US3869449A - New penicillin esters, salts thereof, and methods for their preparation - Google Patents
New penicillin esters, salts thereof, and methods for their preparation Download PDFInfo
- Publication number
- US3869449A US3869449A US243855A US24385572A US3869449A US 3869449 A US3869449 A US 3869449A US 243855 A US243855 A US 243855A US 24385572 A US24385572 A US 24385572A US 3869449 A US3869449 A US 3869449A
- Authority
- US
- United States
- Prior art keywords
- ether
- acid
- formula
- compounds
- reaction
- 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 - Lifetime
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title abstract description 42
- 150000002960 penicillins Chemical class 0.000 title abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- 229930182555 Penicillin Natural products 0.000 claims abstract description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 229940049954 penicillin Drugs 0.000 claims description 7
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 5
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 5
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 abstract description 22
- 239000002253 acid Substances 0.000 abstract description 19
- 239000000543 intermediate Substances 0.000 abstract description 13
- 150000007513 acids Chemical class 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 208000015181 infectious disease Diseases 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 153
- -1 alkyl radical Chemical class 0.000 description 120
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 238000006243 chemical reaction Methods 0.000 description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 45
- 238000003756 stirring Methods 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- 229940093499 ethyl acetate Drugs 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 150000003254 radicals Chemical class 0.000 description 23
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 125000003277 amino group Chemical group 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical class [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 229910052727 yttrium Inorganic materials 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 150000003951 lactams Chemical group 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000005936 piperidyl group Chemical group 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229930195708 Penicillin V Natural products 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000006136 alcoholysis reaction Methods 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 2
- 230000001851 biosynthetic effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940075397 calomel Drugs 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 150000001768 cations Chemical group 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229940056367 penicillin v Drugs 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- CVBUKMMMRLOKQR-UHFFFAOYSA-N 1-phenylbutane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CC=CC=C1 CVBUKMMMRLOKQR-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- PQGAHNJECSVDEI-UHFFFAOYSA-N [CH2]CCCCC Chemical compound [CH2]CCCCC PQGAHNJECSVDEI-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 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
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- AIPVTTKYSPOWFO-UHFFFAOYSA-N azepane-1-carbaldehyde Chemical compound O=CN1CCCCCC1 AIPVTTKYSPOWFO-UHFFFAOYSA-N 0.000 description 1
- 229960004328 azidocillin Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- LLOLSUOTGHEWJN-UHFFFAOYSA-N benzylsulfonyloxymethyl phenylmethanesulfonate Chemical compound C=1C=CC=CC=1CS(=O)(=O)OCOS(=O)(=O)CC1=CC=CC=C1 LLOLSUOTGHEWJN-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- ZYFYTWZIMOACBS-UHFFFAOYSA-N butan-1-ol;ethanol;hydrate Chemical compound O.CCO.CCCCO ZYFYTWZIMOACBS-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- 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 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- FHVMATOIMUHQRC-UHFFFAOYSA-N n,n-dimethyl-2-phenylacetamide Chemical compound CN(C)C(=O)CC1=CC=CC=C1 FHVMATOIMUHQRC-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- OHSJPLSEQNCRLW-UHFFFAOYSA-N triphenylmethyl radical Chemical compound C1=CC=CC=C1[C](C=1C=CC=CC=1)C1=CC=CC=C1 OHSJPLSEQNCRLW-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
Definitions
- R and R represent an alkyl radical having 1 1 References (mid from 1 to 6 carbon atoms, a cycloalkyl or cycloalkylal- UNITED STATES PATENTS kyl radical the cycloalkyl part having from 3 to 10 car- 3,669,978 0/1972 Deist .7 200/2391 bon atoms, or 1 nd R2 t gether ith the nitrogen 3,704,290 11/1972 Hou et a1 v 260/239.1 atom represent a heterocyclic ring with from 4 to 8 3.770.722 11/1973 Bright 260/239.1 carbon atoms; R represents radicals known from nat- FOREIGN PATENTS OR APPLICATIONS ural, biosynthetic, and semisynthetic penicillins; and 2.055.531 5/1971 Germany 260/239.1 pharmaceuncany acceptable salts thereof OTHER PUBLICATIONS Lund, Chemical Abstract 75: 49070k of Ger.
- the new compounds are efficiently absorbed from the gastrointestinal tract and after the absorption they are rapidly transformed into the corresponding free penicillins and amidinopenicillanic acids, whereby a broad-spectrum infection can be combated.
- the new penicillin esters have the general formula I:
- R, and R represent an'alkyl radical having from 1 to 6 carbon atoms, a cycloalkylor cycloalkylalkyl radical the cycloalkyl part having from 3 to carbon atoms, or R and R together with thenitrogen atom represent a heterocyclic ring with from 4 to 8 carbon atoms.
- R, and R which may be the same or different represent e.g.
- radicals R and R may be further substituted with halogen atoms, an alkyl, hydroxy, alkoxy, alkylthio group, an acyl group, a carboxy, carbalkoxy, carbamyl, carbamido, cyano or sulfonyl group, or aminoor substituted amino group.
- R represents radicals known from natural, biosynthetic and semisynthetic penicillins.
