CN109678856B - 一种阿维巴坦中间体的制备方法 - Google Patents
一种阿维巴坦中间体的制备方法 Download PDFInfo
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- CN109678856B CN109678856B CN201710968330.3A CN201710968330A CN109678856B CN 109678856 B CN109678856 B CN 109678856B CN 201710968330 A CN201710968330 A CN 201710968330A CN 109678856 B CN109678856 B CN 109678856B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 229960002379 avibactam Drugs 0.000 title claims abstract description 22
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000007112 amidation reaction Methods 0.000 claims abstract description 19
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 17
- 230000020477 pH reduction Effects 0.000 claims abstract description 13
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- HYTSWLKLRKLRHK-NEPJUHHUSA-N (2s,5r)-7-oxo-6-phenylmethoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Chemical compound C([C@]1(CC[C@H]2C(N)=O)[H])N2C(=O)N1OCC1=CC=CC=C1 HYTSWLKLRKLRHK-NEPJUHHUSA-N 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- -1 o-methylbenzyl Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000009435 amidation Effects 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000005810 carbonylation reaction Methods 0.000 abstract description 6
- 230000006315 carbonylation Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 239000013067 intermediate product Substances 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000003223 protective agent Substances 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 32
- 238000003756 stirring Methods 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000007791 liquid phase Substances 0.000 description 11
- 239000011259 mixed solution Substances 0.000 description 8
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 4
- OWIVQKMLPQEEGV-NEPJUHHUSA-N (2s,5r)-5-(phenylmethoxyamino)piperidine-2-carboxamide Chemical compound C1N[C@H](C(=O)N)CC[C@H]1NOCC1=CC=CC=C1 OWIVQKMLPQEEGV-NEPJUHHUSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UMHGLONVYIYIOU-NEPJUHHUSA-N (2s,5r)-7-oxo-6-phenylmethoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid Chemical compound C([C@]1(CC[C@H]2C(O)=O)[H])N2C(=O)N1OCC1=CC=CC=C1 UMHGLONVYIYIOU-NEPJUHHUSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 2
