kettle, introducing ozone (the mass concentration of the ozone is 25-26 mg/L), starting to add 1.35kg of sodium thiosulfate and 8kg of water, controlling the temperature below 5 ℃, and then adding 0.45kg of thiourea (after 1 hour of addition is finished). After the reaction is finished, the material is pumped into a concentration kettle to begin vacuum distillation to recover methanol, after the distillation is finished, 10kg of water is added, and the mixture is cooled, crystallized and dried to obtain 0.95kg of intermediate G with the yield of 93.1%.
(8) Synthesis of 4-AA
Dissolving 0.78kg of the intermediate G obtained in the previous step in a mixed solvent composed of 2L of dichloromethane, 1L of acetic acid and 1L of acetonitrile, and adding 42G of RuCl3As a catalyst. Controlling the temperature at 0 ℃, continuously dropwise adding 2.5L of acetic acid solution of peroxyacetic acid with the concentration of 1mol/L under stirring, monitoring the reaction process by TLC, after the reaction is finished, distilling and concentrating the product under reduced pressure at 30 ℃, adding saturated salt water to wash for 3 times after the reaction is finished, distilling and concentrating under reduced pressure, recrystallizing to obtain white crystals, and passing through a silica gel column to obtain 0.87kg of 4-AA with the yield of 93.3%.
Example 3
A new synthesis method of a penem drug intermediate (3R,4R) -3- (R) -1-tert-butyl dimethyl silica ethyl ] -4-acetoxyl-2-azetidinone (short for 4-AA) comprises the following steps:
(1) synthesis of intermediate A
5.9kg of (R) -3-hydroxybutyric acid methyl ester, 8L of DMF-DMA and 15L of dichloromethane were added to the reaction vessel, stirred, and reacted at 90 ℃ under reflux for 4 hours, after which the reaction vessel was cooled to room temperature. 10L of distilled water was added and the mixture was washed 3 times. And (3) separating, namely decompressing the organic layer at 60 ℃ to recover dichloromethane, wherein the recovered dichloromethane can be recycled, and the obtained foam is the intermediate A which is not required to be treated and is directly used in the next step. The reaction yield in this step was 76%.
(2) Synthesis of intermediate B
Adding 2.78kg of the intermediate A into a reaction kettle, adding 7.5L of solvent methanol, dropwise adding 2L of p-anisidine methanol solution with the concentration of 0.5mol/L at room temperature, stirring and heating to 60 ℃, preserving the temperature and reacting for 6 hours after 1 hour of dropwise adding, and monitoring the reaction by TLC. After the reaction, the temperature was raised to 80 ℃ to recover methanol. And cooling the concentrated product to 0 ℃, performing suction filtration, leaching a filter cake with cold methanol, and drying to obtain white crystals with the yield of 80.2%.
(3) Synthesis of intermediate C
3kg of intermediate B, 7L of dichloromethane were added to the reaction kettle, and 100g of RoCl was added2[(R)-BINAP]2·N(C2H5)3And carrying out asymmetric chiral hydrogenation reduction reaction with hydrogen at 30 ℃, wherein the pressure of the hydrogen is 4 MPa. The reaction was carried out for 5 hours, after which the temperature was lowered to 0 ℃ and the mixture was filtered and the resulting clear liquid was distilled under reduced pressure leaving a white solid as the desired intermediate C. The yield was 80% and the ee value was 94.9%.
(4) Synthesis of intermediate D
1.75kg of intermediate C and 6kg of Na were added to the reaction kettle2CO3And 7.5L of pyridine, stirring and heating to 80 ℃, and keeping the temperature for reaction for 2 hours. Hot filtering, cooling the filtrate to 5 ℃, adding hydrochloric acid to acidify to pH 5 to obtain a white solid, filtering, and drying the filter cake to obtain a white solid which is intermediate D. The yield thereof was found to be 89.4%.
(5) Synthesis of intermediate E
1kg of intermediate D was added to the reaction vessel, an equimolar amount of triethylamine was added, 20L of MTHF was added, the mixture was dissolved, the mixture was heated to 80 ℃ and reacted with stirring for 15 hours, and the result was monitored by TLC. After the reaction was completed, it was cooled to room temperature. The solvent was recovered by distillation at 70 ℃ under reduced pressure and the residual oil was purified by recrystallization to give intermediate E in 83% yield and 97% purity by HPLC.
(6) Synthesis of intermediate F
Sequentially adding 3L of DMF and 0.5kg of intermediate E into a reaction kettle, uniformly stirring, adding 0.50kg of triethylamine and 0.25kg of tert-butyldimethylsilyl chloride, heating to 30-35 ℃, and keeping the temperature for 12-16 h. The extent of reaction of the compounds was monitored by TLC during this period. After the reaction was complete, 3L of water was added with stirring, cooled to 5 ℃ and extracted three times with 500mL of chloroform, and the organic phases were combined. The organic phase is washed three times by 1L saturated saline solution, and is dried for 24 hours under reduced pressure to obtain a crude product. Recrystallization from methanol-water solution gave F as a gray solid in 85% yield.
