CA1056372A - Method of preparation of 3-methylenecephams - Google Patents
Method of preparation of 3-methylenecephamsInfo
- Publication number
- CA1056372A CA1056372A CA240,644A CA240644A CA1056372A CA 1056372 A CA1056372 A CA 1056372A CA 240644 A CA240644 A CA 240644A CA 1056372 A CA1056372 A CA 1056372A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- methylenecepham
- oxide
- carboxylate
- oxo
- 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
Links
- 238000000034 method Methods 0.000 title claims description 110
- 238000002360 preparation method Methods 0.000 title abstract description 26
- -1 3-methylenecepham sulfoxide Chemical class 0.000 claims abstract description 204
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- 239000003054 catalyst Substances 0.000 claims abstract description 61
- 238000004519 manufacturing process Methods 0.000 claims abstract description 50
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 30
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 23
- 150000001768 cations Chemical class 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims description 78
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 74
- 239000002253 acid Substances 0.000 claims description 44
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 37
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 36
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 36
- 239000000126 substance Substances 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 31
- KWNKLOIQBJJEKH-VFMUOLFISA-N methyl (6r)-7-(1,3-dioxoisoindol-2-yl)-3-methylidene-5,8-dioxo-5$l^{4}-thia-1-azabicyclo[4.2.0]octane-2-carboxylate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C1=O)[C@@H]2N1C(C(=O)OC)C(=C)CS2=O KWNKLOIQBJJEKH-VFMUOLFISA-N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
- YXKPEPQKJIALCJ-UHFFFAOYSA-N methyl 2-[2-chlorosulfinyl-3-(1,3-dioxoisoindol-2-yl)-4-oxoazetidin-1-yl]-3-methylbut-3-enoate Chemical compound O=C1N(C(C(=O)OC)C(C)=C)C(S(Cl)=O)C1N1C(=O)C2=CC=CC=C2C1=O YXKPEPQKJIALCJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002841 Lewis acid Substances 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910001507 metal halide Inorganic materials 0.000 claims description 13
- 239000003377 acid catalyst Substances 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- 150000007517 lewis acids Chemical class 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 241000893044 Chalcides Species 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 8
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- VEZRLVLLNRILSJ-INTATBAPSA-N (6r)-3-methylidene-5,8-dioxo-7-[(2-phenoxyacetyl)amino]-5$l^{4}-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid Chemical compound C1([C@@H]2N(C1=O)C(C(CS2=O)=C)C(=O)O)NC(=O)COC1=CC=CC=C1 VEZRLVLLNRILSJ-INTATBAPSA-N 0.000 claims description 7
- KWSHFDLQSYVQKO-UHFFFAOYSA-N 3-(1,3-dioxoisoindol-2-yl)-1-(1-methoxy-3-methyl-1-oxobut-3-en-2-yl)-4-oxoazetidine-2-sulfinic acid Chemical compound O=C1N(C(C(=O)OC)C(C)=C)C(S(O)=O)C1N1C(=O)C2=CC=CC=C2C1=O KWSHFDLQSYVQKO-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 7
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 7
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 229960002523 mercuric chloride Drugs 0.000 claims description 6
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 claims description 6
- JUDUFOKGIZUSFP-UHFFFAOYSA-M silver;4-methylbenzenesulfonate Chemical compound [Ag+].CC1=CC=C(S([O-])(=O)=O)C=C1 JUDUFOKGIZUSFP-UHFFFAOYSA-M 0.000 claims description 6