- 239000005660 Abamectin Substances 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 229950008167 abamectin Drugs 0.000 description 2
- VBIXEXWLHSRNKB-UHFFFAOYSA-N ammonium oxalate Chemical compound [NH4+].[NH4+].[O-]C(=O)C([O-])=O VBIXEXWLHSRNKB-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- NIQOTLNVEFVMGQ-NEPJUHHUSA-N (2S,5R)-7-oxo-6-phenylmethoxy-1,6-diazabicyclo[3.2.1]octane-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCC1=CC=CC=C1 NIQOTLNVEFVMGQ-NEPJUHHUSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了一种阿维巴坦中间体的简便制备方法。本发明以式Ⅲ化合物为原料,经过碱性条件下水解、然后酸化制备式Ⅳ化合物,所得式Ⅳ化合物和固体光气或双光气于有机碱、催化剂存在下,同时进行环脲化和酰氯化反应,得到式Ⅴ化合物,然后酰胺化得到最终产物(Ⅱ);本发明环脲化、酰氯化、酰胺化反应经“一锅法”完成,中间产物不需要进行分离提纯;本发明原料价廉易得,工艺简洁,可操作性强,不需要特殊的保护剂和羰基化试剂,反应原子经济性高,成本低,生产过程绿色环保,所得产物(Ⅱ)纯度高,收率高,有利于阿维巴坦(Ⅰ)成本降低和绿色生产。
Description
技术领域
本发明涉及一种阿维巴坦中间体的简便制备方法,具体涉及一种(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺的简便制备方法,属于医药生物化工领域。
背景技术
阿维巴坦属于二氮杂双环辛酮化合物的非β-内酰胺类抑制剂,阿维巴坦能抑制A型(包括ESBL和KPC)和C型的β-内酰胺酶,阿维巴坦与各类头孢和碳青霉烯抗生素联合使用时,具有广谱抗菌活性,尤其是对含有超广谱β-内酰胺酶的大肠杆菌和克雷伯肺炎杆菌、含有超量AmpC酶的大肠杆菌以及同时含有AmpC和超广谱β-内酰胺酶的大肠杆菌的活性显著。阿维巴坦(I)的CAS号为1192491-61-4,化学名称为[(1R,2S,5R)-2-(氨基羰基)-7-氧代-1,6- 二氮杂双环[3.2.1]辛-6-基]硫酸钠,结构式如下式I:
文献CN103649051A、CN105294690A、CN106866668A、WO2012086241、US8148540、US9284273、US9567335均使用(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺 (Ⅱ)为中间体制备阿维巴坦(I)。(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2- 甲酰胺(Ⅱ)于不同还原剂(如氢气、三乙基硅烷、甲酸钠、水合肼)钯炭催化下脱苄基,三氧化硫络合物硫酸酯化,铵盐化,离子交换制备阿维巴坦(I),见反应路线1。
(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的制备方法不尽相同,主要分为先酰胺化后环脲化、先环脲化后酰胺化两种路线,见反应路线2。
其中专利CN103649051A、CN105294690A使用先酰胺化后环脲化路线,以5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(Ⅲ)为原料,经氨气甲醇溶液或氨水醇溶液酰胺化,过滤除去草酸铵,甲醇洗涤草酸铵滤饼,浓缩得到的甲醇溶液,甲苯抽提产品,合适的溶剂重结晶,得到(2S,5R)-5- 苄氧氨基哌啶-2-甲酰胺,收率68-99%;所得(2S,5R)-5-苄氧氨基哌啶-2-甲酰胺经氯甲酸-9-芴基甲基酯(FMOC-Cl)保护哌啶环的氨基,羰基二咪唑和苄氧胺羰基化反应,二乙胺脱去哌啶环的保护剂,环脲化得到(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ),收率90%,总收率61.2-89.1%。其中酰胺化反应后处理繁琐,环脲化所用氯甲酸-9-芴基甲基酯保护试剂价格高,氯甲酸-9-芴基甲基酯和羰基二咪唑仅提供一个羰基,反应原子经济性差,不利于环境保护和成本降低。而利用(2S,5R)-5-苄氧氨基哌啶-2-甲酰胺,不经哌啶环氨基保护,直接与三光气、羰基二咪唑进行环脲化收率低(50-56%),无工业化价值。