(7) Synthesis of intermediate G
7.50L of methanol and 0.50kg of intermediate F were added to the reactor, 1.25kg of ammonium ceric nitrate was added slowly at a temperature below 5 ℃ and after the addition, the mixture was heated to 80 ℃ for 8 hours and the reaction was monitored by TLC. After the reaction is finished, the material is pumped into a concentration kettle to begin vacuum distillation to recover methanol, after the distillation is finished, 10kg of water is added, and the mixture is cooled, crystallized and dried to obtain 0.288kg of intermediate G with the yield of 84.2%.
(8)4-AA synthesis:
0.78kg of the intermediate G obtained in the previous step was dissolved in a mixed solvent composed of 2L of dichloromethane, 1L of acetic acid and 1L of acetonitrile, and 42G of RuCl was added3As a catalyst. Controlling the temperature at 0 ℃, continuously dropwise adding 2.5L of acetic acid solution of peroxyacetic acid with the concentration of 1mol/L under stirring, monitoring the reaction process by TLC, after the reaction is finished, distilling and concentrating the product under reduced pressure at 30 ℃, adding saturated salt water to wash for 3 times after the reaction is finished, distilling and concentrating under reduced pressure, recrystallizing to obtain white crystals, and passing through a silica gel column to obtain 0.87kg of 4-AA with the yield of 93.3%.
Comparative example 1
The only difference from example 1 is that in step (1), the solvent used was acetonitrile, the reaction was refluxed at 80 ℃ for 3 hours, and after completion, the reaction vessel was cooled to room temperature. 4L of distilled water was added and the mixture was extracted 3 times with 2L of cyclohexane. Separating, recovering cyclohexane from the upper organic layer at 50 ℃ under reduced pressure, and directly using the residual solid foam as the intermediate A in the next step without treatment. The reaction yield in this step was 50%.
Comparative example 2
The only difference from example 1 is that in step (3), the chiral catalyst used is RuBr2[(R)-BINAP]The other conditions are the same, the reaction yield of the step is75% and ee value 95.1%.
Comparative example 3
The only difference from example 1 is that in step (3), the chiral catalyst used is [ RuCl (C)6H6)((R)-BINAP)]Cl, the remaining conditions were the same, giving a reaction yield of 74.3% for this step and an ee of 96.1%.
Comparative example 4
The difference from example 1 is only that in step (4), the base used is sodium ethoxide, and the other conditions are the same, so that the reaction yield of this step is 77.3%.
Comparative example 5
The only difference from example 1 is that in step (4), the base used is sodium hydroxide, and the other conditions are the same, so that the reaction yield of this step is 85.4%.
Claims (7)
1. A synthetic method of a penem drug intermediate is characterized by comprising the following steps:
(1) taking (R) -3-hydroxybutyric acid ester as a raw material, and reacting with N, N-dimethylformamide dimethyl acetal to obtain an intermediate A shown in a formula (I);
(2) carrying out substitution reaction on the intermediate A and p-anisidine to obtain an intermediate B shown as a formula (II);
(3) under the action of a ruthenium catalyst, carrying out chiral hydrogenation reduction reaction on the intermediate B and hydrogen to obtain an intermediate C shown in a formula (III);
(4) hydrolyzing the intermediate D shown in the formula (IV) by the intermediate C;
(5) under the condition of an alkaline reagent, the intermediate D is subjected to a ring closing reaction to obtain an intermediate E shown in a formula (V), wherein the alkaline reagent is a mixture of triphenylphosphine and 2, 2' -dithiodipyridine or triethylamine;
(6) under the action of an acid-binding agent, reacting the intermediate E with tert-butyldimethylsilyl chloride to obtain an intermediate F shown in a formula (VI), wherein the acid-binding agent is triethylamine, imidazole or 4-N, N-dimethylaminopyridine;
(7) removing a protecting group on nitrogen from the intermediate F under the action of an oxidant to obtain an intermediate G shown in a formula (VII), wherein the oxidant is ozone or ammonium ceric nitrate;
(8) under the catalysis of ruthenium trichloride, reacting the intermediate G with peroxyacetic acid to obtain 4-AA shown in a formula (VIII);
wherein R is methyl or ethyl.
2. The method for synthesizing penem pharmaceutical intermediates of claim 1, wherein in step (1), the reaction solvent is one of methyl tetrahydrofuran, toluene, benzene, dichloromethane and acetonitrile, or a mixture thereof in any proportion.
3. The method for synthesizing the penem pharmaceutical intermediate according to claim 1, wherein in step (3), the catalyst, the intermediate B and the reaction solvent are mixed, 1-6 MPa of hydrogen is charged into each mol of the intermediate B, and the manual hydrogenation reduction reaction is carried out at 30-100 ℃ for 3-10 h to obtain the intermediate C.
4. The method for synthesizing penem intermediates of claim 3, wherein the catalyst is RuBr2[(R)-BINAP]，RuCl2[(R)-BINAP]2·N(C2H5)3Or [ RuCl (C)6H6)((R)-BINAP)]Cl。
5. The method for synthesizing penem intermediates of claim 4, wherein the catalyst is RuCl2[(R)-BINAP]2·N(C2H5)3。
6. The method for synthesizing the penem pharmaceutical intermediate as claimed in claim 1, wherein in step (4), the intermediate C, alkali and reaction solvent are subjected to hydrolysis reaction at 30-100 ℃, and after reaction for 1-3 h, the intermediate C is acidified, filtered and dried to obtain the intermediate D.
