CN102603745A - Preparation method of beta-methyl carbapenem compound - Google Patents
Preparation method of beta-methyl carbapenem compound Download PDFInfo
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- CN102603745A CN102603745A CN2011100424467A CN201110042446A CN102603745A CN 102603745 A CN102603745 A CN 102603745A CN 2011100424467 A CN2011100424467 A CN 2011100424467A CN 201110042446 A CN201110042446 A CN 201110042446A CN 102603745 A CN102603745 A CN 102603745A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000005406 washing Methods 0.000 claims abstract description 21
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000011260 aqueous acid Substances 0.000 claims abstract description 11
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 39
- -1 acyl radical Chemical class 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 15
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 9
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 8
- GFYHSKONPJXCDE-UHFFFAOYSA-N 2,3,5-trimethylpyridine Chemical compound CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 8
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 8
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 claims description 8
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 8
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 5
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-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
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005256 alkoxyacyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 125000005265 dialkylamine group Chemical group 0.000 claims description 2
- 229940061607 dibasic sodium phosphate Drugs 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- DIAIBWNEUYXDNL-UHFFFAOYSA-N n,n-dihexylhexan-1-amine Chemical compound CCCCCCN(CCCCCC)CCCCCC DIAIBWNEUYXDNL-UHFFFAOYSA-N 0.000 claims description 2
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 2
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- OTTZHAVKAVGASB-UHFFFAOYSA-N 2-heptene Natural products CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- VUANUOZDFPZYHK-QQJWGCFSSA-N 6-[(1R)-1-hydroxyethyl]-4-methyl-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound O[C@H](C)C1C2C(C=CN2C1=O)C VUANUOZDFPZYHK-QQJWGCFSSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- LPSOCVUXCQFHPD-UHFFFAOYSA-N [P]Oc1ccccc1 Chemical compound [P]Oc1ccccc1 LPSOCVUXCQFHPD-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- NFIYTPYOYDDLGO-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].OP(O)(O)=O NFIYTPYOYDDLGO-UHFFFAOYSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a beta-methyl carbapenem compound, which comprises the following steps of: carrying out a reaction on a compound showed in a formula (III) and a compound showed in a formula (IV) in an organic solvent for generating a compound showed in a formula (II), washing reaction products by aqueous acid, separating out an organic solution layer containing the compound showed in the formula (II), adding alkali, a catalyst and hydrogen into an organic solution containing the compound showed in the formula (II) for reacting, and crystallizing for generating a compound showed in a formula (I). According to the method, during the steps of preparing the reaction liquid containing the compound showed in the formula (II) from the compound showed in the formula (III), the washing using the aqueous acid is only carried out by one to two times, an additional post-process does not need to be carried out, and then a next reaction step can be carried out.
Description
Technical field
The present invention relates to a kind of preparation method of beta-methyl carbon penicillenic compound; Specifically; Relate to (4R; 5S, 6S)-3-[[(3S, 5S)-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-preparation method of 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid trihydrate.
Background technology
Compound shown in the general formula (I); I.e. (4R; 5S; 6S)-3-[[(3S, 5S)-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid trihydrate is the important source material of production of antibiotics in the pharmaceutical industry.Chinese invention patent application CN101410398A discloses the preparation method of compound shown in the formula (I): in the presence of alkali, and the reaction of compound shown in compound shown in the formula (III) and the formula (IV), compound shown in the synthesis type (II).
The reaction solution that will contain compound shown in the formula (II) extracts/salt solution washing/water washing, obtains containing the water saturation ethyl acetate solution of compound shown in the formula (II).In the water saturation ethyl acetate solution that contains compound shown in the formula (II), add palladium-carbon catalyst; Carry out the hydrogenation deprotection reaction; React the after-filtration that finishes and remove palladium carbon, the reaction solution that will contain compound shown in the formula (I) is with acid for adjusting pH/concentrating under reduced pressure/adding gac stirring/filtration/adding solvent crystallization.In above-mentioned preparation method, a series of last handling processes such as the reaction solution of compound shown in the midbody formula (II) need extract, salt solution washing, water washing; The reaction solution that contains compound shown in the formula (I) that obtains need be used a series of last handling processes such as acid for adjusting pH, concentrating under reduced pressure, the stirring of adding gac and filtration equally; Cause this preparing method's complex steps, cost increase, material loss to increase and increasing environmental pollution, be unfavorable for the suitability for industrialized production of pharmaceutical industry and the environmental requirement of pay attention to day by day.
