CN108069998A - A kind of synthetic method of penem-like pharmaceutical intermediate - Google Patents
A kind of synthetic method of penem-like pharmaceutical intermediate Download PDFInfo
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- CN108069998A CN108069998A CN201711488067.4A CN201711488067A CN108069998A CN 108069998 A CN108069998 A CN 108069998A CN 201711488067 A CN201711488067 A CN 201711488067A CN 108069998 A CN108069998 A CN 108069998A
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- Prior art keywords
- reaction
- penem
- synthetic method
- formula
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Links
- 239000012450 pharmaceutical intermediate Substances 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000000543 intermediate Substances 0.000 claims description 110
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 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 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- -1 (R) -3-hydroxybutyrate ester Chemical class 0.000 claims description 11
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- HBIHVBJJZAHVLE-UHFFFAOYSA-L dibromoruthenium Chemical compound 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-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 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
- 230000009467 reduction Effects 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000012069 chiral reagent Substances 0.000 abstract description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 46
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 12
- 238000005292 vacuum distillation Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000004064 recycling Methods 0.000 description 6
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical group [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000009413 insulation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 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
- 238000000926 separation method Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000004519 grease Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000012044 organic layer Substances 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
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 description 2
- 229960002770 ertapenem Drugs 0.000 description 2
- 238000000605 extraction Methods 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
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 208000015181 infectious disease Diseases 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
- 238000012544 monitoring process Methods 0.000 description 2
- 229950011346 panipenem Drugs 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000012827 research and development 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
- 238000012549 training Methods 0.000 description 2
- 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 2
- AXPZIVKEZRHGAS-UHFFFAOYSA-N 3-benzyl-5-[(2-nitrophenoxy)methyl]oxolan-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1OCC1OC(=O)C(CC=2C=CC=CC=2)C1 AXPZIVKEZRHGAS-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical compound CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 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 1
- 239000004473 Threonine Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 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 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 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 1
- 229960000895 doripenem Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 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
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 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 1
- 229960002182 imipenem Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- XMFOQHDPRMAJNU-UHFFFAOYSA-N lead(ii,iv) oxide Chemical compound O1[Pb]O[Pb]11O[Pb]O1 XMFOQHDPRMAJNU-UHFFFAOYSA-N 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 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
- 150000003952 β-lactams Chemical class 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 kind of synthetic methods of penem-like pharmaceutical intermediate, using (R) 3 butyric ester as raw material, are prepared for 4 AA of penem-like pharmaceutical intermediate, the route raw material is cheap and easily-available, can make a big purchase in large quantities.Step of the present invention is simple, the high income of each step, and reaction is simple.It is not required to use chiral reagent, eliminates chiral resolution, the present invention has at low cost, high income, the advantage that reaction condition is easy to get.
Description
Technical field
The present invention relates to a kind of synthetic methods of the intermediate of pharmaceutical technology field, and in particular in a kind of penem-like pharmaceutical
The synthetic method of mesosome.
Background technology
4-AA, i.e. (3R, 4R) -3- [(R) -1- tert-butyl dimethyl silica ethyls] -4- acetoxyl group -2- azetidins
Ketone is synthesizing imine training southern (imipenem), Panipenem (panipenem), Meropenem (meropenem), faropenem
(faropenem), the moulds such as ertapenem (ertapenem), Biapenem (biapenem), donipenem (doripenem)
The important intermediate of alkene and carbapenem antibiotic.Penem and carbapenem are that research and development the 1980s are successfully new
Atypia beta-lactam antibiotic is respectively provided with Grain-negative and positive bacteria, aerobic bacteria, anaerobic bacteria in broad spectrum high-effect antibacterial work
With, to beta-lactamase stablize, also have good antibacterial action to cynnematin drug-fast bacteria, become treatment severe infection with
The choice drug of multiple infection is one of hot spot of antibacterials research and development.
Have 3 asymmetric carbon atoms in the structure of 4-AA, therefore there are 8 stereoisomers, how Stereoselective structure
It is the key that synthesis and difficult point to build beta-lactam nucleus.The country has many scientific research institutions and the synthesis technology of 4-AA is ground
Study carefully, though having a small amount of production at present, not yet make a breakthrough.