- 229940102001 zinc bromide Drugs 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 5
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 5
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 239000007848 Bronsted acid Substances 0.000 claims description 3
- 229910021623 Tin(IV) bromide Inorganic materials 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 125000004970 halomethyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- LTSUHJWLSNQKIP-UHFFFAOYSA-J tin(iv) bromide Chemical compound Br[Sn](Br)(Br)Br LTSUHJWLSNQKIP-UHFFFAOYSA-J 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 2
- 229910021556 Chromium(III) chloride Inorganic materials 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000359 chromic chloride Drugs 0.000 claims description 2
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 claims description 2
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- XHXCMOPGFBFHTI-FRENBRBJSA-N methyl (6r)-3-methylidene-5,8-dioxo-7-[(2-phenylacetyl)amino]-5$l^{4}-thia-1-azabicyclo[4.2.0]octane-2-carboxylate Chemical compound C1([C@@H]2N(C1=O)C(C(CS2=O)=C)C(=O)OC)NC(=O)CC1=CC=CC=C1 XHXCMOPGFBFHTI-FRENBRBJSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 2
- 125000006007 trichloroethoxy group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 2
- IZYJOLMJKGBANZ-UHFFFAOYSA-N 2-[2-chlorosulfinyl-4-oxo-3-[(2-phenoxyacetyl)amino]azetidin-1-yl]-3-methylbut-3-enoic acid Chemical compound O=C1N(C(C(=C)C)C(O)=O)C(S(Cl)=O)C1NC(=O)COC1=CC=CC=C1 IZYJOLMJKGBANZ-UHFFFAOYSA-N 0.000 claims 2
- WMMKIKLSRXEIEO-MSXBQUPASA-N methyl (6r)-7-(2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidin-1-yl)-3-methylidene-5,8-dioxo-5$l^{4}-thia-1-azabicyclo[4.2.0]octane-2-carboxylate Chemical compound C1([C@@H]2N(C1=O)C(C(CS2=O)=C)C(=O)OC)N(C(N1N=O)(C)C)C(=O)C1C1=CC=CC=C1 WMMKIKLSRXEIEO-MSXBQUPASA-N 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- OGVLQETULPBRTN-UHFFFAOYSA-N benzhydryl 2-[2-chlorosulfinyl-4-oxo-3-[(2-phenoxyacetyl)amino]azetidin-1-yl]-3-methylbut-3-enoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)OC(=O)C(C(=C)C)N(C1=O)C(S(Cl)=O)C1NC(=O)COC1=CC=CC=C1 OGVLQETULPBRTN-UHFFFAOYSA-N 0.000 claims 1
- UFERMRDMWQVSCL-UHFFFAOYSA-N methyl 2-[2-bromosulfinyl-3-(1,3-dioxoisoindol-2-yl)-4-oxoazetidin-1-yl]-3-methylbut-3-enoate Chemical compound O=C1N(C(C(=O)OC)C(C)=C)C(S(Br)=O)C1N1C(=O)C2=CC=CC=C2C1=O UFERMRDMWQVSCL-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000006000 trichloroethyl group Chemical group 0.000 claims 1
- ZRRLCCCOCSDAKF-UHFFFAOYSA-N azetidin-2-one thionyl dichloride Chemical class ClS(Cl)=O.O=C1CCN1 ZRRLCCCOCSDAKF-UHFFFAOYSA-N 0.000 abstract description 16
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 abstract description 12
- 239000000543 intermediate Substances 0.000 abstract description 11
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 abstract description 6
- 239000003242 anti bacterial agent Substances 0.000 abstract description 5
- 229940088710 antibiotic agent Drugs 0.000 abstract description 5
- 150000003452 sulfinic acid derivatives Chemical class 0.000 abstract description 5
- 150000001782 cephems Chemical class 0.000 abstract description 4
- HTFTURZHXAWZPC-SSDOTTSWSA-N (6r)-3-methylidene-5-thia-1-azabicyclo[4.2.0]octan-8-one Chemical class C1C(=C)CS[C@@H]2CC(=O)N21 HTFTURZHXAWZPC-SSDOTTSWSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 239000000203 mixture Substances 0.000 description 92
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 80
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
- 239000000047 product Substances 0.000 description 75