Summary of the invention
Therefore, but the objective of the invention is to seek that a kind of operation is succinct, method that environmental protection and heavy industrialization prepare compound shown in the formula (I).
Be used to realize that the technical scheme of above-mentioned purpose is following:
The preparation method of compound shown in a kind of formula (I), this preparation method may further comprise the steps:
(A) compound shown in compound shown in the formula (III) and the formula (IV) is reacted compound shown in the production (II) in the presence of alkali in organic solvent, use aqueous acid washing reaction product and isolate the organic solution layer that contains compound shown in the formula (II);
(B) in the organic solution that contains compound shown in the formula (II), add alkali, catalyzer and hydrogen and react compound shown in the post crystallization production (I).
Wherein, R
1Be acyl group.
R specifically
1Can be for not replacing or substituted carbonic acyl radical, alkylsulfonyl or phosphoryl;
Preferably, the substituting group of substituted carbonic acyl radical, alkylsulfonyl or phosphoryl be aliphatic group, alicyclic hydrocarbon radical, aromatic base, heterocyclic radical, amino, fatty-oxyl, fragrant oxygen base, by aromatic base or the substituted aliphatic group of heterocyclic radical or by aromatic base or the substituted amino of heterocyclic radical;
Further preferably, said R
1Be selected from alkyloyl, for example formyl radical, ethanoyl, propionyl group, butyryl radicals, pentanoyl and caproyl with 1 to 6 carbon atom; Acryl; Alkyl sulphonyl with 1 to 6 carbon atom, for example methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl and own alkylsulfonyl; Alkoxy acyl with 1 to 5 carbon atom, for example methoxy acyl group, ethoxy acyl group, the third oxygen acyl group, fourth oxygen acyl group and penta kind of acyl group; The propenyloxy group carbonyl; Alcoxyl phosphoryl with 1 to 5 carbon atom, for example diethoxy phosphoryl; Benzoyl group; Benzenesulfonyl, for example p-toluenesulfonyl; The benzene phosphoryl; Benzene oxygen phosphoryl, for example hexichol oxygen phosphoryl; The phenyl amino acyl group, N-phenyl amino formyl radical; Furancarbonyl; The thiazolyl carbonyl; Phenyl acetyl; The phenyl propionyl group; Carbobenzoxy-(Cbz); The imidazolyl ethanoyl;
More preferably, R
1Be two aryloxy phosphoryls;
Most preferably, R
1Be two phenoxy phosphoryls.
In said step (A), said alkali can be organic bases, trialkylamine for example, Trimethylamine, triethylamine, Tributylamine, triamylamine, trihexylamine, trioctylamine and N, N-diisopropyl ethyl amine; Dialkylamine, N, N-diisopropylamine; Pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Quinoline; The N-alkyl morpholine; And in the tetramethyl guanidine one or more, be preferably N, N-diisopropyl ethyl amine, N, N-diisopropylamine or tetramethyl guanidine;
Said organic solvent is selected from: N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; One or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene;
Said aqueous acid is selected from mineral acid, for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, potassium primary phosphate and SODIUM PHOSPHATE, MONOBASIC; Organic acid, the for example aqueous solution of one or more in formic acid, acetate, sulfonic acid and the trifluoroacetic acid.The preferably phosphoric acid sodium dihydrogen.
In said step (A), the mol ratio of said formula (IV) compound and formula (III) compound is 1: 0.8～3.0, is preferably 1: 1.0～1.5 moles; The mol ratio of compound is 1: 0.8～5.0 moles shown in said alkali and the formula (III), is preferably 1: 1.0～3.0 moles; The temperature of said reaction is-50 ℃～50 ℃, is preferably-30 ℃～30 ℃; The mass ratio of compound is 1～40: 1 shown in said organic solvent and the said formula (III), is preferably 2～20: 1; The volume ratio of said aqueous acid and reaction product is 1: 0.1～20, be preferably 1: 0.5～and 10; The concentration of said aqueous acid is 0.01 mol～10 mol, is preferably 0.01 mol～5 mol; The temperature of said washing is 0 ℃～40 ℃, is preferably 20 ℃～40 ℃, more preferably 34 ℃.