另外专利CN102834395A、CN103649051A、CN103328476A、CN106279163A、CN106565712A、US9284273、US9567335均涉及了先环脲化后酰胺化方法,以5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(Ⅲ)为原料,经三光气-有机碱、羰基二咪唑或其它羰基化试剂环脲化,氢氧化锂水溶液等碱性条件下制剂水解得到(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1] 辛烷-2-甲酸,利用三甲基乙酰基氯或其它试剂活化羧基成酸酐,氨水酰胺化得到(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ),总收率34.5-65.5%。环脲化之后所得(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酸酯活性低,不能直接使用氨气甲醇溶液酰胺化,需要水解酯基为羧基,再活化羧基为酸酐,此后才能有效酰胺化,操作过程繁琐,原子经济性差,不利于环境保护和工业化生产。
发明内容
针对现有技术的不足,本发明提供一种阿维巴坦中间体,即(2S,5R)-6-苄氧基-7-氧代-1,6- 二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的简便制备方法;本发明原料价廉易得,工艺简洁,可操作性强,不需要特殊的保护剂和羰基化试剂,反应原子经济性高,成本低,生产过程绿色环保,所得产物(Ⅱ)纯度高,收率高,利用所得(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)可制备阿维巴坦(Ⅰ)。
术语说明:
式Ⅲ化合物:5R-苄氧氨基哌啶-2S-甲酸酯草酸盐;其中,-Bn是指苄基;
式Ⅳ化合物:5R-苄氧氨基哌啶-2S-甲酸;其中,-Bn是指苄基;
式Ⅴ化合物:(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰氯;其中,-Bn 是指苄基。
本说明书中的化合物编号与结构式编号完全一致,具有相同的指代关系。
本发明的技术方案如下:
一种阿维巴坦中间体的简便制备方法,包括步骤:
(1)式Ⅲ化合物在溶剂A中,于碱A存在下水解,经酸化,得式Ⅳ化合物;
其中,式Ⅲ化合物中R为C1-6的脂肪基或烷基取代苯基;优选的,所述R为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、己基、苄基、邻甲基苄基或对甲基苄基中的一种。
(2)于溶剂B中,在有机碱B和催化剂存在下,式Ⅳ化合物和固体光气或双光气同时进行环脲化和酰氯化反应,得到式Ⅴ化合物;不经分离,直接进行下一步反应;
(3)式Ⅴ化合物和氨发生酰胺化反应得(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1] 辛烷-2-甲酰胺(Ⅱ)。
根据本发明优选的,步骤(1)式Ⅲ化合物在碱性条件下水解、经酸化后,用萃取剂萃取得含式Ⅳ化合物的萃取液;所述含式Ⅳ化合物的萃取液经蒸馏去除萃取剂得式Ⅳ化合物或不经蒸馏直接进行下一步反应。
根据本发明优选的,步骤(1)中所述溶剂A为二氯甲烷、1,2-二氯乙烷、三氯甲烷、四氯化碳、四氢呋喃、2-甲基四氢呋喃、甲氧基环戊烷或甲苯中的一种或两种以上的组合。
根据本发明优选的,步骤(1)中所述溶剂A与式Ⅲ化合物的质量比为3-4.5:1。
根据本发明优选的,步骤(1)中所述碱A为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钾或碳酸氢钠中的一种或两种以上混合物;优选的,所述碱A是使用质量浓度为5-15%的碱的水溶液。
根据本发明优选的,步骤(1)中所述碱A和式Ⅲ化合物的摩尔比为2.0-5.0:1。
根据本发明优选的,步骤(1)中所述水解反应温度为0-80℃;优选的,步骤(1)中所述水解反应温度为10-40℃。反应时间为2-5小时。
根据本发明优选的,步骤(1)中所述酸化温度为20-25℃。酸化时间为1-2小时。
根据本发明优选的,步骤(1)中所述酸化是使用酸化试剂调节体系的pH至2-3,所述酸化试剂为质量浓度为10-40%的盐酸、硫酸或硝酸的水溶液。
根据本发明优选的,步骤(2)中所述溶剂B为二氯甲烷、1,2-二氯乙烷、三氯甲烷、四氯化碳、四氢呋喃、2-甲基四氢呋喃、甲氧基环戊烷或甲苯中的一种或两种以上的组合。
根据本发明优选的,步骤(2)中所述溶剂B与式Ⅳ化合物的质量比为4-20:1。
根据本发明优选的,步骤(2)中所述有机碱B为三乙胺、三正丁胺或二异丙基乙胺中的一种或两种以上的组合。
根据本发明优选的,步骤(2)中所述有机碱B与式Ⅳ化合物的摩尔比为3.0-8.0:1。
根据本发明优选的,步骤(2)中所述催化剂为N,N-二甲基甲酰胺、吡啶或4-二甲氨基吡啶中的一种或两种以上的组合。
根据本发明优选的,步骤(2)中所述催化剂的质量是式Ⅳ化合物质量的0.1-5.0%。
根据本发明优选的,步骤(2)中所述固体光气或双光气和式Ⅳ化合物的摩尔比为0.6-2.5: 1。
优选的,所述固体光气和式Ⅳ化合物的摩尔比为0.6-2.0:1。