- Such radicals are e.g. benzyl, phenoxymethyl, 2,6-dimethoxyphenyl, a-azidobenzyl, a-aminobenzyl, a-carboxybenzyl, a-phenoxyethyl, a-phenoxypropyl, 3-phenyl-5-methyl- 4-isoxazolyl, 3-(2-chlorphenyl)-5-methyl-4-isoxazolyl, 3-(2,6-dichlorophenyl)5-methyl-4-isoxazolyl, 3-(2- chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl, 2- ethoxy-l-naphtyl, Z-thienylmethyl, 3-thienylmethyl and a-(3-guanyll-ureido)-benzyl.
- the salts of the new compounds are salts with inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, maleic acid, p-(N,N-dipropylsulfamyl)-benzoic acid and the like acids.
- R R and R contain asymmetric carbon atoms the compounds of the invention will exist in different diastereoisomeric forms and the invention comprises all of these forms as well as mixtures thereof.
- the form in which the compounds are obtained depends on which enantiomer of the starting materials and which method is used to make the compounds.
- the mixtures of the diastereoisomers may be separated by fractional crystallization or other known methods.
- the compounds of the invention are efficiently absorbed from the gastrointestinal tract and after the absorption they are rapidly transformed into the corresponding free penicillins and amidinopenicillanic acids, either spontaneously or under the influence of enzymes present in the body.
- the new esters of the invention give rise to high concentrations of the corresponding free penicillins and amidinopenicillanic acids in the blood and tissues due to efficient absorption combined with rapid hydrolysis in the organism, whereby a broadspectrum infection can be combated, due to the fact that the amidinopenicillins possess strong antibacterial effect especially on gramnegative bacteria.
- the compounds of formula (l) are well tolerated compounds which are administered in clinical practice either as such or, preferably, in the form of one of their salts mixed with carriers and/or auxiliary agents and in any suitable form of pharmaceutical presentation for oral use, such as tablets, pills or dragees, or can be filled in medical containers such as capsules, or as far as suspensions are concerned, filled into bottles.
- Pharmaceutical organic or inorganic, solid or liquid carriers suitable for oral administration can be used to make up the composition.
- Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers for medicaments are all suitable as carriers.
- the preferred salt of the esters is the hydrochloride, but salts with other inorganic or organic acids may be used as mentioned above.
- the compositions may contain other pharmaceutically active components which can appropriately be administered together with the ester in the treatment of the infectious diseases.
- the compounds of the invention can be prepared by several methods.
- a salt of a penicillin of the general formula ll is reacted with a compound of the general formula III in which formulae R is as defined above, X is a cation such as potassium, sodium, ammonium or trialkylammonium ion and Y represents a bromine atom, or iodine atom, an alkylsulphonyloxy group or an arylsulphonyloxy group, preferably in an inert organic solvent, e.g. dimethylformamide or acetone. and at room temperature or at slightly elevated temperatures,
- X is a cation such as potassium, sodium, ammonium or trialkylammonium ion
- Y represents a bromine atom, or iodine atom, an alkylsulphonyloxy group or an arylsulphonyloxy group, preferably in an inert organic solvent, e.g. dimethylformamide or acetone.
- Section A Devoted to the Intermediates of Formula V and their Method of Making
- This invention relates to once unknown derivatives of 6-aminopenicillanic acid, to pharmaceutically acceptable salts thereof, and to methods for the production of these same compounds.
- the compounds of the invention have the general formula:
- R and R represents the same or different substituents and each represents an aliphatic hydrocarbon radical, an aralkyl radical, a cycloalkyl radical, a cycloalkyl-alkyl radical, a heterocyclicically substituted alkyl radical; R and R together with the nitrogen atom represent a ring system; R and R together with the NC atoms represent a ring system; R can furthermore be hydrogen or have the same meaning'as R R represents a hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group radical.
- R R and R represent an aliphatic hydrocarbon radical in which the carbon chain can be straight or branched, saturated or unsaturated, and may be interrupted by an oxygen or sulphur atom, such as methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert. butyl, pentyl, hexyl, dodecyl allyl, butenyl, pentenyl, propargyl, methoxyethyl, ethoxyethyl, methylthioethyl and the like; an aralkyl radical, such as monoor bicyclic aralkyl radical, e.g.
- R represents a hydroxyl group, a substituted hydroxyl group 0R in which R stands for an alkyl radical, aryl radical, aralkyl radical, an alkyl radical substituted with alkoxy, alkanoyl, aroyl, cyano, or a carbalkoxy group, e.g.
- R further represents an acyloxymethyl radical the acyl part of which being an aliphatic, alicyclic, aromatic, ar-aliphatic or heterocyclic radical, such as acetyl, propionyl, butyryl, pivaloyl, cyclohexylacetyl, benzoyl, phenylacetyl, picolinyl, nicotinyl, furylacetyl, thienylacetyl etc., or R can represent an NR R radical, in which R and R are hydrogen, or have the same meanings as defined for R or together with the nitrogen atom form a ring in the same manner as defined for R R N.
- the compounds of formula Ia may be isolated as such or in the form of a salt with a pharmaceutically acceptable acid, such as hydrochloric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, etc.
- a pharmaceutically acceptable acid such as hydrochloric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, etc.
- R stands for a hydroxyl group
- the compounds of formula Ia may be isolated as the acid and as a salt thereof, preferably the alkali metal salts and the ammonium salts.
- the invention comprises all possible isomeric forms of the compound of formula la.
- the invention also comprises methods for the preparation of the above described compounds.