In said step (A), when isolating the organic solution layer that contains compound shown in the formula (II), add and the immiscible organic solvent of water, be preferably halohydrocarbon, for example methylene dichloride and trichloromethane; Ester, for example ETHYLE ACETATE and methyl acetate; Hydrocarbon, for example sherwood oil and Skellysolve A; Aromatic hydrocarbon, for example toluene; Alcohol, for example propyl carbinol and Pentyl alcohol; Ketone, for example 2-butanone and 2 pentanone; Ether, for example one or more in the ether.
In said step (B), the organic solution that will contain compound shown in the formula (II) before the reaction is concentrated, reacts perhaps that organic solution that forward direction contains compound shown in the formula (II) adds entry and/or one or more are selected from N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; Methyl alcohol, ethanol, n-propyl alcohol and Virahol; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, the organic solvent of one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene.
In said step (B), said alkali is selected from organic bases, for example pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Morpholine; Quinoline; Pyrimidine; The 4-Dimethylamino pyridine; Triethylamine, diethylamine, Tributylamine, diisopropylethylamine and diisopropylamine; Mineral alkali, for example Sodium phosphate, dibasic, potassium hydrogenphosphate; In yellow soda ash and the salt of wormwood one or more; Said catalyzer is the catalyzer that contains palladium and/or platinum, is preferably the catalyzer that contains palladium, more preferably is carried on the palladium catalyst on the gac; Said crystalline solvent is selected from nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol, one or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example are preferably in methylene dichloride, THF, acetonitrile, acetone and the methyl alcohol one or more.
In said step (B), the pressure of hydrogen is 0.05～6.0MPa, is preferably 0.1～4.0MPa; The temperature of said reaction is 0～70 ℃, is preferably 15～50 ℃; The volume ratio of said crystalline solvent and reaction product is 0.2～50: 1, is preferably 1～10: 1.
In said step (B), add crystal seed during said crystallization; Stir in the said crystallisation process or do not stir.
The inventor is through discover in a large number; The reaction solution that contains compound shown in the formula (II) that the reaction of compound shown in compound shown in the formula (III) and the formula (IV) obtains only need be used acidiferous solution washing one to ten time; Be preferably five times; Need not to carry out other aftertreatment and promptly can be used for next step reaction, otherwise can have influence on the subsequent reactions product, be i.e. the quality product and the yield of compound shown in the formula (I).And the reaction solution that contains compound shown in the formula (II) that will pass through this kind processing concentrates; Add entry, organic solvent, alkali, noble metal catalyst; In autoclave, feed the reaction solution that the hydrogen deprotection obtains containing compound shown in the formula (I), remove by filter catalyzer, the reaction solution of this moment need not to carry out other aftertreatment; Directly add the recrystallisation solvent crystallization, promptly can obtain compound shown in good, the high-quality formula of yield (I).
Embodiment
Below in conjunction with embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Embodiment 1
Initial compounds IIIa prepares according to Chinese patent ZL200610057578.6 disclosed method.If no special instructions, other test materials is commercially available.
Compound (4R; 5S; 6S)-3-[[(3S, 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid is to the preparation of nitrobenzyl ester (II)
Compound (4R with 33.0g; 5R; 6S)-3-two phenoxy phosphorus acyloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid joins in the reaction flask nitrobenzyl ester (IIIa); Add 200.0g acetonitrile, 10.0g diisopropylethylamine, compound shown in the 19.0g formula IV is-10 ℃ of reactions down.Reaction finishes, and in reaction solution, adds 500g ETHYLE ACETATE, and with 6% (g/mL) SODIUM PHOSPHATE, MONOBASIC solution washing twice of 500 milliliters, wash temperature is 34 ℃, and phase-splitting obtains containing the organic solution of compound shown in the formula II.
Embodiment 2
(4R, 5S, 6S)-3-[[(3S, 5S)-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-preparation of 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid trihydrate (I)
With obtain among the embodiment 1 contain compound (II) (promptly (and 4R, 5S, 6S)-3-[[(3S; 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-(dimethylamino carbonyl)-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid is to the nitrobenzyl ester) organic solution concentrate, liquid concentrator imports in the autoclave, adds the THF of 600g; The lutidine that adds the palladium-carbon catalyst 3.5g of 20g imports hydrogen, and pressure is to the 0.5MPa; Temperature is controlled at 0～50 ℃ of reaction; Reaction finishes, and removes by filter catalyzer such as palladium carbon, and filtrating is transferred in the crystallization bottle; The acetone that adds 1000g is in 0 ℃ of left and right sides stirred crystallization.Filter, obtain the compound (I) of 18.2g.