- 150000003462 sulfoxides Chemical class 0.000 description 57
- 239000000243 solution Substances 0.000 description 54
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 229940093499 ethyl acetate Drugs 0.000 description 41
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 40
- 235000019341 magnesium sulphate Nutrition 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 35
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 33
- 239000012267 brine Substances 0.000 description 31
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000007858 starting material Substances 0.000 description 26
- 238000007363 ring formation reaction Methods 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 22
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 230000000875 corresponding effect Effects 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 16
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 229940073584 methylene chloride Drugs 0.000 description 14
- 239000006260 foam Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 229930182555 Penicillin Natural products 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 9
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 235000011167 hydrochloric acid Nutrition 0.000 description 8
- 229960000443 hydrochloric acid Drugs 0.000 description 8
- 229940049954 penicillin Drugs 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 150000005309 metal halides Chemical class 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- 125000004442 acylamino group Chemical group 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 6
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 5
- 229960001701 chloroform Drugs 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
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- PJUFIZCMUUWIOW-UHFFFAOYSA-N phenacyl 3-methyl-2-[2-oxo-4-(2-phenylethylsulfinothioyl)-3-[(2-phenyl-2-phenylmethoxyacetyl)amino]azetidin-1-yl]but-3-enoate Chemical compound C=1C=CC=CC=1C(=O)COC(=O)C(C(=C)C)N(C1=O)C(S(=S)CCC=2C=CC=CC=2)C1NC(=O)C(C=1C=CC=CC=1)OCC1=CC=CC=C1 PJUFIZCMUUWIOW-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229940054334 silver cation Drugs 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 description 1
- 229910000161 silver phosphate Inorganic materials 0.000 description 1
- 229940019931 silver phosphate Drugs 0.000 description 1
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 description 1
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 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
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LMBSWTBRHBYZGP-UHFFFAOYSA-N tert-butyl 2-[2-chlorosulfinyl-3-(1,3-dioxoisoindol-2-yl)-4-oxoazetidin-1-yl]-3-methylbut-3-enoate Chemical compound O=C1N(C(C(=C)C)C(=O)OC(C)(C)C)C(S(Cl)=O)C1N1C(=O)C2=CC=CC=C2C1=O LMBSWTBRHBYZGP-UHFFFAOYSA-N 0.000 description 1
- ASOWDIVNHQXOIM-UHFFFAOYSA-N tert-butyl 2-[2-methoxysulfinyl-4-oxo-3-(phenylmethoxycarbonylamino)azetidin-1-yl]-3-methylbut-3-enoate Chemical compound O=C1N(C(C(C)=C)C(=O)OC(C)(C)C)C(S(=O)OC)C1NC(=O)OCC1=CC=CC=C1 ASOWDIVNHQXOIM-UHFFFAOYSA-N 0.000 description 1
- IDEVTQJDYJXZQS-UHFFFAOYSA-N tert-butyl 3-methyl-2-[3-[(4-nitrophenyl)methoxycarbonylamino]-2-oxo-4-phenylsulfinothioylazetidin-1-yl]but-3-enoate Chemical compound O=C1N(C(C(=C)C)C(=O)OC(C)(C)C)C(S(=S)C=2C=CC=CC=2)C1NC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 IDEVTQJDYJXZQS-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA320,196A CA1080221A (en) | 1974-12-24 | 1979-01-24 | Method of preparation of 3-methylenecephams |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53628074A | 1974-12-24 | 1974-12-24 | |