- the compounds of formula Ia are prepared in two steps from amides of the general formula II:
- Hal stands for halogen, preferably chlorine or bromine.
- All well-known halogenating agents can be used, but it is preferable to use halogenating agents, which .throughout the course of the reaction form gaseous byproducts, such as phosgene or oxalyl chloride or bromide but also others, eg thionyl halides, may be used.
- the reaction can be performed in inert, dry, organic solvents, e.g. ether or toluene, in which the amide halide in most cases will be insoluble and from which it can be isolated by filtration after the reaction is completed.
- the compounds of formula III are hygroscopic and rather unstable and are therefore preferably used in the next step without purification.
- R., has the meaning defined above.
- the reaction is performed at low temperature and in inert organic solvents, which are dry and free from traces of alcohols, preferably chloroform, in which the reaction components are soluble, but solvents in which the amide halide isinsoluble, e.g. ether, may be used as well.
- the reaction is performed under cooling and in the presence of at least one equivalent of a tertiary amine. In the case where one equivalent of the tertiary amine is used, the reaction product will be isolated as the hydro halide, whereas the free amidines will be obtained when two or more equivalents of the tertiary amine are used.
- the reaction time depends on the reactants, the temperature and the solvents used in the process.
- R.,, stands for a hydroxyl group
- the preparation of the trimethylsilyl ester of 6-aminopenicillanic acid is known from the literature.
- the trimethylsilylester of the amidine is preferably cleaved by a hydrolysis or an alcoholysis under mild conditions.
- reaction products of formula Ia can be purified and isolated in usual manner and may be obtained either in free state or in the form of a salt.
- the free acid can also be obtained from some of the esters by an enzymatic hydrolysis or a mild hydrogenolysis, and if the 6 free acid is the reaction product the esters and the amides can be prepared therefrom by methods known from the literature.
- the compounds of formula I'Va are partly known compounds and may be prepared byesterification or amidation of -aminopenicillanic acid or a protected -aminopenicillanic acid, such as the 6-trityl derivative thereof.
- the tritylgroup may be split off after the reaction under conditions not affecting the lactam ring. They can also be prepared by es'terification or amidation of the generally industrially used penicillins, whereafter the acyl side chain can be split off chemically or enzymatically under such conditions that the ester group or the amide group is not affected.
- the starting material N-formyllhexamethyleneimine was prepared from hexamethyleneimine and chloral and had a boiling point of lll-l l2/1O mm Hg.
- EXAMPLE 3a Pivaloyloxymethyl 6-( N,N-dimethylphenylacetamidino-N') penicillanate nitrate.
- Cyanomethyl 6-aminopenicillanate was liberated from 4.7 g. of the p-toluenesulfonate according to the procedure of Example 1 and dissolved in 15 ml. of dry, alcohol-free chloroform. Dry triethylamine (3.1 ml.) was added and the solution was cooled to 30 C.. A solution of 1.7 g. crude amide chloride in 15 ml. of dry,
- EXAMPLE 5a y-Phenylpropyl 6-[(hexahydro-1l-l-azepin-l-yl)- methylene-amine]-penicillanate hydrochloride A. 'y-Phenylpropyl 6-aminopenicillanate.
- EXAMPLE 6a 6-[(Hexahydro-lH-azepin-1-y1)-methyleneamino]- penicillanic acid A solution of the amide chloride described in 6 1a (4.6 g) in dry, alcohol-free chloroform (20 ml.) was added slowly 5.18 a solution of trimethylsilyl 6- aminopenicillanate (7.2 g.) and triethylamine (3.5 ml.) 20
- the compounds of formula V111 are described in the following Section B, or perhaps rather subsection.
- the compounds which it describes are in places-described as the compounds of the invention or the like, but this is merely for convenience in designation and does not mean that they are among those compounds on which a patent is being sought in this application.
- the suffix b has been appended to them.
- the compounds of formula Vllb are those of formula V111 when R is hydrogen and R is hydrogen.
- Section B as to the Compounds of Formula V111
- This invention relates to a series of penicillin esters, to salts thereof and to methods of their preparation
- the said penicillin esters have the general formula:
- R and R are radicals known from bisynthetic, semi-synthetic and naturally occurring penicillins, such as alkyl, aryl or aralkyl radicals optionally substituted with hydroxy and etherified hydroxy, halogen, amino, azido, heterocyclic or spirocyclic radicals, for instance a benzyl radical, a phenoxymethyl radical, a dimethoxyphenyl radical, an alphaazidobenzyl radimethyl, trifluoromethyl, phenyl and benzyl radicals.
- penicillins such as alkyl, aryl or aralkyl radicals optionally substituted with hydroxy and etherified hydroxy, halogen, amino, azido, heterocyclic or spirocyclic radicals, for instance a benzyl radical, a phenoxymethyl radical, a dimethoxyphenyl radical, an alphaazidobenzyl radimethyl, trifluoromethyl, phenyl and
- the salts of the said compounds are salts with inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, maleic acid and the like acids.
- R and/or R contain asymmetric carbon atoms or when R is different from hydrogen and R different from R the compounds of the invention will exist in different epimeric forms and the invention comprises these epimers as well as mixtures thereof.
- the form in which the compounds are obtained depends on which enantiomer of the starting materials and which method is used to make the compounds.
- the mixtures of the epimeric forms may be separated by fractional crystallization or other known methods.