The determination of physical appearance result of compound (I):
UV
max H2Onm：297
IR
max KBrcm
-1：1755，1627，1393，1252，1130。
NMRδ(D
2O)：1.25(3H，d，J＝6.4Hz)，1.81-1.96(1H，m)，2.96(3H，s)，3.03(3H，s)，3.14-3.20(3H，m)，3.31-3.41(2H，m)，3.62-3.72(1H，m)，3.90-4.00(1H，m)，4.14-4.26(2H，m)，4.63(1H，t，J＝8.5Hz)。
Embodiment 3
Present embodiment is used for research and from the aftertreatment of the reaction solution of compound shown in the compound formula (II) shown in the formula (III), adopts the influence of different treatment method to preparation feedback.
Adopt with embodiment 1 to prepare compound shown in the formula (I) with embodiment 2 similar methods, different is in compound aftertreatment shown in the midbody formula (II), to adopt following two kinds of methods to handle respectively:
Method is 1.: use washing once, use the salt solution washed twice, use washing once then;
Method is 2.: use potassium primary phosphate (KH
2PO
4) solution washing five times.
Obtain following result according to above-mentioned two kinds of treatment processs:
(1) 1. method of use is handled, and occurs being prone to emulsification in the treating processes, and phase-splitting is difficult, needs the long period phase-splitting; 2. method of use then is prone to phase-splitting, and processing reaction speed is fast;
See from the liquid phase collection of illustrative plates that (2) after aftertreatment, 1. method of use is handled, have little impurity peaks to become big phenomenon, promptly impurity obviously increases, and causes serious adverse drug reaction easily; 2. method of use is handled does not then have this phenomenon;
(3) 1. 2. to handle the product productive rate that obtains obviously different with method for method of use.
Adopt with embodiment 1 and prepare compound shown in the formula (I) with embodiment 2 similar methods; Different is in compound aftertreatment shown in the midbody formula (II), to adopt method 1. 2. to handle with method respectively; 1. two batches of experiments have been carried out according to method; 2. carry out a collection of experiment according to method and compared result such as table 1.
Table 1 different treatment method is to the influence of product productive rate
Can find out that from table 1 2. method of use handle, the product productive rate that obtains is obviously higher.
Conclusion: shown in the formula (III) shown in the compound formula (II) in the reaction solution of compound method of use 2. can so that to the organic solution system that contains compound shown in the formula (II) purer; Thereby make shown in the formula (II) shown in the compound formula (I) that reaction system can obtain product through direct crystallization in the compound after reacting completely, and purity and yield are higher; And if in that method of use is 2. in the reaction solution of compound shown in the compound formula (II) shown in the formula (III); Instant brine wash; On the one hand, occur emulsion in the last handling process easily, can cause the reduction on compound yield losses shown in the product solution Chinese style (II) and the purity; On the other hand; If shown in the formula (II) shown in the compound formula (I) in the compound according to direct crystallization method of the present invention; The product purity of compound shown in the formula that obtains (I) can be influenced; Thereby must adopt loaded down with trivial details post-treating method to obtain the purity high product, its yield reduces greatly.
Embodiment 4
Present embodiment is used for studying and is adopting the influence of different types of washing soln to product output and yield shown in the formula (III) shown in the compound formula (II) in the aftertreatment of the reaction solution of compound.
Adopt with embodiment 1 to prepare compound shown in the formula (I) with embodiment 2 similar methods, different is in compound aftertreatment shown in the midbody formula (II) respectively the solution shown in the employing table 2 wash, the result is as shown in table 2.
The different types of washing soln of table 2 is to the influence of product output and yield
Can know by last table 2,, select washing soln very crucial shown in the formula (III) shown in the compound formula (II) in the aftertreatment of the reaction solution of compound; Different washing solns is very big to the purity and the yield influence of the finished product; Use acidic aqueous solution, for example the aqueous solution of SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate is compared with other kinds solution; Can improve the purity and the yield of compound bullion output shown in the formula (I) greatly so that the organic solution system of compound is purer shown in the formula that arrives (II).It can also be seen that by table 2 aqueous solution that uses potassium primary phosphate is as the washing soln better effects if.