优选的,所述双光气和式Ⅳ化合物的的摩尔比为1.0-2.5:1。
根据本发明优选的,步骤(2)中所述环脲化和酰氯化反应温度均为-20-60℃;优选的,所述环脲化和酰氯化反应温度均为0-40℃。反应时间均为1-8小时。
根据本发明优选的,步骤(3)中所述氨是使用氨气、氨气的甲醇溶液或氨水中的一种。
根据本发明优选的,步骤(3)中所述氨和式Ⅳ化合物的摩尔比为1.0-5.0:1。
根据本发明优选的,步骤(3)中所述酰胺化反应温度为-20-80℃;优选的,步骤(3)中所述酰胺化反应温度为10-50℃。反应时间为1-6小时。
本发明以5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(Ⅲ)为原料,经过碱性条件下水解、然后酸化制备5R-苄氧氨基哌啶-2S-甲酸(Ⅳ),所得化合物Ⅳ和固体光气或双光气于有机碱、催化剂存在下,同时进行环脲化和酰氯化反应,得到(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰氯(Ⅴ),然后酰胺化得到(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1] 辛烷-2-甲酰胺(Ⅱ),环脲化、酰氯化、酰胺化反应经“一锅法”完成,中间产物不需要进行分离提纯;反应路线如下(反应路线3):
本发明的有益效果:
1、与现有技术相比,本发明既避免了先酰胺化后环脲化需要保护哌啶环和使用特殊羰基化试剂的弊端,又避免了先环脲化后酰胺化需要酯基水解、成酸酐活化、酰胺化的繁琐操作,本发明环脲化、酰氯化、酰胺化反应为“一锅法”,中间产物无需进行分离、提纯等后处理,步骤简单,过程绿色环保,成本低。
2、本发明原料价廉易得,所涉及反应类型经典,反应条件易于控制,操作简便,可操作性强,工艺简洁,环脲化过程中不需要特殊的保护和羰基化试剂,反应原子经济性高,生产过程绿色环保,环脲化得到的产物活性适宜,经氨气、氨水等即可酰胺化,步骤简单,成本低;并且本发明的方法制备得到的(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2- 甲酰胺(Ⅱ)纯度、收率高,有利于阿维巴坦(Ⅰ)成本降低和绿色生产。
具体实施方式
以下结合实施例详细说明了本发明,但本发明不仅局限于此。
实施例中的%均为质量百分比,有特别说明的除外。
所用原料5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(Ⅲ)可市购获得,济南勤思药业公司有售,白色粉末固体,光学纯度99.6%。
利用气相或液相色谱仪监控反应过程和产品纯度,利用配有手性柱(ES-OVS,150mm×4.6mm,安捷伦公司)的液相色谱仪检测光学纯度(面积比%),并计算收率和e.e%值。
实施例1:5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克二氯甲烷,150克质量浓度为10%的氢氧化钠水溶液,43.0克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸苄酯草酸盐(Ⅲ),20-30℃搅拌反应3小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为2.5-3.0,室温下搅拌1-2 小时;分层,水层以二氯甲烷萃取三次,每次50克。合并有机相,得到有机相混合液;用20 克饱和氯化钠溶液洗涤1次,所得有机相回收溶剂后,得到24.5克5R-苄氧氨基哌啶-2S-甲酸,液相纯度99.9%,收率为98.0%。
所得产品核磁数据如下:1H-NMR(400MHz,DMSO-d6)δ:1.10(1H,q),1.27(1H, q),1.82(2H,d),2.23(1H,t),2.76(1H,m),2.90(1H,d),3.13(1H,d), 4.70(2H,s),6.54(1H,d),7.35(5H,m),13.51(1H,br)。
实施例2:5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克1,2-二氯乙烷,80克质量浓度为10%的氢氧化锂水溶液,43.0克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸苄酯草酸盐(Ⅲ),20-25℃搅拌反应4小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为2.5-3.0,室温下搅拌1-2 小时;分层,水层以1,2-二氯乙烷萃取三次,每次50克。合并有机相,得到有机相混合液;用20克饱和氯化钠溶液洗涤1次,将所得有机相回收溶剂后,得到24.6克5R-苄氧氨基哌啶-2S- 甲酸,液相纯度99.9%,收率为98.5%。