- the compounds of formula radical, and other radicals containing one or two amino lllb are, f instance, methylene iodide, methylene groups.
- R and R may represent the same or different mide, chloroidomethane, bismethanesulfonyloxy radicals but at least one of them shall contain an amino 25 methane or bis-toluenesulfonyloxymethane.
- R a penicillin salt of formula 11b in which R, may be the same as, or different from, the first R thereby intermediate of formula lVb are obtained.
- These can be converted into the compounds of the invention as described above.
- the reactions are performed in inert organic solvents such as dimethylformamide or acetone and at room temperature or at slightly elevated temperatures.
- the intermediates of formula lVb are not isolated but directly converted into the compounds of the invention.
- the isolation of the reaction products is done in usual manner and if the epimers are to be separated this can be done, for instance, by means of fractional crystallization in suitable solvents.
- amino groups are present in the R and R radicals, these amino groups are preferably protected during the reactions or are replaced by groups which can be converted to amino groups as a last step of the synthesis.
- Z is selected from groups which are capable of being converted to an amino group by means of methods mild enough to avoid destruction of the molecule at the ester group or at the lactam ring.
- 2, is a benzyloxycarbonyl-amino radical, a p-halo-, p-nitro-, or p-methoxy-benzyloxy-carbonylamino radical, a B,B,,8-trichloro-ethoxycarbonyl-amino or an allyloxycarbonyl-amino radical; or 2,, is a sulphur containing radical, such as a tritylsulphenyl-amino or arylsulphenylamino radical, ie an o-nitrophenylsulphenylamino radical; 2;, may also be a tritylamino radical, a-
- tertiary butoxycarbonyl-amino radical or a radical obtained by reacting the free amino group with a B-dicarbony] compound such as acetylacetone, an acetoacetic ester or benzoylacetone to form enamines or Schiff bases.
- a B-dicarbony] compound such as acetylacetone, an acetoacetic ester or benzoylacetone to form enamines or Schiff bases.
- any group represented by 2 which can be converted by reduction, by mild acid hydrolysis or by other mild reactions known per se, into an amino group will be suitable, since experiments have shown that the esters of formula lb formed by the reaction in question are stable under such conditions.
- the conversion of 2,, into an amino group can be effected by different procedures depending on what 2;, stands for.
- Catalytic hydrogenation will be preferred when 2,, stands for benzyl-oxycarbonyl-amino and re lated derivatives thereof, and for trityl-amino.
- This hydrogenation is preferably performed at room temperature and at atmospheric or slightly elevated pressure in a solvent which may be a non-reducible organic solvent or a mixture thereof with water.
- the preferred catalysts are noble metal catalysts such as palladium or platinum or RaneyNickel, but other catalysts can also be used.
- Electrolytic reduction can also be used in these cases.
- 2, stands for a B,B,B-trichloroethoxycarbonylamino radical
- reduction with zinc in acetic acid is preferred.
- a mild acid hydrolysis is preferred in the case where 2,, stands for a sulphur-containing radical, an enamine or a Schiff base, for instance at a pH of about 2 in a diluted solution of hydrogen chloride preferably in aqueous tetrahydrofurane.
- An acid hydrolysis for instance with hydrochloric acid, acetic acid, p-toluenesulfonic acid or trifluoroacetic acid can also be used for elimination of the trityl and tert.butoxycarbonyl radical.
- lf 2 is an azido or a nitro group or a hydrogen atom, especially a bromime atom, these groups may be transformed into the free amino group in a known manner, the azido and the nitro group by a catalytic hydrogenation with a noble metal catalyst or with Raney-Nickel or by an electrolytic reduction, and the halogen atom by an amination, for instance with hexamethylenetetramine.
- radicals R and R contain a free hydroxy group it can be protected during the reaction by generally known methods, e.g. by etherification or acylation.
- the compounds of the invention can also be prepared from 6-aminopenicillanic acid which, in the form of a salt, reacts with the compounds of formula lllb to form an ester of the following formula Vlb:
- R is as defined above.
- the amino groups are preferably, but not necessarily, protected for instance with a triphenylmethyl radical and the process can be performed under reaction conditions similar to those described above for the reaction between compounds of formulae llb and llb.
- 117 is, however, phosphorus pentachloride, because the reaction in this case can be performed at low temperature increasing the stability of the intermediate formed, which presumably is an imino halide.
- the reaction can be performed in different solvents, but the preferred are chloroform and methylene chloride.
- the intermediate is not isolated but is treated with an excess ofa primary alcohol to form an imino ether.
- the reaction temperature and the reaction time depend on the alcohol used; in most cases temperatures from 20C to 20C will be convenient.
- the esters of 6-aminopenicillanic acid can be isolated from the reaction mixture as such or in the form of a salt with an inorganic or organic acid such as the hydrochloride or the tosylate.
- Y and Y in the compounds of formula lIlb can be the same or different. If Y is substantially more reactive than Y the reaction will be a two-step process and the first reaction product will be an a-Y ester of 6-amino-penicillanic acid or a protected 6-aminopenicillanic acid. Both these esters and the above described corresponding esters of formula Vb are such compounds which also constitute a part of this invention. It is evident that they are especially valuable intermediates for the preparation of compounds of the invention in which R and R are different.