Embodiment 5
Present embodiment is used for studying and is adopting the influence of different wash temperatures to product output shown in the formula (III) shown in the compound formula (II) in the aftertreatment of the reaction solution of compound.
Adopt with embodiment 1 similar method to prepare compound shown in the formula (II), different is in aftertreatment respectively the wash temperature shown in the employing table 3 wash, the result is as shown in table 3.
The different wash temperatures of table 3 are to the influence of product output
Can know by table 3; Compound shown in compound shown in the formula (III) and the formula (IV) is being reacted in organic solvent in the presence of alkali in the reaction solution of compound shown in the production (II), and use aqueous acid washing reaction product is also isolated in the organic solution layer that contains compound shown in the formula (II), and wash temperature has very big influence to the output of compound shown in the formula (II); Consider ultimate capacity; Wash temperature can be 0 ℃～40 ℃, is preferably 20 ℃～40 ℃, and the best is 34 ℃.
Claims (9)
1. the preparation method of compound shown in the formula (I), this preparation method may further comprise the steps:
(A) compound shown in compound shown in the formula (III) and the formula (IV) is reacted compound shown in the production (II) in the presence of alkali in organic solvent, use aqueous acid washing reaction product and isolate the organic solution layer that contains compound shown in the formula (II);
(B) in the organic solution that contains compound shown in the formula (II), add alkali, catalyzer and hydrogen and react compound shown in the post crystallization production (I).
Wherein, R
1Be acyl group.
2. preparation method according to claim 1 is characterized in that, said R
1For not replacing or substituted carbonic acyl radical, alkylsulfonyl or phosphoryl;
Preferably, the substituting group of substituted carbonic acyl radical, alkylsulfonyl or phosphoryl be aliphatic group, alicyclic hydrocarbon radical, aromatic base, heterocyclic radical, amino, fatty-oxyl, fragrant oxygen base, by aromatic base or the substituted aliphatic group of heterocyclic radical or by aromatic base or the substituted amino of heterocyclic radical;
Further preferably, said R
1Be selected from alkyloyl, for example formyl radical, ethanoyl, propionyl group, butyryl radicals, pentanoyl and caproyl with 1 to 6 carbon atom; Acryl; Alkyl sulphonyl with 1 to 6 carbon atom, for example methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl and own alkylsulfonyl; Alkoxy acyl with 1 to 5 carbon atom, for example methoxy acyl group, ethoxy acyl group, the third oxygen acyl group, fourth oxygen acyl group and penta kind of acyl group; The propenyloxy group carbonyl; Alcoxyl phosphoryl with 1 to 5 carbon atom, for example diethoxy phosphoryl; Benzoyl group; Benzenesulfonyl, for example p-toluenesulfonyl; The benzene phosphoryl; Benzene oxygen phosphoryl, for example hexichol oxygen phosphoryl; The phenyl amino acyl group, N-phenyl amino formyl radical; Furancarbonyl; The thiazolyl carbonyl; Phenyl acetyl; The phenyl propionyl group; Carbobenzoxy-(Cbz); The imidazolyl ethanoyl;
More preferably, R
1Be two aryloxy phosphoryls;
Most preferably, R
1Be two phenoxy phosphoryls.
3. preparation method according to claim 1 and 2 is characterized in that, in said step (A), said alkali is organic bases, trialkylamine for example, Trimethylamine, triethylamine, Tributylamine, triamylamine, trihexylamine, trioctylamine and N, N-diisopropyl ethyl amine; Dialkylamine, N, N-diisopropylamine; Pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Quinoline; The N-alkyl morpholine; And in the tetramethyl guanidine one or more, be preferably N, N-diisopropyl ethyl amine, N, N-diisopropylamine or tetramethyl guanidine;
Said organic solvent is selected from: N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; One or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene;
Said aqueous acid is selected from mineral acid, for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, potassium primary phosphate and SODIUM PHOSPHATE, MONOBASIC; Organic acid, the for example aqueous solution of one or more in formic acid, acetate, sulfonic acid and the trifluoroacetic acid; Be preferably potassium primary phosphate or SODIUM PHOSPHATE, MONOBASIC.