At present, the main fully synthetic route of 4-AA can be summarized as following five main production roads with different material classification
Line：
The first with 6-amino-penicillanic acid (6-APA) be raw material, but the route due to cost of material is too high, total recovery too
Low unsuitable industrialized production.
Second using 3-hydroxybutyrate ester as starting material, but the route total recovery is low, high expensive.
The third is using methyl acetoacetate as starting material, using (R)-BINAP-Ru as chiral catalyst, because using expensive
Metallic catalyst, price are relatively high.
4th kind using chiral 1,3-BDO as starting material, be a preferable industrialized route, Japanese enterprises are main
Using this route, but domestic this raw material there is no production, be not suitable for the big production of domestic industryization.
5th kind using L-threonine as starting material, which is conveniently easy to get, and reaction condition is easier to, be suitble to industry
Metaplasia is produced, but intermediate is prepared, separated, purifying highly difficult, and makees oxidant using substantial amounts of lead orthoplumbate, cerous nitrate, has
The shortcomings of heavy metal pollution.
Therefore, to solve problem in the prior art, suddenly wait to find an of low cost, environmental-friendly and suitable rule
The synthetic route of modelling production.
The content of the invention
To overcome the shortcomings that above-mentioned, especially heavy metal pollution, the deficiency of low yield, the present invention proposes a kind of southern class medicine of training
The synthetic method of object intermediate, the synthetic route are easy to get compared with other routes with raw material, each to walk stable reaction conditions temperature
With avoid the use of chiral reagent.
The technical solution adopted by the present invention is as follows：
A kind of synthetic method of penem-like pharmaceutical intermediate, comprises the following steps：
(1) using (R) -3-hydroxybutyrate ester as raw material, formula (I) is obtained by the reaction with n,N-Dimethylformamide dimethylacetal
Shown intermediate A；
(2) intermediate A and P-nethoxyaniline carry out substitution reaction, obtain the intermediate B shown in formula (II)；
(3) under catalyst action, chiral hydrogenation reduction reaction occurs for intermediate B and hydrogen, obtains shown in formula (III)
Intermediate C；
(4) the intermediate D shown in intermediate C hydrolyzing types (IV)；
(5) under alkaline reagent, ring closure reaction occurs for intermediate D, obtains the intermediate E shown in formula (VI)；
(6) under acid binding agent effect, intermediate E is reacted with tert-butyl chloro-silicane, in obtaining shown in formula (VI)
Mesosome F；
(7) intermediate F sloughs the protecting group on nitrogen under oxidant effect, obtains the intermediate G shown in formula (VII)；
(8) under the catalysis of ruthenium trichloride, intermediate G is reacted with Peracetic acid, obtains the 4-AA shown in formula (VIII)；
Wherein, R is methyl or ethyl.
The synthetic route of the present invention is as follows：
(R) -3-hydroxybutyrate ester is (R) -3-hydroxybutyrate methyl esters or (R)-ethyl 3-hydroxybutanoate.
In step (1), by (R) -3-hydroxybutyrate ester, n,N-Dimethylformamide dimethylacetal and reaction dissolvent 30
1~5h of condensation reaction, washing are carried out at~150 DEG C, liquid separation obtains intermediate A after concentration, intermediate A need not be further processed, directly
It connects for the next step；
Wherein, (R) -3-hydroxybutyrate ester and the molar ratio of n,N-Dimethylformamide dimethylacetal (DMF-DMA) are
1：0.5~2, preferably, the molar ratio of (R) -3-hydroxybutyrate ester and DMF-DMA are 1：1.5；
In step (1), reaction dissolvent be methyltetrahydrofuran, toluene, benzene, dichloromethane and acetonitrile in one kind or its
Meaning scalemic thereof, preferably, reaction dissolvent is methyltetrahydrofuran, raw material (R) -3-hydroxybutyrate ester is in methyl tetrahydrochysene furan
Middle solubility of muttering is preferable, and (R) -3-hydroxybutyrate ester solution of higher concentration is conducive to the positive progress of reaction；
Preferably, in step (1), reaction temperature is 70~120 DEG C, and the reaction time is 1~3h.