- esters of o-aminopenicillanic acid in free or protected form can be reacted with a salt of a penicillin of formula llb whereby, if necessary after elimination of of a protecting group on the amino group, a compound of the following formula Vllb is obtained:
- the lR-spectrum (CHCl shows strong bands at: 2110,1780, 1690 and 1510 cm
- the lR-spectrum (KBr) shows strong bands at: 17701790 (broad) and 1690 em
- the mixture is diluted with ethyl acetate 500 ml.) and ether (500 ml.), filtered, and the filtrate washed with water- (3 X 250 ml.), 0.5 M aqueous sodiumbic'arbonate (l00,ml.), and water (2X 100 ml.).
- Example lb B performed asde'scribed in Example lb B.
- the aqueous phase is separated and freeze-dried to afford-the desired compound as a colourless amorphous powder.
- the IR-spectrum (KBr) shows strongbands at'1.780, 1 690,.15 15, 1495, 1292, 1240, 1205. and 977 cm.
- the NMR-spectrum (CD OD) shows peaks at 1.45 (S), 1.48 (s) 1.53 (s), 1.60 (s),-4.47 (s), 4.57 (s),-4.'65 (s), 5.17 (s), 5..405.80 (m), 5.95 (s), 6.907.80 (m) g and 7.55. (s), .TMS beingused as internal reference.
- the crude material is purified by dry column chromatography on silica gel (cycloheXane ethyl acetate 7:3) and'th e pure chloromethyl benzylpenicillinate thus obtained is crystallized from ether'z' petroleum ether to yield colourless crystals with m .p 92 -"93, C..
- TMS is used as internal reference.
- the IR-spectrum (CHCl shows strong bands at 2130, 1785, 1668, 1510, 1295 and 980 cm
- the NMR-spectrum (CDCl shows peaks at 8 1.47 (s), 1.52 (s), 1.63 (s), 3.63 (s), 4.42 (s), 4.48 (s), 5.13 (s), 5.40-5.90 (m), 5.88 (s), 7.33 (s), and 7.43 (s). (TMS being used as internal standard).
- EXAMPLE 4 b A. Bis(6B-phenylacetamido-penicillanoyloxy)- methane To a stirred suspension of potassium benzylpenicilli-' nate (22.3 g.) in dimethylformamide 1 10 ml.) is added chloroiodomethane (5.3 g. After stirring for 48 hours at room temperature the mixture is diluted with ethyl 3-(o-chlorophenyl) -5- I acetate (330 ml.) and extracted with water (2 X 60 ml.), 2% aqueous sodium bicarbonate (60 ml.) and water (2 X 60 ml.).
- the organic phase is dried and evaporated to dryness in vacuo to yield the desired compound as an amorphous powder.
- the lR-spectrum (CHCI shows strong bands at 1780, 1675, 1505, 1290, 1135 and 982 cm.
- the aqueous phase is separated and the pH adjusted to 7.5 by addition of sodium bicarbonate.
- the aqueous phase is extracted with ether (25 ml.).
- the organic phase is separated, dried and evaporated to dryness in vacuo to yield a mixture of the desired compound and quinoline.
- EXAMPLE 5b A. Bis-(6/3-amino-penicillanoyloxy)-methane To a solution of PCl (1.28 g.) in dry, alcohol-free Cl-lCl (30 ml.) is added quinoline (1.46 ml.) with stirring. The solution is cooled to -l0 C. and bis-(6B- phenylacetamido-penicillanoyloxy)-methane (1.36 g.) is added. After stirring for minutes at 10 C. n-
- propyl alcohol (6.6 ml.) is added. The temperature is kept at -10 C. for a further 15 minutes. Then the mixture is poured into water (50 ml.) and petroleum ether 1 10 ml.) is added.
- R represents a hydrogen atom
- the intermediates of formula Vlll can be used directly in the next step, and if R represents a protective group this is first removed, e.g. by hydrogenation or hydroly- SIS.
- R and R have the meanings defined before, and R stands for O or S to yield the compounds of formula l.
- the amides of formula IX can by welbknown methods be transferred into reactive derivatives such as acid amide halides, acid amide dialkyl sulphate complexes or acid amide acetals.
- the acid amide halides used are preferably the chlorides or bromides, and they can be prepared by treating the amides with halogenating agents. It is preferred to use halogenating agents which throughout the reaction form gaseous by-products, such as phosgene, oxalyl halides, or thionyl halides, but also others may be used.
- the reaction can be performed in inert, dry, organic solvents, e.g.
- amide halide in most cases will be insoluble and from which it can be isolated by filtration after the reaction is completed.
- the acid amide halides are hygroscopic and rather unstable and are therefrom preferably used in the next step without purification.
- the acid amide dialkyl sulphate complexes can be prepared by treating the amides with dialkyl sulphate, preferably dimethyl sulphate, under well-known conditions.
- dialkyl sulphate preferably dimethyl sulphate
- acid amide dialkyl sulphate complexes with sodium lower alcoholates, e.g. sodium methoxide, acid amide acetals of the general formula lXa:
- R1 N-cn(oR IXa R2 6 2 in which R and R have the meanings defined above and R, is a lower alkyl group, are formed, which acetals may also be used in the next step.
- a reactive derivative in form of an acid thioamide alkyl halide complex can be formed by treatment with alkyl halides, eLg. lower-alkyl iodide. This reaction is well known from the chemical literature.
- reaction conditions for the reaction between the amide derivative and the compound of formula VIII depend on the reaction components used in the process.
- the reaction temperature depends on the reaction components.
- the reaction is performed in inert organic solvents, for instance ether.
- reaction is also performed in inert organic solvents, which are dry'and free from traces of alcohols, preferably chloroform, in which the reaction components are soluble, but solvents in which the starting materials are insoluble, e.g. ether, may be used as well.
- inert organic solvents which are dry'and free from traces of alcohols, preferably chloroform, in which the reaction components are soluble, but solvents in which the starting materials are insoluble, e.g. ether, may be used as well.
- the reaction is performed under cooling and in the presence of at least one equivalent of a tertiary amine, for example trimethylamine, triethylamine, N,N- diisopropylethylamine or N-methylmorpholine.
- the reaction product will be obtained as a salt when an acid amide halide is used, and as the free esters of formula I when the dialkyl sulphate complexes and thioamide alkyl halide complexes are used.
- the reaction time depends on the reactants, the temperature and the solvents used in the process.
- a compound of the above formula V1 is reacted with a compound of the above formula VII under the same conditions as described above for the reaction between the compounds of formula IV and formula VII to yield a compound of formula X:
- EXAMPLE 1 6-[ (Hexahydrol H-azepinl -yl )-methyleneamino]- penicillanovloxvmethvl benzvlnenicillinatp
- a suspension of sodium 6-[(hexahydro-IH- azepin-l-yl)-methyleneamino]-penicillanate (3.5 g.) in dimethylformamide (50 ml.) was added chloromethyl benzylpenicillinate (3.8 g.). After stirring at room temperature for 65 hours, the mixture was diluted with ethyl acetate (200 ml.) and washed with water (3 X 25 ml.).
- the organic phase was extracted with dilute hydrochloric acid (pl-l 2.5).
- the aqueous phase was separated and made alkaline by adding sodium bicarbonate.
- the oil which separated was taken up in ethyl acetate and the solution was dried and evaporated to dryness in vacuo to yield the desired compound as an amorphous powder.
- the NMR-spectrum (CDCl showed peaks at 8 1.47 (s), 1.65 (s), 1.58 (m), 3.37 (m), 3.63 (s), 4.38 (s),'4.40 (s), 5.08 (dd), 5.4 5.8 (m), 5.87 (s), 6.20 (d), 7.32 (s) and 7.59 ((1) ppm.
- TMS was used as internal reference.
- the IR-spectrum (CHCI showed strong bands at 1773, 1673 and 1630 cm".
- the starting materials used in the above example are prepared in the following manner: 6-[(Hexahydro-lH-azepin-l-yl)-methyleneamino]- penicillanic acid dihydrate.
- A. l-Hexamethyleneiminecarboxaldehyde dimethyl acetal was prepared from the N-formylhexamethyleneimine-dimethyl sulfate complex by reaction with sodium methoxide according to the method of Bredereck et al. (Chem. Ber. 101,41 (1968). The boiling point was 83 -84C./12 mm Hg.
- the IR-spectrum (KBr) showed strong bands at: 1785, 1770, 1655,1547,1303, 1139,1118 and 712 cm.
- EXAMPLE 2 6-[(Hexahydro-1 H-azepin- 1 -y1)-methyleneamino]- penicillanoyloxymethyl benzylpenicillinate, hydrochloride.
- EXAMPLE 3 6-[(I-1exahydro-ll-l-azepin-lyl)-methyleneamino]- penicillanoyloxymethyl phenoxymethylpenicillinate.
- This compound was obtainedas described in Example l by using chloromethyl phenoxymethylpenicillinate instead of chloromethyl benzylpenicillinate.
- EXAMPLE 4 6-[(1-lexahydro-lI-l-azepin-l-yl)-methyleneamino]- penicillanoyloxymethyl phenoxymethylpenicillinate, hydrochloride.
- the organic phase was extracted with dilute hydrochloric acid (pH -2.5).
- the aqueous phase was separated and made alkaline by adding sodium bicarbonate.
- the oil which separated was taken up in ethyl acetate and the solution was dried and evaporated to dryness in vacuo to yield the desired compound as a yellow oil.
- EXAMPLE 7 A. 6-Amino-penicillanoyloxymethyl benzylpenicillinate. A
- TMS was used as internal reference.
- EXAMPLE 8 By following the procedure described in Example 1 and by replacing the chloromethyl benzylpenicillinate with the chloromethyl esters of 3-(2-chloro-6- fluorophenyl)-5-methyl-4-isoxazolylpenicillin and D(-)-a-azidobenzylpenicillin, respectively, the follow- 'ing compounds were prepared: 6-[(hexahydro-1H- EXAMPLE 9 6-[(Hexahydro-lH-azepin-l-yl)-methyleneamino]- penicillanoyloxymethyl D(-)-a-aminobenzylpenicillinate, dihydrochloride.
- Example II Following the procedure described in Example I the above compound was prepared from sodium 6-[(N- ethyl-N-isopropylamino)-methyleneamino]- penicillanate and chloromethyl 3-(o-chlorophenyl)-5- methyl-4-isoxazolylpenicillinate. The compound was isolated as an amorphous powder.
- Chloromethyl 3-(o-chlorophenyl)-5-methvl-4-isoxazolylpenicillinate was prepared in analogy with chloromethyl benzylpenicillinate (cfr. Example 1). The compound was isolated as an amorphous powder.
- This compound was prepared from sodium 6- [(hexahydro-l-(2H)-azocinnyl)-methyleneamino]- penicillanate and chloromethyl benzylpenicillinate following the procedure described in Example I. It was obtained as an amorphous powder.
- a penicillin ester of the formula I H H R1 l E 2 N-CH l L 5 O C N CH H H CH R com. S 5 5 I li B (1% N----CH V Q in which R and R together with the nitrogen atom to which they are attached represent hexahydroazepinyl; R represents a member selected from the group consisting of benzyl, phenoxymethyl, 3-(2'-chloro-6'- fluorophenyl)-5-methyl-4-isoxazolyl,D(-)-alphaazidobenzyl, D(-)-alpha-aminobenzyl and 3-(0- chlorophenyl)-5-methyl-4-isoxazolyl; and pharmaceutically acceptable, non-toxic salts thereof.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1335871 | 1971-05-05 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US05/554,423 Division US4554160A (en) | 1971-05-05 | 1975-03-03 | Penicillin esters, salts thereof and methods for their preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
US3869449A true US3869449A (en) | 1975-03-04 |
Family
ID=10021514
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US243855A Expired - Lifetime US3869449A (en) | 1971-05-05 | 1972-04-13 | New penicillin esters, salts thereof, and methods for their preparation |
Country Status (10)
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4181659A (en) * | 1976-04-15 | 1980-01-01 | Leo Pharmaceutical Products Ltd. A/S | Bis-penicillanoyloxy-alkanes |
US4244951A (en) * | 1979-05-16 | 1981-01-13 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4309347A (en) * | 1979-05-16 | 1982-01-05 | Pfizer Inc. | Penicillanoyloxymethyl penicillanate 1,1,1',1'-tetraoxide |
US4323499A (en) * | 1981-01-05 | 1982-04-06 | Pfizer Inc. | 6-(2-Aryl-2-(1,1-dioxopenicillanoyloxy-methoxycarbonyl)acetamido penicillanic acids |
US4340539A (en) * | 1980-01-21 | 1982-07-20 | Bristol-Myers Company | Derivatives of 6-bromo penicillanic acid |
US4342772A (en) * | 1979-02-13 | 1982-08-03 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | β-Lactam compounds, antibacterial compositions thereof and method of use |
US4345071A (en) * | 1976-06-29 | 1982-08-17 | Leo Pharmaceutical Products, Ltd. A/S | Derivatives of penicillanic acid |
US4377524A (en) * | 1979-05-16 | 1983-03-22 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4407751A (en) * | 1979-02-13 | 1983-10-04 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Processes for preparing β-lactams |
US4432903A (en) * | 1980-09-08 | 1984-02-21 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4488994A (en) * | 1980-09-08 | 1984-12-18 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4508723A (en) * | 1977-05-17 | 1985-04-02 | Ciba Geigy Corporation | 6-Azaoligocycloalkylmethyleneaminopenam compounds |
US4540687A (en) * | 1981-09-09 | 1985-09-10 | Pfizer Inc. | Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds |
US4582829A (en) * | 1981-09-09 | 1986-04-15 | Pfizer Inc. | Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds |
US6642377B1 (en) * | 1999-07-30 | 2003-11-04 | Eisai Co., Ltd. | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL59257A (en) * | 1979-02-13 | 1983-09-30 | Rech Applications Therap | 6-(n-(cyclic amino-substituted methylene)amino)penicillanates and salts thereof,their production and pharmaceutical compositions containing them |
DE3051044C2 (enrdf_load_stackoverflow) * | 1979-06-19 | 1989-03-30 | Leo Pharmaceutical Products Ltd. A/S (Loevens Kemiske Fabrik Produktionsaktieselskab), Ballerup, Dk |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3669978A (en) * | 1970-05-28 | 1972-06-13 | American Home Prod | Process for the production of semi-synthetic penicillin intermediate |
US3704290A (en) * | 1970-12-09 | 1972-11-28 | American Home Prod | 6-(1 - substituted aminocycloalkane-carboxamido)-penicillanic acid and salts |
US3770722A (en) * | 1971-10-04 | 1973-11-06 | Pfizer | 6 - (alpha - (aryl substituted)acylamino-acylamino)penicillanic acidsand derivatives thereof |
-
1971
- 1971-04-20 GB GB1335871A patent/GB1335718A/en not_active Expired
-
1972
- 1972-04-13 US US243855A patent/US3869449A/en not_active Expired - Lifetime
- 1972-04-17 ZA ZA722545A patent/ZA722545B/xx unknown
- 1972-04-20 DK DK193172A patent/DK140481B/da unknown
- 1972-04-26 CA CA140,652A patent/CA1112569A/en not_active Expired
- 1972-05-02 JP JP4337972A patent/JPS5541240B1/ja active Pending
- 1972-05-03 NL NL7205957A patent/NL7205957A/xx not_active Application Discontinuation
- 1972-05-04 SE SE7205896A patent/SE417098B/xx unknown
- 1972-05-04 DE DE19722221912 patent/DE2221912A1/de not_active Withdrawn
- 1972-05-05 FR FR7216200A patent/FR2135339B1/fr not_active Expired
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3669978A (en) * | 1970-05-28 | 1972-06-13 | American Home Prod | Process for the production of semi-synthetic penicillin intermediate |
US3704290A (en) * | 1970-12-09 | 1972-11-28 | American Home Prod | 6-(1 - substituted aminocycloalkane-carboxamido)-penicillanic acid and salts |
US3770722A (en) * | 1971-10-04 | 1973-11-06 | Pfizer | 6 - (alpha - (aryl substituted)acylamino-acylamino)penicillanic acidsand derivatives thereof |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4181659A (en) * | 1976-04-15 | 1980-01-01 | Leo Pharmaceutical Products Ltd. A/S | Bis-penicillanoyloxy-alkanes |
US4345071A (en) * | 1976-06-29 | 1982-08-17 | Leo Pharmaceutical Products, Ltd. A/S | Derivatives of penicillanic acid |
US4508723A (en) * | 1977-05-17 | 1985-04-02 | Ciba Geigy Corporation | 6-Azaoligocycloalkylmethyleneaminopenam compounds |
US4840944A (en) * | 1979-02-13 | 1989-06-20 | Leo Pharmaceutical Products Ltd. | Antibacterial beta-lactams, pharmaceuticals thereof and methods of using them |
US4342772A (en) * | 1979-02-13 | 1982-08-03 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | β-Lactam compounds, antibacterial compositions thereof and method of use |
US4407751A (en) * | 1979-02-13 | 1983-10-04 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Processes for preparing β-lactams |
US4244951A (en) * | 1979-05-16 | 1981-01-13 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4309347A (en) * | 1979-05-16 | 1982-01-05 | Pfizer Inc. | Penicillanoyloxymethyl penicillanate 1,1,1',1'-tetraoxide |
US4377524A (en) * | 1979-05-16 | 1983-03-22 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4340539A (en) * | 1980-01-21 | 1982-07-20 | Bristol-Myers Company | Derivatives of 6-bromo penicillanic acid |
US4488994A (en) * | 1980-09-08 | 1984-12-18 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4432903A (en) * | 1980-09-08 | 1984-02-21 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4323499A (en) * | 1981-01-05 | 1982-04-06 | Pfizer Inc. | 6-(2-Aryl-2-(1,1-dioxopenicillanoyloxy-methoxycarbonyl)acetamido penicillanic acids |
US4540687A (en) * | 1981-09-09 | 1985-09-10 | Pfizer Inc. | Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds |
US4582829A (en) * | 1981-09-09 | 1986-04-15 | Pfizer Inc. | Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds |
US6642377B1 (en) * | 1999-07-30 | 2003-11-04 | Eisai Co., Ltd. | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
Also Published As
Publication number | Publication date |
---|---|
DK140481B (da) | 1979-09-10 |
DE2221912A1 (de) | 1972-11-16 |
FR2135339A1 (enrdf_load_stackoverflow) | 1972-12-15 |
SE417098B (sv) | 1981-02-23 |
JPS5541240B1 (enrdf_load_stackoverflow) | 1980-10-22 |
NL7205957A (enrdf_load_stackoverflow) | 1972-11-07 |
ZA722545B (en) | 1973-01-31 |
GB1335718A (en) | 1973-10-31 |
CA1112569A (en) | 1981-11-17 |
FR2135339B1 (enrdf_load_stackoverflow) | 1975-06-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3869449A (en) | New penicillin esters, salts thereof, and methods for their preparation | |
US3697507A (en) | Esters of {60 -aminobenzylpenicillin | |
US5608082A (en) | Compounds useful as antiproliferative agents and GARFT inhibitors | |
CY1205A (en) | Penicillin derivatives | |
US4229443A (en) | Derivatives of penicillanic acid | |
SE445644B (sv) | 7beta-amino-3-cefem-3-amino-4-karbonsyra-foreningar som mellanprodukter for framstellning av 7beta-amino-3-cefem-3-ol-4-karbonsyra-foreningar | |
NO811740L (no) | Dioksydforbindelser, fremgangsmaate til deres fremstilling og deres anvendelse | |
US3658802A (en) | Cephalosporine derivatives and process | |
IE47080B1 (en) | New derivatives of amidino penicillanic acid | |
US3850908A (en) | Aminoacyloxymethyl esters of penicillins | |
US4492692A (en) | Cephalosporin derivatives | |
US3833580A (en) | 3-morpholino-n6-cyclohexylcarbonyl sydnonimine | |
US3546211A (en) | Polycyclic b-lactams | |
DE2636962C2 (enrdf_load_stackoverflow) | ||
US3864331A (en) | Acyloxymethyl esters of {60 -aminopenicillins | |
US4554160A (en) | Penicillin esters, salts thereof and methods for their preparation | |
US3719668A (en) | Semi-synthetic penicillin esters | |
US4576939A (en) | Penem derivatives | |
US3951957A (en) | Chloromethyl ester of penicillins | |
US3660575A (en) | Esters of alpha-aminobenzylpenicillin in dosage unit form | |
US3819643A (en) | Esters of 6-amino penicillanic acid | |
US4345071A (en) | Derivatives of penicillanic acid | |
EP0128718B1 (en) | Process for 6-(aminomethyl)penicillanic acid 1,1-dioxide and derivatives thereof | |
JPS62198687A (ja) | 2β−置換チオメチルペニシリン誘導体 | |
US3847913A (en) | Cephalosporanic acid esters |