4. according to each described preparation method in the claim 1 to 3, it is characterized in that in said step (A), the mol ratio of said formula (IV) compound and formula (III) compound is 1: 0.8～3.0, is preferably 1: 1.0～1.5 moles; The mol ratio of compound is 1: 0.8～5.0 moles shown in said alkali and the formula (III), is preferably 1: 1.0～3.0 moles; The temperature of said reaction is-50 ℃～50 ℃, is preferably-30 ℃～30 ℃; The mass ratio of compound is 1～40: 1 shown in said organic solvent and the said formula (III), is preferably 2～20: 1; The volume ratio of said aqueous acid and reaction product is 1: 0.1～20, be preferably 1: 0.5～and 10; The concentration of said aqueous acid is 0.01 mol～10 mol, is preferably 0.01 mol～5 mol; The temperature of said washing is 0 ℃～40 ℃, is preferably 20 ℃～40 ℃, more preferably 34 ℃.
5. according to each described preparation method in the claim 1 to 4; It is characterized in that, in said step (A), when isolating the organic solution layer that contains compound shown in the formula (II), add and the immiscible organic solvent of water; Be preferably halohydrocarbon, for example methylene dichloride and trichloromethane; Ester, for example ETHYLE ACETATE and methyl acetate; Hydrocarbon, for example sherwood oil and Skellysolve A; Aromatic hydrocarbon, for example toluene; Alcohol, for example propyl carbinol and Pentyl alcohol; Ketone, for example 2-butanone and 2 pentanone; Ether, for example one or more in the ether.
6. according to each described preparation method in the claim 1 to 5; It is characterized in that; In said step (B); The organic solution that will contain compound shown in the formula (II) before the reaction is concentrated, reacts perhaps that organic solution that forward direction contains compound shown in the formula (II) adds entry and/or one or more are selected from N-Methyl pyrrolidone, N-ethyl pyrrolidone; N, dinethylformamide, DMAC N,N; Nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride, trichloromethane and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol; Methyl alcohol, ethanol, n-propyl alcohol and Virahol; Be preferably methylene dichloride, THF, acetonitrile, ETHYLE ACETATE, N, the organic solvent of one or more in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the toluene.
7. according to each described preparation method in the claim 1 to 6, it is characterized in that in said step (B), said alkali is selected from organic bases, for example pyridine; Have substituent pyridine on the pyridine ring, for example 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,3-picoline, 2-picoline and 4-picoline; Morpholine; Quinoline; Pyrimidine; The 4-Dimethylamino pyridine; Triethylamine, diethylamine, Tributylamine, diisopropylethylamine and diisopropylamine; Mineral alkali, for example Sodium phosphate, dibasic, potassium hydrogenphosphate; In yellow soda ash and the salt of wormwood one or more; Said catalyzer is the catalyzer that contains palladium and/or platinum, is preferably the catalyzer that contains palladium, more preferably is carried on the palladium catalyst on the gac; Said crystalline solvent is selected from nitrile, for example acetonitrile; Halohydrocarbon, for example methylene dichloride; Aromatic hydrocarbon, for example toluene; Ketone, for example acetone and butanone; THF; Ester, ETHYLE ACETATE and methyl acetate; Alcohol, one or more in methyl alcohol, ethanol, n-propyl alcohol and the Virahol for example are preferably in methylene dichloride, THF, acetonitrile, acetone and the methyl alcohol one or more.
8. according to each described preparation method in the claim 1 to 7, it is characterized in that in said step (B), the pressure of hydrogen is 0.05～6.0MPa, is preferably 0.1～4.0MPa; The temperature of said reaction is 0～70 ℃, is preferably 15～50 ℃; The volume ratio of said crystalline solvent and reaction product is 0.2～50: 1, is preferably 1～10: 1.
9. according to each described preparation method in the claim 1 to 8, it is characterized in that, in said step (B), add crystal seed during said crystallization; Stir in the said crystallisation process or do not stir.
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| EP1426376A1 (en) * | 2001-08-13 | 2004-06-09 | Eisai Co., Ltd. | Process for preparation of carbapenem antibiotics |
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| CN101914098A (en) * | 2010-07-20 | 2010-12-15 | 深圳市海滨制药有限公司 | Preparation method of Meropenem trihydrate crystals |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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| EP1426376A1 (en) * | 2001-08-13 | 2004-06-09 | Eisai Co., Ltd. | Process for preparation of carbapenem antibiotics |
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
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Application publication date: 20120725 |