7. The method for synthesizing penem pharmaceutical intermediate according to claim 6, wherein the base is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide or sodium ethoxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711488067.4A CN108069998B (en) | 2017-12-29 | 2017-12-29 | Synthetic method of penem drug intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711488067.4A CN108069998B (en) | 2017-12-29 | 2017-12-29 | Synthetic method of penem drug intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108069998A CN108069998A (en) | 2018-05-25 |
| CN108069998B true CN108069998B (en) | 2020-05-08 |
Family
ID=62156145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711488067.4A Active CN108069998B (en) | 2017-12-29 | 2017-12-29 | Synthetic method of penem drug intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108069998B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053793B (en) * | 2018-08-27 | 2020-11-10 | 浙江大学宁波理工学院 | Method for preparing penem drug intermediate 4-AA by removing N-alkyl through photocatalysis |
| CN109946396B (en) * | 2019-03-26 | 2022-02-08 | 深圳市海滨制药有限公司 | Method for determining biapenem and/or related substances by adopting high performance liquid chromatography |
| CN114933611A (en) * | 2022-04-12 | 2022-08-23 | 中国科学院大连化学物理研究所 | Method for continuously preparing penem antibiotic intermediate 4-acetoxy azetidinone |
| CN115385950B (en) * | 2022-10-27 | 2023-04-28 | 天津凯莱英医药科技发展有限公司 | System and method for preparing 4-acetoxyazetidinone by continuous ozone oxidation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007836A1 (en) * | 2006-07-13 | 2008-01-17 | Choongwae Pharma Corporation | Method for preparing 4-acetoxyazetidinone and derivatives thereof |
| CN102002066A (en) * | 2010-11-01 | 2011-04-06 | 山东鑫泉医药中间体有限公司 | Synthesis method of 4-acetoxyl-2-azetidinone |
| CN103665021A (en) * | 2013-12-03 | 2014-03-26 | 西安赛美科医药研发有限公司 | Synthetic method of biapenem drug intermediate 4-AA |
-
2017
- 2017-12-29 CN CN201711488067.4A patent/CN108069998B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007836A1 (en) * | 2006-07-13 | 2008-01-17 | Choongwae Pharma Corporation | Method for preparing 4-acetoxyazetidinone and derivatives thereof |
| CN102002066A (en) * | 2010-11-01 | 2011-04-06 | 山东鑫泉医药中间体有限公司 | Synthesis method of 4-acetoxyl-2-azetidinone |
| CN103665021A (en) * | 2013-12-03 | 2014-03-26 | 西安赛美科医药研发有限公司 | Synthetic method of biapenem drug intermediate 4-AA |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108069998A (en) | 2018-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108069998B (en) | Synthetic method of penem drug intermediate | |
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| CN109705011B (en) | Synthetic method of Upacatinib intermediate and intermediate | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| CN108586517B (en) | Synthetic method of carbapenem antibiotic drug intermediate | |
| CN108239089B (en) | Method for synthesizing avibactam sodium | |
| CN107686488B (en) | Synthesis method of biotin intermediate | |
| CN108314688B (en) | A kind of synthetic method of sitagliptin | |
| CN108997229B (en) | 1,2,3, 4-tetrahydroquinoxaline-6-carboxylic acid methyl ester and preparation method thereof | |
| CN111454163A (en) | Synthesis method of 1-aminomethyl-1-cyclopropanol | |
| GB2451384A (en) | 2-cyanophenylboronic acid with reduced impurities or ester thereof,and production method thereof | |
| CN107216335B (en) | A kind of tert-butyl 1- (methylol) -3- oxa- -9- azaspiro [5.5] hendecane -9- formic acid base ester preparation method | |
| CN107216332B (en) | The synthetic method of 5 (6H) formic acid base ester of tert-butyl -7- methylol -7,8- dihydro 4H pyrazolo diazepine | |
| CN105859747A (en) | Cefepime dihydrochloride preparation method suitable for industrial production | |
| CN108947919A (en) | A kind of novel processing step and its key intermediate of gout suppressant Lesinurad | |
| JP4994772B2 (en) | Method for producing piperidin-4-one derivative using bisaminol ether compound | |
| CN101514201A (en) | Preparation method for (4,7-cis)-octahydro-pyrrolo[3,4-b]pyridine and moxifolxacin | |
| KR100781821B1 (en) | Process for preparing carbapenem compound | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester | |
| CN110790708B (en) | Preparation method of Ailixipine intermediate | |
| CN103450182B (en) | Preparation and purification methods of Retapamulin | |
| JP5695434B2 (en) | Optically active fluorine-containing 2,3-dihydropyridone derivative and production method thereof. | |
| JPH02196744A (en) | Production of adamantanetriols | |
| CN115417794B (en) | Preparation method of saxagliptin intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |