CN1285596C - 由头孢烷衍生物制备青霉烷衍生物的方法 - Google Patents
由头孢烷衍生物制备青霉烷衍生物的方法 Download PDFInfo
- Publication number
- CN1285596C CN1285596C CNB028295005A CN02829500A CN1285596C CN 1285596 C CN1285596 C CN 1285596C CN B028295005 A CNB028295005 A CN B028295005A CN 02829500 A CN02829500 A CN 02829500A CN 1285596 C CN1285596 C CN 1285596C
- Authority
- CN
- China
- Prior art keywords
- general formula
- formula
- described method
- methyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims description 42
- 238000002360 preparation method Methods 0.000 title description 8
- 150000002959 penams Chemical class 0.000 title description 7
- 150000001781 cephams Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- -1 methyl penam derivatives Chemical class 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- 229910052751 metal Inorganic materials 0.000 claims abstract description 3
- 239000002184 metal Substances 0.000 claims abstract description 3
- 239000007800 oxidant agent Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 125000003368 amide group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 235000012204 lemonade/lime carbonate Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 229960001708 magnesium carbonate Drugs 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229940116318 copper carbonate Drugs 0.000 claims description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 2
- 229960004643 cupric oxide Drugs 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 125000001399 1,2,3-triazolyl group Chemical class N1N=NC(=C1)* 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 3
- 125000004442 acylamino group Chemical group 0.000 abstract 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 2
- 125000005544 phthalimido group Chemical group 0.000 abstract 2
- 229910003204 NH2 Inorganic materials 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000013019 agitation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- WSHJJCPTKWSMRR-RXMQYKEDSA-N penam Chemical compound S1CCN2C(=O)C[C@H]21 WSHJJCPTKWSMRR-RXMQYKEDSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 239000002132 β-lactam antibiotic Substances 0.000 description 3
- 229940124586 β-lactam antibiotics Drugs 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- VTOXMULTYGBBCR-UHFFFAOYSA-N 2H-triazol-4-ylsilane Chemical class [SiH3]C1=CNN=N1 VTOXMULTYGBBCR-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 150000000475 acetylene derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- QSRFYFHZPSGRQX-UHFFFAOYSA-N benzyl(tributyl)azanium Chemical compound CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 QSRFYFHZPSGRQX-UHFFFAOYSA-N 0.000 description 1
- RXGGBFMKDBEMJH-UHFFFAOYSA-N benzyl(trioctyl)azanium Chemical compound CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CC1=CC=CC=C1 RXGGBFMKDBEMJH-UHFFFAOYSA-N 0.000 description 1
- BNQRPLGZFADFGA-UHFFFAOYSA-N benzyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1=CC=CC=C1 BNQRPLGZFADFGA-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005474 detonation Methods 0.000 description 1
- ZASWJUOMEGBQCQ-UHFFFAOYSA-L dibromolead Chemical compound Br[Pb]Br ZASWJUOMEGBQCQ-UHFFFAOYSA-L 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052809 inorganic oxide Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- HWSZZLVAJGOAAY-UHFFFAOYSA-L lead(II) chloride Chemical compound Cl[Pb]Cl HWSZZLVAJGOAAY-UHFFFAOYSA-L 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 238000012587 nuclear overhauser effect experiment Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供一种制备通式(Ⅰ)所示2β-杂环基甲基青霉烷衍生物的新方法:(Ⅰ)式中,R1表示氢、羧酸保护基如酯或药物可接受的盐;R2和R3可以相同或不同,分别表示氢、卤素、NH2、酰氨基、邻苯二酰亚氨基,其前提是R2和R3不是都为NH2、酰氨基、邻苯二酰亚氨基;Het表示包含NH的5或6元杂环***,它包含一个或多个选自O、S或N的杂原子,所述方法包括:(i)在溶剂和碱存在下,在-10到110℃下使通式(Ⅶ)所示化合物(L表示离去基)和通式(Ⅷ)所示化合物(其中Het如上所述)反应,制得通式(Ⅸ)所示的化合物;(ii)使用常规氧化剂,在可水混溶的溶剂和有机酸存在下氧化通式(Ⅸ)所示的化合物,制得通式(Ⅰ)所示的化合物;并且若需要的话,(iii)在碱和水不混溶的溶剂存在下,使用金属催化剂将其中R1为羧基保护剂的通式(Ⅰ)所示化合物脱酯成其中R1是氢的通式(Ⅰ)所示化合物。
Description
技术领域
本发明涉及从头孢烷(cepham)衍生物制备2α-甲基-2β-取代甲基青霉烷(penam)衍生物的方法。具体的是,本发明涉及制备通式(I)所示2β-杂环基甲基青霉烷衍生物的新方法:
式中,R1表示氢、羧酸保护基如酯或药物可接受的盐;R2和R3可以相同或不同,分别表示氢、卤素、NH2、酰氨基、邻苯二酰亚氨基,其前提是R2和R3不是都为NH2、酰氨基、邻苯二酰亚氨基;Het表示包含NH的5或6元杂环***,它包含一个或多个选自O、S或N的杂原子。
通式(I)所示2β-杂环基甲基青霉烷衍生物可以用作β-内酰胺抗生素。
β-内酰胺抗生素的应用限于微生物通过β-内酰胺酶作用而表现的抗性。所述酶通过***这些抗生素的β-内酰胺环来其作用,由此破坏药物,导致活性损失。因此,需要β-内酰胺酶抑制剂,它可以抵消β-内酰胺酶,并消除药物抗性。所述β-内酰胺酶抑制剂可以和β-内酰胺抗生素一起使用,促进抗生素活性。由此继续新青霉烷衍生物及其制备方法的研究。
背景技术
有几个专利已经公开了各种制备2β-取代甲基青霉烷衍生物的方法。例如,美国专利4529592、4562073&4668514和EP 97446公开了一种方法,所述方法包括在封闭反应器中,在高温高压下用乙炔/乙炔衍生物或乙烯衍生物处理通式(II)所示2β-叠氮甲基青霉烷衍生物,之后用合适的试剂进行脱保护,制得通式(I)所示β-内酰胺酶抑制剂:
然后,通过在极性水性非质子性溶剂中用叠氮化钠进行处理,由通式(III)所示2β-取代甲基青霉烷衍生物制备通式(II)所示2β-叠氮甲基青霉烷衍生物,之后进行氧化:
式中,R=羧酸保护剂;X=氯或溴。
上述方法受到仅引入极少种类杂环如1,2,3-***基(不能引入其它各种杂环)的限制。此外,所述方法需要在高压高温下处理乙炔气,由于其***速度高,这会带来固有的危险,因此这不太适合工业应用,且对生态不利。加之这种方法也需要处理过量的叠氮化钠,留下大量的叠氮化物进行ETP处理,由于叠氮酸存在潜在的***和严重的健康风险,释放叠氮酸存在危险。
EP 0273699公开了不同的途径,它涉及通过用1H-1,2,3-***处理通式(III)所示2β-卤代甲基青霉烷衍生物(式中,X=氯或溴;R=羧基保护基),制备通式(IV)所示2β-***基甲基青霉烷衍生物:
所得产物进行氧化并脱保护,制得通式(I)所示2β-取代甲基青霉烷衍生物。
EP 306924公开了使用铅化合物如氯化铅或溴化铅,由通式(V)所示6,6-二溴-2β-***基甲基青霉烷衍生物制备通式(IV)所示2β-***基甲基青霉烷衍生物的还原方法。
式中,R1、R2可以是H、Br;Br、Br;R是羧基保护基。
在美国专利489591公开了另一种方法,在高温的闭管中用2-三甲基甲硅烷基-1,2,3-***处理通式(VI)所示青霉烷亚砜,制得一种混合物:
式中,R表示羧基保护基;上述混合物需要使用柱色谱法进行纯化,由此分离通式(IV)所示的2β-***基甲基青霉烷衍生物(n=0)。
在所述多数方法中,通式(III)所示的2β-卤代甲基青霉烷可以用作关键的中间体。这对上述叠氮路线和***路线也是如此。但是,通式(III)所示5元2-卤代甲基青霉烷本身是不稳定的中间体,因此,大量制造和储存这种中间体总是很棘手。已经发现这种中间体即使在低温下以析离形式及在其从中分离的溶剂中储存时都会降解。因此,制备这种中间体有关的所有操作要快速进行,并且所述分离的中间体要立即转化成最终产物。由于这些限制,工业规模总是受困于低产率和低质量低,最终导致低水平的一致性。
所有上述方法和如下一个或多个局限有关:(i)关键中间体的不稳定性质,(ii)使用危险和***性试剂,(iii)需要高温高压,尤其是对乙炔时,(iv)使用过量的叠氮钠,之后导致出现环境和***问题,(v)使用毒性和污染高的重金属化合物,如铅化合物,尤其在制药的次末阶段中。这些因素影响了中间体和最终产物的质量和产率的一致性,以及制造规模中的安全性。
为了克服以上限制,我们研究了一种新方法,所述方法包括制备2β-取代甲基青霉烷衍生物的稳定中间体和安全试剂/反应条件。在我们的试验中,我们进行大量的研究,并调查了各种合成方案和方法,找到了制备所述青霉烷的新方法。
发明内容
本发明的主要目的是提供制备通式(I)所示2β-杂环基甲基青霉烷衍生物的方法,所述方法包括6元环青霉烷部分。
本发明的另一目的是提供以良好产率和高纯度制备通式(I)所示2β-杂环基甲基青霉烷衍生物的方法。
本发明的另一目的是提供制备纯净形式的没有被其它异构体污染的2β-杂环基甲基青霉烷衍生物的方法。
基于我们持续的努力,我们发现了一种新途径,它使用和迄今使用的青霉烷衍生物不同的头孢烷部分。使用6元环的头孢烷部分的优势在于,和迄今使用的青霉烷类不同,它是稳定的中间体,因此使用这种中间体可以克服上述的限制。
虽然在所有已知文献中,使用通式(III)所示2β-氯代甲基青霉烷制备通式(IV)所示2β-***甲基取代的青霉烷,但是本发明依赖于将通式(VII)所示6元的3-卤代甲基头孢烷转化成通式(I)所示2β-杂环基甲基青霉烷的环缩现象。
因此,本发明提供一种制备通式(I)所示2β-杂环基甲基青霉烷衍生物的方法:
式中,R1表示氢、羧酸保护基如酯或药物可接受的盐;R2和R3可以相同或不同,分别表示氢、卤素、NH2、酰氨基、邻苯二酰亚氨基,其前提是R2和R3不都为NH2、酰氨基、邻苯二酰亚氨基;Het表示包含NH的5或6元杂环***,它包含一个或多个选自O、S或N的杂原子,所述方法包括:
(i)在溶剂和碱存在下,在-10到110℃下使通式(VII)所示化合物(L表示离去基)和通式(VIII)所示化合物(其中Het如上所述)反应,制得通式(IX)所示的化合物;
(ii)使用常规氧化剂,在可水混溶的溶剂和有机酸存在下氧化通式(IX)所示的化合物,制得通式(I)所示的化合物;并且若需要的话,
(iii)在碱和水不可混溶的溶剂存在下,使用金属催化剂将其中R1为羧基保护剂的通式(I)所示化合物脱酯成其中R1是氢的通式(I)所示化合物。
所述方法如方案1所示:
具体实施方式
在本发明一个实施方式中,羧酸保护基如酯选自对-硝基苄基、对-甲氧基苯基、二苯基甲基等。
在本发明另一实施方式中,L表示离去基,选自卤素,如氯、溴、碘,对-甲苯磺酰氧基、甲磺酰氧基。
在本发明另一实施方式中,Het所示的基团选自吡咯基、吡咯烷基、哌啶基、咪唑基、噁唑烷基、1,2,3-***基、1,2,4-***基等。
在本发明另一实施方式中,酰氨基表示的基团选自苯乙酰氨基、苯氧基乙酰氨基或苯甲酰氨基。
在本发明另一实施方式中,在存在或不存在相转移催化剂的条件下,在存在或不存在碱的条件下,在合适溶剂中进行通式(VII)所示的3-取代的头孢烷衍生物和通式(VIII)所示化合物之间的反应。以通式(VII)所示头孢烷化合物计,通式(VIII)所示化合物的摩尔比约为1-30倍,较好是1-10倍。所用杂环胺以游离形式或其无机酸或有机磺酸或羧酸的盐形式使用。
所述溶剂不起主要作用,因此,可以使用各种溶剂,如醚类溶剂如THF、二噁烷、二甘醇二甲醚、单甘醇二甲醚等,极性非质子溶剂如DMF、DMAC、DMSO、丙酮、乙酸乙酯、环丁砜、乙腈等,质子溶剂如正丁醇、异丙醇、甲醇、乙醇、环己醇等,芳族溶剂如甲苯、苯甲醚等,氯化溶剂如二氯乙烷、二氯甲烷、四氯化碳、氯苯等。这些有机溶剂可以单独使用,或者和一些水(作为添加组分)混合使用。当为水不混溶溶剂时,所述反应使用相转移催化剂在剧烈搅拌条件下在双相介质中进行。所述相转移催化剂可以是季铵盐,如溴化四丁基铵、溴化苄基三丁基铵、溴化苄基三辛基铵等,或者鏻盐如溴化苄基三苯基鏻等。所述碱可以是无机或有机的,较好是碱金属或碱土金属的无机氧化物或碳酸盐,如碳酸镁、碳酸钙、碳酸铯、碳酸钡、碳酸氢钾、碳酸钠、碳酸氢钠、氧化铜、碳酸铜、碳酸钾等。所述反应的温度通常为-10到110℃,较好是30-65℃。
由上述反应制得的产物可以进行纯化,除去不想要的异构体,或者无需纯化就直接用于下一步中,这是因为下一步制得的产物要除去杂质和异构体,由此提供纯的化合物。由此制得的产物分离成糊状,并在酸性水介质中用氧化剂氧化。所述氧化剂是常规的硫氧化剂,如高锰酸钾、过乙酸、三氟过乙酸、m-氯代过苯甲酸、过硫酸氢钾(oxone)等,较好是高锰酸钾。所述氧化反应在有机酸如脂族羧酸、脂族磺酸等,较好是乙酸、甲磺酸等存在下进行。所述反应温度为-30到50℃,较好是-10到30℃。所述反应需要的时间为15分钟到8小时,较好是15分钟到2小时。在反应结束时,用合适试剂破坏过量的氧化剂,由此停止所述反应混合物,并用无机碱如碳酸氢钠中和所述反应介质。这时,所述产物在乙酸乙酯中进行纯化,所述反应物的其它异构体溶解在溶剂中。纯化除去不想要的异构体的选择性在其它溶剂中比较小,因此为了得到纯的异构体,优选的溶剂是乙酸乙酯。
根据羧基保护基的类型,通过合适的脱酯方法将由此制得的通式(IX)所示2β-***甲基取代的青霉烷转化成通式(I)所示的2β-***基甲基青霉烷衍生物。例如,当为对硝基苄基保护基时,以下方法说明了脱保护制得通式(I)所示的β-内酰胺抑制剂。在高压氢气源存在下,在双相介质中的无机碱存在下,在贵金属催化剂存在下,将所述通式(I)所示2β-***甲基取代的青霉烷(n=2,R是羧基保护基)转化成通式(I)所示的化合物(n=2,R=H)。所述贵金属催化剂可以是5-10%Pd/C,5%Pt,Adam催化剂等,较好是10%Pd。所述反应在存在或不存在有机或无机碱的条件下进行,较好是无机碱存在下进行。所述无机碱是碱金属或碱土金属的碳酸盐,较好是碳酸氢钠。虽然所述反应可以在单相或双相介质中进行,但是较好使用水性有机双相介质,包含水不混溶溶剂,如甲苯、乙酸乙酯、乙酸甲酯等,较好是乙酸乙酯。后处理之后,通过从水性介质中进行结晶来分离所述产物。
参考以下实施例详细说明了制备通式(I)所示2β-***基甲基青霉烷衍生物的方法,上述实施例仅用于说明,不应认为是对本发明范围的限制。
注意到,在由6元的头孢烷衍生物制得的5元的青霉烷衍生物中,所述反应途径的立体化学过程有利于选择性制得β-异构体。此外,在将通式(VII)所示3-取代的头孢烷衍生物环缩成通式(I)所示2β-杂环基甲基青霉烷衍生物的过程中,并未改变羧基的构型。所述羧基对于2β-***基甲基呈反式。所述相对立体化学通过NOE实验清楚的证实。
实施例
实施例1
制备通式(IX)所示的4-硝基苄基2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸酯
在室温下,往2升RB烧瓶中所含的4-硝基苄基3-溴-3-甲基头孢烷-4-羧酸酯(50g)的丙酮(250ml)溶液中加入水(65ml)和1H-1,2,3-***(100ml)。在剧烈搅拌下,往透明溶液中加入碳酸钙(25g)。在15分钟内将反应混合物加热至50-60℃,并在这一温度下,在剧烈搅拌下保持9小时。所述反应过程由TLC控制。所述反应结束之后,过滤所述反应混合物,除去无机盐,并用丙酮(50ml)洗涤所述床。在真空条件下蒸馏所述透明的溶液,在30℃以下除去丙酮。除去丙酮之后的溶液倒入二氯甲烷(250ml)中,并在26-28℃下搅拌。分离所述有机层,并用纯水(200ml)洗涤四次。在真空条件下浓缩所述有机层,除去二氯甲烷,开始时在25℃以下进行,最后在35-40℃以下进行。由此制得的糊剂无需进行纯化就用于下一步中。
实施例2
制备通式(I)所示的4-硝基苄基2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸酯-1,1-二噁烷:
在20℃下,往2升RB烧瓶中的乙酸(350ml)中加入4-硝基苄基2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸酯(以上实施例所制得的)和纯水(35ml)。所述均匀的反应混合物在搅拌条件下冷却至5-10℃。在1.5-2.0小时内,往所述均匀的反应混合物中加入12批粉末状的高锰酸钾(30g),同时保持温度在5-10℃。继续搅拌0.5小时,并通过TLC控制所述反应。当反应结束之后,在0.5-1.0小时内,在剧烈搅拌条件下将所述反应混合物加入碎冰(500g)中。往所述物质中加入冷的乙酸乙酯(500ml),同时保持在0-5℃的温度下。在1小时内缓慢加入过氧化氢稀释溶液(25%,40ml),使温度保持在0-5℃下。当褪色完成之后,加入乙酸乙酯(200ml)。往所述几乎是无色的溶液中加入氯化钠(100g),搅拌15分钟。将所述乙酸乙酯层分离,并用水洗涤两次(250ml)。往所述乙酸乙酯层中加入8%碳酸氢钠溶液(~400ml),直到水层的pH大于7.2。再搅拌所述反应混合物15分钟,再次检查所述pH。当pH稳定在7.2以上之后,停止搅拌,并分离所述层。用水(250ml)洗涤所述有机层两次,并用活性炭(10g)进行处理。当所述产物从介质中分离时,在真空中将所述有机层浓缩,除去乙酸乙酯,直到剩余150ml。在搅拌条件下保持5小时之后,过滤所述材料,并用乙酸乙酯(30ml)洗涤。在真空中干燥,制得纯形式的无色4-硝基苄基2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸酯-1,1-二噁烷,产率为50-75%。
质谱m/e:在436.3处的M+1峰;1H NMR数据(CDCl3):81.29(3H,s,2a-Me),3.53(1H,dd,J=1.9 & 16.3Hz,7H-反式),3.61(1H,dd,J=4.3 & 16.3Hz,7H-顺式),4.63(1H,s,CH-CO2),4.66(1H,dd,J=1.9 & 4.2Hz,6H),5.07(2H,Abq,J=15.1Hz,20-CH2),5.35(2H,Abq,J=14Hz,COO-CH2),7.61(2H,d,J=8.7Hz,芳族邻位质子),8.30(2H,d,J=8.7Hz,芳族间位质子)以及7.75 & 7.79(2H,***质子)。
实施例3
制备通式(I)所示的2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸-1,1-二噁烷:
往2升高压氢气发生器中加入乙酸乙酯(500ml)、10%Pd/C(2.5cm)和4-硝基苄基2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸酯-1,1-二噁烷(25g)。在搅拌条件下,将所述非均匀的反应混合物冷却至20-22℃。在20-22℃下,在10-15分钟内加入碳酸氢钠溶液(24g,在375ml纯水中)。所述氢气发生器用氮气冲洗,在20-22℃下,在10分钟内施加200psi的氢气压力。所述氢气压力保持1.5-2.0小时,并监测所述反应过程。当反应结束之后,释放氢气压力,并用氮气冲洗。将所述反应物质冷却至0-5℃。通过过滤回收催化剂Pd/C,并用冷的纯水(50ml)洗涤所述床。分离所述水层,并用乙酸乙酯(150ml)洗涤三次。用6N HCl(~37ml)将pH设定为6.4-6.6,并用乙酸乙酯(150ml)洗涤所述水层。在15分钟内,所述水层用活性炭(4g)处理,并用纯水(50ml)洗涤所述床。用6N HCl(~60ml)将PH设定为3.2,并保持15分钟。出现结晶。在这一pH下继续搅拌30分钟。再用6N HCl(~15ml)将pH设定为2.5-2.6,并保持2小时。过滤所述结晶,并用水洗涤,之后用乙酸乙酯(40ml)洗涤。所述材料在26-30℃下,在真空中干燥5小时。所述产物2β-(1H-1,2,3-***-1-基甲基)-2α-甲基青霉烷-3α-羧酸-1,1-二噁烷的产率约为85-90%。
质谱m/e:在299.1处的M-1峰;1H NMR数据(DMSO-d6):81.33(3H,s,2a-Me),3.31(1H,dd,J=1.4 & 16.5Hz,7H-反式),3.71(1H,dd,J=4.5 & 16.5Hz,7H-顺式),4.80(1H,s,CH-CO2),4.91(1H,d,J=15.3Hz,2β-CH2的H),5.19(1H,dd,J=1.5 & 4.4Hz,H6),5.24(1H,d,J=15.3Hz,2β-CH2的H”)以及7.8 & 8.1(2H,***质子)。所述2α-甲基和2β-亚甲基的立体化学通过NOE实验来证实。
Claims (12)
1.一种制备通式(I)所示2β-杂环基甲基青霉烷衍生物的方法:
式中,R1表示氢、羧酸保护基或药物可接受的盐;R2和R3可以相同或不同,分别表示氢、卤素、NH2、酰氨基、邻苯二酰亚氨基,其前提是R2和R3不都为NH2、酰氨基、邻苯二酰亚氨基;Het表示包含NH的5元杂环***,它包含一个或多个N杂原子,所述方法包括:
(i)在溶剂和碱存在下,在-10到110℃下使通式(VII)所示化合物
式中,L表示离去基,选自氯、溴或碘;所有其它取代基如上所述;和通式(VIII)所示化合物反应,
Het-H (VIII)式中,Het如上所述;制得通式(IX)所示的化合物;
式中,所有其它取代基如上所述;
(ii)使用常规氧化剂,在可水混溶的溶剂和有机酸存在下氧化通式(IX)所示的化合物,制得通式(I)所示的化合物;并且若需要的话,
(iii)在碱和水不可混溶的溶剂存在下,使用金属催化剂将其中R1为羧基保护剂的通式(I)所示化合物脱酯成其中R1是氢的通式(I)所示化合物。
2.权利要求1所述的方法,其特征在于,步骤(i)所用的溶剂选自THF、二噁烷、二甘醇二甲醚、单甘醇二甲醚、DMF、DMAC、DMSO、丙酮、乙酸乙酯、环丁砜、乙腈、正丁醇、异丙醇、甲醇、乙醇、环己醇、甲苯、苯甲醚、二氯乙烷、二氯甲烷、四氯化碳、氯苯或它们的混合物。
3.权利要求1所述的方法,其特征在于,步骤(i)所用的碱选自碳酸镁、碳酸钙、碳酸铯、碳酸钡、碳酸氢钾、碳酸钠、碳酸氢钠、氧化铜、碳酸铜或碳酸钾。
4.权利要求1所述的方法,其特征在于,步骤(ii)所用的氧化剂选自高锰酸钾、过乙酸、三氟过乙酸、m-氯代过苯甲酸或过硫酸氢钾。
5.权利要求1所述的方法,其特征在于,步骤(ii)所用的有机酸选自乙酸或甲磺酸。
6.权利要求1所述的方法,其特征在于,使用5-10%Pd/C,5%Pt或Adam催化剂来进行步骤(iii)中的脱酯反应。
7.权利要求1所述的方法,其特征在于,步骤(iii)所用的碱选自碳酸镁、碳酸钙、碳酸铯、碳酸钡、碳酸氢钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸氢钠。
8.权利要求1所述的方法,其特征在于,步骤(iii)所用水不混溶的溶剂选自甲苯、乙酸乙酯或乙酸甲酯。
9.权利要求1所述的方法,其特征在于,所述羧基保护基选自对-硝基苄基、对-甲氧基苯基或二苯基甲基。
10.权利要求1所述的方法,其特征在于,R1表示氢,Het所示的基团选自吡咯基、吡咯烷基、哌啶基、咪唑基、噁唑烷基、1,2,3-***基或1,2,4-***基。
11.权利要求1所述的方法,其特征在于,所述酰氨基选自苯乙酰氨基、苯氧基乙酰氨基或苯甲酰氨基。
12.权利要求1所述的方法,其特征在于,形成的通式(I)所示化合物是β-异构体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN434CH2002 | 2002-06-07 | ||
IN434/MAS/2002 | 2002-06-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1649880A CN1649880A (zh) | 2005-08-03 |
CN1285596C true CN1285596C (zh) | 2006-11-22 |
Family
ID=29727195
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028295005A Expired - Fee Related CN1285596C (zh) | 2002-06-07 | 2002-06-12 | 由头孢烷衍生物制备青霉烷衍生物的方法 |
Country Status (12)
Country | Link |
---|---|
US (1) | US6936711B2 (zh) |
EP (1) | EP1554287B1 (zh) |
JP (1) | JP2005534662A (zh) |
KR (1) | KR100671881B1 (zh) |
CN (1) | CN1285596C (zh) |
AU (1) | AU2002309162A1 (zh) |
BR (1) | BR0215776A (zh) |
CA (1) | CA2487883C (zh) |
DE (1) | DE60215867T2 (zh) |
ES (1) | ES2274978T3 (zh) |
RU (1) | RU2284329C2 (zh) |
WO (1) | WO2003104241A1 (zh) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100431052B1 (ko) * | 2001-10-08 | 2004-05-12 | 주식회사 네오텍리서치 | 표면 굴곡에 의하여 형성된 다중 영역 효과를 가지는 액정표시 장치 |
US7417143B2 (en) * | 2004-04-07 | 2008-08-26 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of Tazobactam in pure form |
JP4716708B2 (ja) * | 2004-10-28 | 2011-07-06 | 大塚化学株式会社 | ペナム化合物の製造方法 |
US20060173177A1 (en) | 2005-01-28 | 2006-08-03 | Gego Csaba L | Process for preparation of penam derivatives |
CN102304139B (zh) * | 2011-07-12 | 2014-06-04 | 江西富祥药业股份有限公司 | 一种2β-***甲基青霉烷酸二苯甲酯二氧化物的制备方法 |
WO2013036783A2 (en) | 2011-09-09 | 2013-03-14 | Cubist Pharmaceuticals, Inc. | Methods for treating intrapulmonary infections |
US8809314B1 (en) | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
MX2020004205A (es) | 2013-03-15 | 2021-11-16 | Merck Sharp & Dohme Llc | Composiciones antibioticas de ceftolozano. |
US20140274991A1 (en) | 2013-03-15 | 2014-09-18 | Cubist Pharmaceuticals, Inc. | Ceftolozane pharmaceutical compositions |
US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
EP3043797B1 (en) | 2013-09-09 | 2020-04-08 | Merck Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
US20150094293A1 (en) | 2013-09-27 | 2015-04-02 | Calixa Therapeutics, Inc. | Solid forms of ceftolozane |
CN115246844A (zh) * | 2021-04-28 | 2022-10-28 | 苏州朗科生物技术股份有限公司 | 一种他唑巴坦中间体的制备方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU541028B2 (en) | 1982-06-21 | 1984-12-13 | Taiho Pharmaceutical Co., Ltd. | 6-unsubstituted penicillin derivatives |
JPS58225091A (ja) * | 1982-06-21 | 1983-12-27 | Taiho Yakuhin Kogyo Kk | ペニシリン誘導体及びその製造法 |
FI77459C (fi) * | 1982-12-08 | 1989-03-10 | Erba Farmitalia | Foerfarande foer framstaellning av (5r)-penemderivat. |
US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
CA1239392A (en) * | 1983-10-13 | 1988-07-19 | Shigeru Yamabe | Penicillin derivatives and process for preparing the same |
JPH067257B2 (ja) | 1986-12-23 | 1994-01-26 | 富士写真フイルム株式会社 | 感光材料現像装置 |
JP2603082B2 (ja) | 1987-09-07 | 1997-04-23 | 大塚化学株式会社 | ペニシラン酸誘導体の製造法 |
JP2602685B2 (ja) * | 1988-03-01 | 1997-04-23 | 大鵬薬品工業株式会社 | 2α−メチル−2β―(1,2,3−トリアゾール−1−イル)メチルペナム−3α−カルボン酸誘導体の製造法 |
-
2002
- 2002-06-12 CN CNB028295005A patent/CN1285596C/zh not_active Expired - Fee Related
- 2002-06-12 JP JP2004511310A patent/JP2005534662A/ja active Pending
- 2002-06-12 DE DE60215867T patent/DE60215867T2/de not_active Expired - Lifetime
- 2002-06-12 WO PCT/IB2002/002230 patent/WO2003104241A1/en active IP Right Grant
- 2002-06-12 ES ES02735829T patent/ES2274978T3/es not_active Expired - Lifetime
- 2002-06-12 EP EP02735829A patent/EP1554287B1/en not_active Expired - Lifetime
- 2002-06-12 CA CA2487883A patent/CA2487883C/en not_active Expired - Fee Related
- 2002-06-12 RU RU2004139100/04A patent/RU2284329C2/ru not_active IP Right Cessation
- 2002-06-12 AU AU2002309162A patent/AU2002309162A1/en not_active Abandoned
- 2002-06-12 BR BR0215776-4A patent/BR0215776A/pt not_active IP Right Cessation
- 2002-06-12 KR KR1020047019933A patent/KR100671881B1/ko not_active IP Right Cessation
- 2002-12-04 US US10/309,201 patent/US6936711B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN1649880A (zh) | 2005-08-03 |
WO2003104241A1 (en) | 2003-12-18 |
RU2284329C2 (ru) | 2006-09-27 |
KR100671881B1 (ko) | 2007-01-19 |
RU2004139100A (ru) | 2005-06-10 |
DE60215867D1 (de) | 2006-12-14 |
BR0215776A (pt) | 2005-03-01 |
CA2487883C (en) | 2011-04-19 |
KR20050024318A (ko) | 2005-03-10 |
DE60215867T2 (de) | 2007-09-06 |
US6936711B2 (en) | 2005-08-30 |
EP1554287B1 (en) | 2006-11-02 |
US20030232983A1 (en) | 2003-12-18 |
AU2002309162A1 (en) | 2003-12-22 |
EP1554287A1 (en) | 2005-07-20 |
JP2005534662A (ja) | 2005-11-17 |
ES2274978T3 (es) | 2007-06-01 |
CA2487883A1 (en) | 2003-12-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1285596C (zh) | 由头孢烷衍生物制备青霉烷衍生物的方法 | |
KR100433436B1 (ko) | 벤즈이미다졸화합물의합성방법 | |
CN102304139B (zh) | 一种2β-***甲基青霉烷酸二苯甲酯二氧化物的制备方法 | |
Alvarez et al. | Synthesis of 3-Aryl-and 3-Heteroaryl-7-azaindoles | |
EP3757089A1 (en) | Process for the preparation of a nitric oxide donating prostaglandin analogue | |
EP1813619B1 (en) | Process for producing penam compound | |
JP2003513983A (ja) | 高純度セフポドキシムプロキセチルの製造方法 | |
HUT66046A (en) | New 2-spirocyclopropyl-4-acylcephem and process for the preparation thereof | |
EP0523585A2 (en) | Improvements in or relating to beta lactam production | |
EP0623622B1 (en) | Process for producing cephem compound | |
CN111763222B (zh) | 用于制备依度沙班游离碱的中间体及其制备方法和应用 | |
EP0503603A2 (en) | Process for preparing 2-exo-methylenepenam derivatives | |
KR970004047B1 (ko) | 세펨 화합물의 신규한 제조방법 | |
Tanaka et al. | A facile reductive removal of bromine atom (s) of 6, 6-dibromo-and 6-bromopenicillanate derivatives in a Pb/Al bimetal system. | |
EP1666482B1 (en) | Process for producing penicillanic acid compound | |
KR0184036B1 (ko) | 베타락탐 유도체의 제조방법 | |
KR840002046B1 (ko) | 세팔로스포린의 제조방법 | |
KR890001404B1 (ko) | 벤즈이미다졸 유도체의 제조방법 | |
JPH01242589A (ja) | セフエム化合物 | |
US5457193A (en) | Hydroxy protecting group removal in penems | |
JPS58194856A (ja) | 新規2−アゼチジノン誘導体 | |
JPH02138256A (ja) | 1‐ハロ‐4‐ヒドロキシ‐2,2,6,6‐テトラアルキルピペリジンの製造方法 | |
JPS60115562A (ja) | アゼチジノン誘導体の製造法 | |
JPH06321953A (ja) | セファロスポラン酸誘導体 | |
JPH10130270A (ja) | 1−メチルカルバペネム誘導体の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20061122 Termination date: 20120612 |