In step (2), intermediate A and reaction dissolvent are mixed, it is anti-at 30~120 DEG C that P-nethoxyaniline solution is added dropwise
2~5h is answered, rising temperature reclamation by-product filters, and washs, dry, obtains intermediate C；
Wherein, P-nethoxyaniline solution is prepared to obtain by P-nethoxyaniline with corresponding reaction dissolvent, concentration 0.3
~1.0mol/L；
As active ingredients, intermediate A and the molar ratio of P-nethoxyaniline are 0.5~2：1, preferably, intermediate A
Molar ratio with P-nethoxyaniline is 0.5~1:1；
In step (2), reaction dissolvent be toluene, methanol, acetonitrile, benzene, dichloromethane and tetrahydrofuran in one kind or its
Arbitrary proportion mixture, preferably, the step reaction dissolvent is toluene；
Preferably, in step (2), reaction temperature is 80~110 DEG C, and the reaction time is 2~5h, and under the conditions of being somebody's turn to do, yield is most
It is high.
In step (3), catalyst, intermediate B and reaction dissolvent are mixed, 1~6MPa hydrogen is filled with per mol intermediate Bs,
Green hand's property hydrogenation reduction is issued at 30~100 DEG C, the reaction time is 3~10h, obtains intermediate C；
The catalyst be ruthenium 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)3, compared with other ruthenium catalysts, RuCl2[(R)-BINAP]2·N(C2H5)3In N (C2H5)3With intermediate B in hand
Property position affinity it is strong, can be effectively reduced activation energy in the reaction, and the knot of catalyst is utilized in chiral site
Structure selectivity, can improve optical selective well；
The dosage of catalyst is the 3~10% of intermediate B mole；Preferably, the dosage of catalyst is rubbed for intermediate B
The 5~8% of that amount；
In step (3), reaction dissolvent is methanol, ethyl alcohol, dichloromethane, acetonitrile, toluene, one kind in chloroform or it is arbitrary
Scalemic thereof, preferably, reaction dissolvent is dichloromethane；
Preferably, in step (3), reaction temperature is 30~60 DEG C, and the reaction time is 3~6h.
In step (4), reaction is hydrolyzed in intermediate C, alkali, reaction dissolvent at 30~100 DEG C, after reacting 1~3h
Acidifying is filtered, dry, obtains intermediate D；
Wherein, the molar ratio of intermediate C and alkali is 0.5~2:1；
The alkali be sodium hydroxide, sodium carbonate, sodium acid carbonate, potassium hydroxide or sodium ethoxide, the base strength of alkali used
The progress of reaction can be significantly affected, it is huge on the degree of hydrolysis influence of raw material, suitable alkali is only selected, hydrolysis could be smoothly
It carries out；Preferably, the alkali is sodium carbonate, the alkalescence of sodium carbonate is moderate, is conducive to the hydrolysis of intermediate C.
In step (4), reaction dissolvent DMF, DMAC and one kind or its arbitrary proportion mixture in pyridine；
Preferably, in step (4), reaction temperature is 70~100 DEG C, and the reaction time is 1~3h.
In step (5), the alkaline reagent be triphenyl phosphorus and 2, the mixture or triethylamine of 2 '-two sulphur, two pyridine,
Preferably, the alkaline reagent is triethylamine；
In step (5), intermediate E and alkaline reagent are mixed, add in reaction dissolvent, react 10 at 30~120 DEG C~
For 24 hours, it is post-treated to obtain intermediate E.Wherein, reaction dissolvent is one kind or its arbitrary proportion in methyltetrahydrofuran and acetonitrile
Mixture；Preferably, reaction dissolvent is acetonitrile.
In step (6), the acid binding agent is triethylamine, imidazoles or 4-N, N- dimethylamino naphthyridine, in reaction dissolvent
It is reacted, reaction temperature is 30~100 DEG C, and the reaction time is 8~15h, wherein, reaction dissolvent is n,N-Dimethylformamide
(DMF), one kind or its arbitrary proportion mixture of dichloromethane and chloroform.
In step (7), the oxidant is ozone or ammonium ceric nitrate, is reacted in reaction dissolvent, wherein, reaction
Solvent is methanol, one kind of acetonitrile and acetone or its arbitrary proportion mixture.
Compared with prior art, the invention has the advantages that：
(1) the present invention provides a new 4-AA synthetic route, the route raw material is cheap and easily-available, can make a big purchase in large quantities.
(2) step is simple, the high income of each step, and reaction is simple.
(3) chiral reagent need not be used, eliminates chiral resolution, the present invention has at low cost, high income, reaction condition
The advantage being easy to get.
Specific embodiment
The present invention will be further described with reference to embodiments, but the present invention claims protection domain be not limited in reality
Apply the scope that example is stated.
Embodiment 1
A kind of penem-like pharmaceutical intermediate (3R, 4R) -3- (R) -1- tert-butyl dimethyl silica ethyls] -4- acetoxyl groups -
2- aza cyclo-butanones are (referred to as：Novel synthesis 4-AA), this method are made of the following steps：
(1) synthesis of intermediate A
5.9kg (R) -3-hydroxybutyrate methyl esters, 7.1L DMF-DMA and 10L methyltetrahydrofurans are added in a kettle
(MTHF), stir, reaction kettle after finishing, is cooled to room temperature by the back flow reaction 3h at 90 DEG C.Add in 10L distillation water washings 3
It is secondary.MTHF is recovered under reduced pressure at 70 DEG C in upper organic layer by liquid separation, the MTHF reusable edibles recycled, the foam of gained
Shape object need not be handled for intermediate A, be directly used in next step.The step reaction yield is 95%.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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
3kg intermediate As are added in a kettle, add in solvent 5L toluene, and the concentration that 2L is added dropwise at room temperature is 0.5mol/L
P-nethoxyaniline toluene solution, 1 is added dropwise when small, stirring be warming up to 60 DEG C of insulation reactions 4 it is small when.It is cold after reaction
But to 0 DEG C, filter, filter cake is eluted with cold methanol, dries to obtain white crystal, yield 90.8%.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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 intermediate Bs, the dichloromethane of 7L are added in a kettle, and add in 100gRuCl2[(R)-BINAP]2·N
(C2H5)3, at 50 DEG C and asymmetric chiral hydrogenation reduction reaction occurs for hydrogen, and hydrogen pressure is 4MPa.React 5 it is small when, terminate
After reduce the temperature to 0 DEG C, filter mixture, obtained supernatant liquid vacuum distillation, remaining white solid is required
Intermediate C.Yield is that 93%, ee values are 96.1%.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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 intermediates C, 6kg Na are added in a kettle2CO3With 5L DMF, stirring is warming up to 80 DEG C, insulation reaction
2h.Heat filtering, filtrate are cooled to 5 DEG C, add in hydrochloric acid and are acidified to pH=5, obtain white solid, filter, filtration cakes torrefaction obtains white solid
Body 1.57kg is intermediate D.Yield 95.4%.
The intermediate D of gained is used1H-NMR,13C-NMR, FT-IR detect to obtain data as follows：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 intermediate D are added in a kettle, and add in the triethylamine of equimolar amounts, and add in the acetonitrile of 20L, are dissolved
Mixture heats the mixture to 80 DEG C, stirs lower reaction 15h, is as a result monitored with TLC.After the completion of reaction, it is cooled to room temperature.
Remaining grease is purified acquisition intermediate E, product by the vacuum distillation recovered solvent at 60 DEG C in a manner of by recrystallization
Yield for 92%, detected with HPLC, purity 97%.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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 DMF and 0.5kg intermediate Es are sequentially added in a kettle, are stirred evenly, are cooled at a temperature of -8 DEG C.Again
Secondary that 0.25kg imidazoles and 0.25kg tert-butyl chloro-silicanes is slowly added dropwise, 45min is added dropwise, insulation reaction 45min, rises
Temperature reacts 10h at such a temperature to 80 DEG C.During this period with the extent of reaction of TLC monitoring compounds.After completion of the reaction, exist
3L water is added with stirring, with the extraction of 500mL chloroforms three times, merges organic phase.Organic phase three times, subtracts through 1L saturated common salts water washing
Press dry it is dry for 24 hours, obtain crude product.Gray solid F, yield 91% are recrystallized to obtain with methanol-water solution.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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
4L methanol, 1.50kg intermediate F are added in a kettle, are passed through ozone (25~26mg/L of ozone mass concentration),
It is initially added into 1.35kg sodium thiosulfate, 8kg water, control temperature is below 5 DEG C, then adds 0.45kg thiocarbamides (1h is added).Reaction
After finishing, material is extracted into concentration kettle and starts vacuum distillation recycling methanol, after the completion of distillation, add 10kg water, cooling, crystallization are dried
Do to obtain 0.95kg intermediate G, yield 93.1%.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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
The obtained intermediate G of previous step 0.78kg are dissolved in the mixed of 2L dichloromethane, 1L acetic acid and 1L acetonitriles composition
In bonding solvent, the RuCl of 42g is added in3As catalyst.Temperature is controlled at 0 DEG C, stirring the lower 2.5L concentration that is constantly added dropwise is
The acetic acid solution of the Peracetic acid of 1mol/L monitors reaction process with TLC, after completion of the reaction, concentration is evaporated under reduced pressure at 30 DEG C
Product, adds in saturated common salt water washing 3 times after reaction, and vacuum distillation concentration is recrystallized to give white crystal, crosses silicagel column
Obtain 0.87kg 4-AA, yield 93.3%.HPLC purity 99.34%, 105-106 DEG C of fusing point.
With1H-NMR,13C-NMR, FT-IR are detected, and data are 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。
Embodiment 2
A kind of penem-like pharmaceutical intermediate (3R, 4R) -3- (R) -1- tert-butyl dimethyl silica ethyls] -4- acetoxyl groups -
2- aza cyclo-butanones are (referred to as：Novel synthesis 4-AA), this method are made of the following steps：
(1) synthesis of intermediate A
5.9kg (R) -3-hydroxybutyrate methyl esters, 8L DMF-DMA and 8kg toluene, stirring, in 110 are added in a kettle
Reaction kettle after finishing, is cooled to room temperature by back flow reaction 3h at DEG C.The mixture of gained is concentrated under reduced pressure at 70 DEG C recycling first
Benzene, by the concentrate of gained with methanol/petroleum ether (20:80) silica gel column chromatography purification is carried out for mobile phase, obtains intermediate A, it should
It is 85% to walk reaction yield.
(2) synthesis of intermediate B
3kg intermediate As are added in a kettle, add in solvent 5L acetonitriles, and the concentration that 2L is added dropwise at room temperature is 0.5mol/L
P-nethoxyaniline acetonitrile solution, 1 is added dropwise when small, stirring be warming up to 60 DEG C of insulation reactions 5 it is small when, after reaction,
80 DEG C of recycling acetonitriles are warming up to, crude product is cooled to 0 DEG C, filters, and filter cake is eluted with cold methanol, dries to obtain white crystal, yield
86.2%.
(3) synthesis of intermediate C
3kg intermediate Bs, the toluene of 7L are added in a kettle, and add in 100gRuCl2[(R)-BINAP]2·N
(C2H5)3, at 50 DEG C and asyininetric hydrogenation occurs for hydrogen, and hydrogen pressure is 3MPa.React 5 it is small when, after by temperature
0 DEG C is dropped to, filters mixture, obtained supernatant liquid vacuum distillation, remaining white solid is required intermediate C.
Yield is that 84%, ee values are 95.5%.
(4) synthesis of intermediate D
1.75kg intermediates C, 5kg Na are added in a kettle2CO3With 5L DMAC, stirring is warming up to 100 DEG C, and heat preservation is anti-
Answer 1h.Heat filtering, filtrate are cooled to 5 DEG C, add in hydrochloric acid and are acidified to pH=5, obtain white solid, filter, filtration cakes torrefaction obtains white
Solid, for intermediate D, yield 90.7%.
(5) synthesis of intermediate E
1kg intermediate D, and the triphenyl phosphorus of quality and two thiopyridines of 0.25kg such as addition are added in a kettle, and
The acetonitrile of 5L is added in, dissolving mixt at a temperature of heating the mixture to 80 DEG C, when reaction 15 is small under stirring, as a result uses TLC
Monitoring.After the completion of reaction, it is cooled to room temperature.Remaining grease is passed through weight by solvent vacuum distillation recovered solvent at 65 DEG C
The mode of crystallization purifies acquisition intermediate E, and the yield of product is 89%, is detected with HPLC, purity 97%.
(6) synthesis of intermediate F
3L DMF and 0.5kg intermediate Es are sequentially added in a kettle, are stirred evenly, addition 0.50kg triethylamines,
0.25kg tert-butyl chloro-silicanes, temperature rise to 30~35 DEG C, keep the temperature 12~16h.During this period compound is monitored with TLC
The extent of reaction.After completion of the reaction, 3L water is added under stiring, is cooled to 5 DEG C and is extracted three times with 500mL chloroforms, is merged organic
Phase.Organic phase three times, is dried under reduced pressure for 24 hours through 1L saturated common salts water washing, obtains crude product.Recrystallize grey with methanol-water solution
Color solid F, yield 85%.
(7) synthesis of intermediate G
4L methanol, 1.50kg intermediate F are added in a kettle, are passed through ozone (25~26mg/L of ozone mass concentration),
It is initially added into 1.35kg sodium thiosulfate, 8kg water, control temperature is below 5 DEG C, then adds 0.45kg thiocarbamides (1h is added).Reaction
After finishing, material is extracted into concentration kettle and starts vacuum distillation recycling methanol, after the completion of distillation, add 10kg water, cooling, crystallization are dried
Do to obtain 0.95kg intermediate G, yield 93.1%.
(8) synthesis of 4-AA
The obtained intermediate G of previous step 0.78kg are dissolved in the mixed of 2L dichloromethane, 1L acetic acid and 1L acetonitriles composition
In bonding solvent, the RuCl of 42g is added in3As catalyst.Temperature is controlled at 0 DEG C, stirring the lower 2.5L concentration that is constantly added dropwise is
The acetic acid solution of the Peracetic acid of 1mol/L monitors reaction process with TLC, after completion of the reaction, concentration is evaporated under reduced pressure at 30 DEG C
Product, adds in saturated common salt water washing 3 times after reaction, and vacuum distillation concentration is recrystallized to give white crystal, crosses silicagel column
Obtain 0.87kg 4-AA, yield 93.3%.
Embodiment 3
A kind of penem-like pharmaceutical intermediate (3R, 4R) -3- (R) -1- tert-butyl dimethyl silica ethyls] -4- acetoxyl groups -
2- aza cyclo-butanones are (referred to as：Novel synthesis 4-AA), this method are made of the following steps：
(1) synthesis of intermediate A
5.9kg (R) -3-hydroxybutyrate methyl esters is added in a kettle, 8L DMF-DMA and 15L dichloromethane stirs, in
Reaction kettle after finishing, is cooled to room temperature by back flow reaction 4h at 90 DEG C.Add in 10L distillations water washing 3 times.Liquid separation, by organic layer
Dichloromethane is recovered under reduced pressure at 60 DEG C, the dichloromethane reusable edible recycled, the foam of gained is intermediate A
Without processing, it is directly used in next step.The step reaction yield is 76%.
(2) synthesis of intermediate B
2.78kg intermediate As are added in a kettle, add in 7.5L solvent methanols, and the concentration that 2L is added dropwise at room temperature is
The P-nethoxyaniline methanol solution of 0.5mol/L, 1h are added dropwise, and stirring is warming up to 60 DEG C of insulation reaction 6h, is monitored with TLC
Reaction.80 DEG C of recycling methanol are warming up to after reaction.Product is cooled to 0 DEG C after concentration, filters, and filter cake is eluted with cold methanol,
Dry to obtain white crystal, yield 80.2%.
(3) synthesis of intermediate C
3kg intermediate Bs, the dichloromethane of 7L are added in a kettle, and add in 100gRuCl2[(R)-BINAP]2·N
(C2H5)3, at 30 DEG C and asymmetric chiral hydrogenation reduction reaction occurs for hydrogen, and hydrogen pressure is 4MPa.React 5 it is small when, terminate
After reduce the temperature to 0 DEG C, filter mixture, obtained supernatant liquid vacuum distillation, remaining white solid is required
Intermediate C.Yield is that 80%, ee values are 94.9%.
(4) synthesis of intermediate D
1.75kg intermediates C, 6kg Na are added in a kettle2CO3With 7.5L pyridines, stirring is warming up to 80 DEG C, and heat preservation is anti-
Answer 2h.Heat filtering, filtrate are cooled to 5 DEG C, add in hydrochloric acid and are acidified to pH=5, obtain white solid, filter, filtration cakes torrefaction obtains white
Solid is intermediate D.Yield 89.4%.
(5) synthesis of intermediate E
1kg intermediate D are added in a kettle, and add in the triethylamine of equimolar amounts, and add in the MTHF of 20L, are dissolved
Mixture heats the mixture to 80 DEG C, stirs lower reaction 15h, is as a result monitored with TLC.After the completion of reaction, it is cooled to room temperature.
Remaining grease is purified acquisition intermediate E, product by the vacuum distillation recovered solvent at 70 DEG C in a manner of by recrystallization
Yield for 83%, detected with HPLC, purity 97%.
(6) synthesis of intermediate F
3L DMF and 0.5kg intermediate Es are sequentially added in a kettle, are stirred evenly, addition 0.50kg triethylamines,
0.25kg tert-butyl chloro-silicanes, temperature rise to 30~35 DEG C, keep the temperature 12~16h.During this period compound is monitored with TLC
The extent of reaction.After completion of the reaction, 3L water is added under stiring, is cooled to 5 DEG C and is extracted three times with 500mL chloroforms, is merged organic
Phase.Organic phase three times, is dried under reduced pressure for 24 hours through 1L saturated common salts water washing, obtains crude product.Recrystallize grey with methanol-water solution
Color solid F, yield 85%.
(7) synthesis of intermediate G
7.50L methanol, 0.50kg intermediate F are added in a kettle, and 1.25kg cerous nitrates are slowly added to below 5 DEG C
Ammonium heats the mixture to 80 DEG C, when reaction 8 is small, and is monitored and reacted with TLC after adding.After the completion of reaction, material is extracted into concentration
Starting vacuum distillation recycling methanol in kettle, after the completion of distillation, add 10kg water, 0.288kg intermediate G are dried to obtain in cooling, crystallization,
Yield 84.2%.
(8) synthesis of 4-AA：
The obtained intermediate G of previous step 0.78kg are dissolved in what is be made of 2L dichloromethane, 1L acetic acid and 1L acetonitriles
In the mixed solvent adds in the RuCl of 42g3As catalyst.Temperature is controlled at 0 DEG C, stirring the lower 2.5L concentration that is constantly added dropwise is
The acetic acid solution of the Peracetic acid of 1mol/L monitors reaction process with TLC, after completion of the reaction, concentration is evaporated under reduced pressure at 30 DEG C
Product, adds in saturated common salt water washing 3 times after reaction, and vacuum distillation concentration is recrystallized to give white crystal, crosses silicagel column
Obtain 0.87kg 4-AA, yield 93.3%.
Comparative example 1
With differing only in step (1) for embodiment 1, solvent for use is acetonitrile, the back flow reaction 3h at 80 DEG C, is completed
Afterwards, reaction kettle is cooled to room temperature.4L distilled water is added in, extraction 3 times is washed with the hexamethylene of 2L.Liquid separation, by upper organic layer
Hexamethylene is recovered under reduced pressure at 50 DEG C, the remaining solid foam object obtained need not be handled for intermediate A, is directly used in next step.
The step reaction yield is 50%.
Comparative example 2
With differing only in step (3) for embodiment 1, chiral catalyst used is RuBr2[(R)-BINAP], remaining
Condition is identical, then the step reaction yield is that 75%, ee values are 95.1%.
Comparative example 3
With differing only in step (3) for embodiment 1, chiral catalyst used is [RuCl (C6H6)((R)-BINAP)]
Cl, remaining condition is identical, then the step reaction yield is that 74.3%, ee values are 96.1%.
Comparative example 4
With differing only in step (4) for embodiment 1, alkali used is sodium ethoxide, remaining condition is identical, then the step is anti-
It is 77.3% to answer yield.
Comparative example 5
With differing only in step (4) for embodiment 1, alkali used is sodium hydroxide, remaining condition is identical, then the step
Reaction yield is 85.4%.
Claims (7)
1. a kind of synthetic method of penem-like pharmaceutical intermediate, which is characterized in that comprise the following steps：
(1) using (R) -3-hydroxybutyrate ester as raw material, it is obtained by the reaction with n,N-Dimethylformamide dimethylacetal shown in formula (I)
Intermediate A；
(2) intermediate A and P-nethoxyaniline carry out substitution reaction, obtain the intermediate B shown in formula (II)；
(3) under catalyst action, chiral hydrogenation reduction reaction occurs for intermediate B and hydrogen, obtains the centre shown in formula (III)
Body C；
(4) the intermediate D shown in intermediate C hydrolyzing types (IV)；
(5) under alkaline reagent, ring closure reaction occurs for intermediate D, obtains the intermediate E shown in formula (VI)；
(6) under acid binding agent effect, intermediate E is reacted with tert-butyl chloro-silicane, obtains the intermediate shown in formula (VI)
F；
(7) intermediate F sloughs the protecting group on nitrogen under oxidant effect, obtains the intermediate G shown in formula (VII)；
(8) under the catalysis of ruthenium trichloride, intermediate G is reacted with Peracetic acid, obtains the 4-AA shown in formula (VIII)；
Wherein, R is methyl or ethyl.
2. the synthetic method of penem-like pharmaceutical intermediate according to claim 1, which is characterized in that in step (1), reaction
Solvent is one kind or its arbitrary proportion mixture in methyltetrahydrofuran, toluene, benzene, dichloromethane and acetonitrile.
3. the synthetic method of penem-like pharmaceutical intermediate according to claim 1, which is characterized in that in step (3), will urge
Agent, intermediate B and reaction dissolvent mixing, are filled with 1~6MPa hydrogen per mol intermediate Bs, green hand's property are issued at 30~100 DEG C
Hydrogenation reduction, reaction time are 3~10h, obtain intermediate C.
4. the synthetic method of penem-like pharmaceutical intermediate according to claim 3, which is characterized in that the catalyst is
Ruthenium catalyst is specially RuBr2[(R)-BINAP], RuCl2[(R)-BINAP]2·N(C2H5)3Or [RuCl (C6H6)((R)-
BINAP)]Cl。
5. the synthetic method of penem-like pharmaceutical intermediate according to claim 4, which is characterized in that the catalyst is
RuCl2[(R)-BINAP]2·N(C2H5)3。
6. the synthetic method of penem-like pharmaceutical intermediate according to claim 1, which is characterized in that in step (4), by
Reaction is hydrolyzed in mesosome C, alkali, reaction dissolvent at 30~100 DEG C, is acidified after reacting 1~3h, filters, dry, obtains centre
Body D.
7. the synthetic method of penem-like pharmaceutical intermediate according to claim 6, which is characterized in that the alkali is hydrogen-oxygen
Change sodium, sodium carbonate, sodium acid carbonate, potassium hydroxide or sodium ethoxide.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053793A (en) * | 2018-08-27 | 2018-12-21 | 浙江大学宁波理工学院 | The method that photocatalysis removing N- alkyl prepares penem-like pharmaceutical intermediate 4-AA |
| CN109946396A (en) * | 2019-03-26 | 2019-06-28 | 深圳市海滨制药有限公司 | A method of using high effective liquid chromatography for measuring Biapenem and/or related substance |
| 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 |
| CN115385950A (en) * | 2022-10-27 | 2022-11-25 | 天津凯莱英医药科技发展有限公司 | System and method for preparing 4-acetoxyazetidinone through 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053793A (en) * | 2018-08-27 | 2018-12-21 | 浙江大学宁波理工学院 | The method that photocatalysis removing N- alkyl prepares penem-like pharmaceutical intermediate 4-AA |
| 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 |
| CN109946396A (en) * | 2019-03-26 | 2019-06-28 | 深圳市海滨制药有限公司 | A method of using high effective liquid chromatography for measuring Biapenem and/or related substance |
| 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 |
| CN115385950A (en) * | 2022-10-27 | 2022-11-25 | 天津凯莱英医药科技发展有限公司 | System and method for preparing 4-acetoxyazetidinone through continuous ozone oxidation |
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