实施例3:5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克二氯甲烷,120克质量浓度为10%的氢氧化钠水溶液,37.0克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸乙酯草酸盐(Ⅲ),20-25℃搅拌反应4小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为2.5-3.0,室温下搅拌1-2 小时;分层,水层以二氯甲烷萃取三次,每次50克。合并有机相,得到有机相混合液;用20 克饱和氯化钠溶液洗涤1次,将所得有机相回收溶剂后,得到24.1克5R-苄氧氨基哌啶-2S-甲酸,液相纯度99.9%,收率为96.4%。
实施例4:5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克二氯甲烷,150克质量浓度为10%的氢氧化钠水溶液,39.5克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸叔丁酯草酸盐(Ⅲ),20-30℃搅拌反应3小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为2.5-3.0,室温下搅拌1-2 小时;分层,水层以二氯甲烷萃取三次,每次50克。合并有机相,得到有机相混合液;用20 克饱和氯化钠溶液洗涤1次,将所得有机相回收溶剂后,得到24.3克5R-苄氧氨基哌啶-2S-甲酸,液相纯度99.9%,收率为97.2%。
实施例5:(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克四氢呋喃,12.5克(0.05摩尔)实施例2制备的5R-苄氧氨基哌啶-2S-甲酸,50克三正丁胺,0.1克N,N-二甲基甲酰胺,冷却,于 -10-0℃,滴加23.8克(0.08摩尔)固体光气和80克四氢呋喃的溶液,滴毕10-20℃搅拌反应4 小时。于10-20℃之间,通入3.0-3.5克氨气,15-20℃之间搅拌反应3小时,将反应液体倒至300 克冰水混合物中,分层,水层以二氯甲烷萃取两次,每次50克。合并有机相,饱和氯化钠溶液洗涤两次,每次20克,所得有机相回收溶剂后,加入10.0克冷的氯丁烷,打浆洗涤,过滤得到12.6克(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺,液相纯度99.9%, 收率为91.6%。
所得产品核磁数据如下:1H-NMR(400MHz,DMSO-d6)δ:1.65(2H,m),1.84(1H, br),2.06(1H,m),2.90(2H,s),3.62(1H,s),3.68(1H,d),4.93(2H,dd), 7.30-7.46(7H,m)。
实施例6:(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克二氯甲烷,12.5克(0.05摩尔)实施例2制备的5R-苄氧氨基哌啶-2S-甲酸,60克二异丙基乙胺,0.1克N,N-二甲基甲酰胺,冷却,于-10-0℃,滴加23.8克(0.08摩尔)固体光气和80克二氯甲烷的溶液,滴毕10-20℃搅拌反应 4小时。于10-20℃之间,加入25克质量浓度为10%的氨气的甲醇溶液,15-20℃之间搅拌反应 3小时,将反应液体倒至300克冰水混合物中,分层,水层以二氯甲烷萃取两次,每次50克。合并有机相,饱和氯化钠溶液洗涤两次,每次20克,所得有机相回收溶剂后,加入10.0克冷的氯丁烷,打浆洗涤,过滤得到12.7克(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2- 甲酰胺,液相纯度99.9%,收率为92.5%。
实施例7:(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克二氯甲烷,12.5克(0.05摩尔)实施例2制备的5R-苄氧氨基哌啶-2S-甲酸,60克二异丙基乙胺,0.1克N,N-二甲基甲酰胺,冷却,于-10-0℃,滴加24.0克(0.12摩尔)双光气和60克二氯甲烷的溶液,滴毕20-25℃搅拌反应3 小时。于20-25℃之间,加入25克质量浓度为10%的氨气的甲醇溶液,20-25℃之间搅拌反应3 小时,将反应液体倒至300克冰水混合物中,分层,水层以二氯甲烷萃取两次,每次50克。合并有机相,饱和氯化钠溶液洗涤两次,每次20克,所得有机相回收溶剂后,加入10.0克冷的氯丁烷,打浆洗涤,过滤得到12.5克(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2- 甲酰胺,液相纯度99.9%,收率为91.0%。
实施例8:(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克二氯甲烷,12.5克(0.05摩尔)实施例2制备的5R-苄氧氨基哌啶-2S-甲酸,40克三乙胺,0.1克N,N-二甲基甲酰胺,冷却,于 -10-0℃,滴加23.8克(0.08摩尔)固体光气和80克二氯甲烷的溶液,滴毕10-20℃搅拌反应4 小时。于10-20℃之间,加入25克质量浓度为10%的氨水,15-20℃之间搅拌反应3小时,将反应液体倒至200克冰水混合物中,分层,水层以二氯甲烷萃取两次,每次50克。合并有机相,饱和氯化钠溶液洗涤两次,每次20克,所得有机相回收溶剂后,加入10.0克冷的氯丁烷,打浆洗涤,过滤得到12.1克(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺,液相纯度99.8%,收率为88.0%。
实施例9:(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)的制备
5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备中,将得到的有机相混合液直接进行下一步反应,具体步骤如下:
向装有搅拌、温度计的500毫升四口烧瓶中加入150克二氯甲烷,120克质量浓度为10%的氢氧化钠水溶液,37.0克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸乙酯草酸盐(Ⅲ),20-25℃搅拌反应4小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为2.5-3.0,室温下搅拌1-2 小时;分层,水层以二氯甲烷萃取三次,每次50克。合并有机相,得到有机相混合液;
将所得有机相混合液转移至另一500毫升四口烧瓶中,加入60克二异丙基乙胺,0.1克N,N-二甲基甲酰胺,冷却,于-10-0℃,滴加26.7克(0.09摩尔)固体光气和80克二氯甲烷的溶液,滴毕10-20℃搅拌反应4小时。于10-20℃之间,加入25克质量浓度为10%的氨气的甲醇溶液,15-20℃之间搅拌反应3小时,将反应液体倒至300克冰水混合物中,分层,水层以二氯甲烷萃取两次,每次50克。合并有机相,饱和氯化钠溶液洗涤两次,每次20克,所得有机相回收溶剂后,加入10.0克冷的氯丁烷,打浆洗涤,过滤得到24.9克(2S,5R)-6-苄氧基-7-氧代 -1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺,液相纯度99.9%,总收率为90.5%。
对比例1:5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克二氯甲烷,70克质量浓度为10%的氢氧化钠水溶液,43.0克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸苄酯草酸盐(Ⅲ),20-30℃搅拌反应3小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为2.5-3.0,室温下搅拌1-2 小时;分层,水层以二氯甲烷萃取三次,每次50克。合并有机相,得到有机相混合液;用20 克饱和氯化钠溶液洗涤1次,所得有机相回收溶剂后,得到9.5克5R-苄氧氨基哌啶-2S-甲酸,液相纯度98.1%,收率为38.1%。
由本对比例可知,5R-苄氧氨基哌啶-2S-甲酸制备过程中,碱的量过低,会使水解不彻底,导致5R-苄氧氨基哌啶-2S-甲酸的产率严重下降。
对比例2:5R-苄氧氨基哌啶-2S-甲酸(Ⅳ)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克二氯甲烷,150克质量浓度为10%的氢氧化钠水溶液,43.0克(0.1摩尔)5R-苄氧氨基哌啶-2S-甲酸苄酯草酸盐(Ⅲ),20-30℃搅拌反应3小时。用质量浓度为30%的盐酸水溶液酸化至体系pH值为1.5-1.9,室温下搅拌1-2 小时;分层,水层以二氯甲烷萃取三次,每次50克。合并有机相,得到有机相混合液;用20 克饱和氯化钠溶液洗涤1次,所得有机相回收溶剂后,得到18.2克5R-苄氧氨基哌啶-2S-甲酸,液相纯度99.7%,收率为72.8%。
由本对比例可知,5R-苄氧氨基哌啶-2S-甲酸制备过程中,酸化的pH值偏低时,导致部分产物成盐酸盐,会溶于水,进而降低了5R-苄氧氨基哌啶-2S-甲酸的产率。
Claims (13)
1.一种阿维巴坦中间体的制备方法,包括步骤:
(1)式Ⅲ化合物在溶剂A中,于碱A存在下水解,经酸化,得式Ⅳ化合物;所述碱A和式Ⅲ化合物的摩尔比为2.0-5.0:1;所述酸化是使用酸化试剂调节体系的pH至2-3;所述酸化试剂为质量浓度为10-40%的盐酸、硫酸或硝酸的水溶液;
其中,式Ⅲ化合物中R为C1-6的脂肪基或烷基取代苯基;
(2)于溶剂B中,在有机碱B和催化剂存在下,式Ⅳ化合物和固体光气或双光气同时进行环脲化和酰氯化反应,得到式Ⅴ化合物;不经分离,直接进行下一步反应;
(3)式Ⅴ化合物和氨发生酰胺化反应得(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(Ⅱ)。
2.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,式Ⅲ化合物中R为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、己基、苄基、邻甲基苄基或对甲基苄基中的一种。
3.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(1)式Ⅲ化合物在碱性条件下水解、经酸化后,用萃取剂萃取得含式Ⅳ化合物的萃取液;所述含式Ⅳ化合物的萃取液经蒸馏去除萃取剂得式Ⅳ化合物或不经蒸馏直接进行下一步反应。
4.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(1)中所述溶剂A为二氯甲烷、1,2-二氯乙烷、三氯甲烷、四氯化碳、四氢呋喃、2-甲基四氢呋喃、甲氧基环戊烷或甲苯中的一种或两种以上的组合;步骤(1)中所述溶剂A与式Ⅲ化合物的质量比为3-4.5:1;
步骤(1)中所述碱A为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钾或碳酸氢钠中的一种或两种以上混合物。
5.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(1)中所述水解反应温度为0-80℃;所述酸化温度为20-25℃。
6.根据权利要求5所述的阿维巴坦中间体的制备方法,其特征在于,步骤(1)中所述水解反应温度为10-40℃。
7.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(2)中所述溶剂B为二氯甲烷、1,2-二氯乙烷、三氯甲烷、四氯化碳、四氢呋喃、2-甲基四氢呋喃、甲氧基环戊烷或甲苯中的一种或两种以上的组合;步骤(2)中所述溶剂B与式Ⅳ化合物的质量比为4-20:1;
步骤(2)中所述有机碱B为三乙胺、三正丁胺或二异丙基乙胺中的一种或两种以上的组合;步骤(2)中所述有机碱B与式Ⅳ化合物的摩尔比为3.0-8.0:1;
步骤(2)中所述催化剂为N,N-二甲基甲酰胺、吡啶或4-二甲氨基吡啶中的一种或两种以上的组合;步骤(2)中所述催化剂的质量是式Ⅳ化合物质量的0.1-5.0%。
8.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(2)中所述固体光气或双光气和式Ⅳ化合物的摩尔比为0.6-2.5:1。
9.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(2)中所述环脲化和酰氯化反应温度均为-20-60℃。
10.根据权利要求9所述的阿维巴坦中间体的制备方法,其特征在于,所述环脲化和酰氯化反应温度均为0-40℃。
11.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(3)中所述氨是使用氨气、氨气的甲醇溶液或氨水中的一种;步骤(3)中所述氨和式Ⅳ化合物的摩尔比为1.0-5.0:1。
12.根据权利要求1所述的阿维巴坦中间体的制备方法,其特征在于,步骤(3)中所述酰胺化反应温度为-20-80℃。
13.根据权利要求12所述的阿维巴坦中间体的制备方法,其特征在于,步骤(3)中所述酰胺化反应温度为10-50℃。
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CN109956941B (zh) * | 2017-12-25 | 2020-08-04 | 新发药业有限公司 | 一种阿维巴坦的简便制备方法 |
CN113387950A (zh) * | 2020-03-11 | 2021-09-14 | 天津科伦药物研究有限公司 | 一种阿维巴坦钠中间体的精制方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103649051A (zh) * | 2011-06-17 | 2014-03-19 | 阿斯利康(瑞典)有限公司 | 制备包括反-7-氧代-6-(磺基氧基)-1,6-二氮杂二环[3,2,1]辛烷-2-甲酰胺的杂环化合物及其盐的方法 |
CN106279163A (zh) * | 2016-08-12 | 2017-01-04 | 上海龙翔生物医药开发有限公司 | 一种合成阿维巴坦及其中间体光学异构体的方法 |
CN106749242A (zh) * | 2015-11-23 | 2017-05-31 | 上海医药工业研究院 | 阿维巴坦中间体的制备方法 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2812635B1 (fr) * | 2000-08-01 | 2002-10-11 | Aventis Pharma Sa | Nouveaux composes heterocycliques, preparation et utilisation comme medicaments notamment comme anti- bacteriens |
FR2825705B1 (fr) | 2001-06-08 | 2005-05-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens |
FR2835186B1 (fr) * | 2002-01-28 | 2006-10-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, actifs comme inhibiteurs de beta-lactamases |
US20120053350A1 (en) * | 2009-04-30 | 2012-03-01 | Ian Mangion | Preparation of alkyl esters of n-protected oxo-azacycloalkylcarboxylic acids |
FR2951171A1 (fr) | 2009-10-09 | 2011-04-15 | Novexel | Nouveau sel de sodium d'un compose azabicyclique sous forme enantiomere cristallisee et nouvelles formes polymorphes et pseudopolymorphes ainsi que leur preparation |
KR101836554B1 (ko) | 2010-12-22 | 2018-04-19 | 메이지 세이카 파루마 가부시키가이샤 | 광학 활성인 디아자비시클로옥탄 유도체 및 그의 제조법 |
US8772490B2 (en) | 2010-12-22 | 2014-07-08 | Meiji Seika Pharma Co., Ltd. | Optically active diazabicyclooctane derivatives and process for preparing the same |
US8916709B2 (en) * | 2012-03-30 | 2014-12-23 | Cubist Pharmaceuticals, Inc. | 1,2,4-oxadiazole and 1,2,4-thiadiazole β-lactamase inhibitors |
SG11201503427TA (en) * | 2012-11-01 | 2015-06-29 | Kaneka Corp | Process for producing optically active bicyclic urea compound |
WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
BR112016006246B8 (pt) * | 2013-09-24 | 2021-10-05 | Meiji Seika Pharma Co Ltd | Processos de produção de derivados de diazabiciclo-octano e compostos intermediários dos mesmos |
US9688677B1 (en) * | 2014-03-29 | 2017-06-27 | Wockhardt Limited | Process for preparation of sodium (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate |
CN106565712A (zh) | 2016-09-30 | 2017-04-19 | 天津津泰生物医药技术有限公司 | 一种阿维巴坦钠中间体的制备方法 |
CN106866668B (zh) * | 2017-01-23 | 2019-01-11 | 齐鲁天和惠世制药有限公司 | 一锅法制备阿维巴坦钠的方法 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103649051A (zh) * | 2011-06-17 | 2014-03-19 | 阿斯利康(瑞典)有限公司 | 制备包括反-7-氧代-6-(磺基氧基)-1,6-二氮杂二环[3,2,1]辛烷-2-甲酰胺的杂环化合物及其盐的方法 |
CN106749242A (zh) * | 2015-11-23 | 2017-05-31 | 上海医药工业研究院 | 阿维巴坦中间体的制备方法 |
CN106279163A (zh) * | 2016-08-12 | 2017-01-04 | 上海龙翔生物医药开发有限公司 | 一种合成阿维巴坦及其中间体光学异构体的方法 |
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KR102212495B1 (ko) | 2021-02-08 |
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JP2019537550A (ja) | 2019-12-26 |
US10570133B2 (en) | 2020-02-25 |
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CN109678856A (zh) | 2019-04-26 |
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