| US63273375A | 1975-11-19 | 1975-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1056372A true CA1056372A (en) | 1979-06-12 |
Family
ID=27065082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA240,644A Expired CA1056372A (en) | 1974-12-24 | 1975-11-27 | Method of preparation of 3-methylenecephams |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS606960B2 (en, 2012) |
| AR (1) | AR220505A1 (en, 2012) |
| AT (1) | AT341672B (en, 2012) |
| AU (1) | AU503202B2 (en, 2012) |
| BE (1) | BE837041A (en, 2012) |
| BG (2) | BG31072A4 (en, 2012) |
| CA (1) | CA1056372A (en, 2012) |
| CH (3) | CH625528A5 (en, 2012) |
| CS (1) | CS191291B2 (en, 2012) |
| DD (2) | DD130933A5 (en, 2012) |
| DE (1) | DE2556045A1 (en, 2012) |
| DK (1) | DK157137C (en, 2012) |
| ES (2) | ES443829A1 (en, 2012) |
| FR (2) | FR2333804A1 (en, 2012) |
| GB (1) | GB1536288A (en, 2012) |
| GR (1) | GR59922B (en, 2012) |
| HU (2) | HU175226B (en, 2012) |
| IE (1) | IE42190B1 (en, 2012) |
| IL (1) | IL48565A (en, 2012) |
| NL (1) | NL182880C (en, 2012) |
| PL (2) | PL113883B1 (en, 2012) |
| RO (2) | RO74273A (en, 2012) |
| SE (2) | SE431547B (en, 2012) |
| SU (1) | SU799667A3 (en, 2012) |
| YU (2) | YU324875A (en, 2012) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4289695A (en) * | 1978-11-13 | 1981-09-15 | Eli Lilly And Company | Process for preparing 2-chlorosulfinylazetidinones |
| US4190724A (en) * | 1978-11-13 | 1980-02-26 | Eli Lilly And Company | Process for 3-exomethylenecepham sulfoxides |
| GB2099817B (en) * | 1981-04-10 | 1985-05-15 | Otsuka Kagaku Yakuhin | Azetidinone derivatives and process for the preparation of the same |
| US4436596A (en) * | 1982-11-16 | 1984-03-13 | Eli Lilly And Company | N-Substituted-2-(R)-(sulfinic acid)-3-(S)-(acylamido)-4-oxo-azetidines and process |
| DE4230053A1 (de) * | 1992-09-08 | 1994-03-10 | Pliva Handels Gmbh | 4-Oxo-azetidin-2-sulfonsäureamide und ihre Salze, Verfahren zu deren Herstellung und ihre Verwendung |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3843682A (en) * | 1972-05-15 | 1974-10-22 | Lilly Co Eli | 2-chlorosulfinyl-3-imido-azetedin-4-ones |
-
1975
- 1975-11-27 GR GR49473A patent/GR59922B/el unknown
- 1975-11-27 CA CA240,644A patent/CA1056372A/en not_active Expired
- 1975-11-28 IL IL48565A patent/IL48565A/xx unknown
- 1975-11-28 AU AU87084/75A patent/AU503202B2/en not_active Expired
- 1975-11-28 IE IE2596/75A patent/IE42190B1/en unknown
- 1975-12-12 DE DE19752556045 patent/DE2556045A1/de active Granted
- 1975-12-16 CH CH1630475A patent/CH625528A5/de not_active IP Right Cessation
- 1975-12-17 DD DD7500198426A patent/DD130933A5/xx unknown
- 1975-12-17 DD DD190224A patent/DD124985A5/xx unknown
- 1975-12-18 GB GB51980/75A patent/GB1536288A/en not_active Expired
- 1975-12-19 YU YU03248/75A patent/YU324875A/xx unknown
- 1975-12-22 JP JP50153926A patent/JPS606960B2/ja not_active Expired
- 1975-12-22 SE SE7514550A patent/SE431547B/xx not_active IP Right Cessation
- 1975-12-22 DK DK585875A patent/DK157137C/da not_active IP Right Cessation
- 1975-12-23 SU SU752301511A patent/SU799667A3/ru active
- 1975-12-23 AT AT980475A patent/AT341672B/de not_active IP Right Cessation
- 1975-12-23 HU HU75EI686A patent/HU175226B/hu unknown
- 1975-12-23 ES ES443829A patent/ES443829A1/es not_active Expired
- 1975-12-23 CS CS758835A patent/CS191291B2/cs unknown
- 1975-12-23 PL PL1975212224A patent/PL113883B1/pl unknown
- 1975-12-23 BE BE1007103A patent/BE837041A/xx not_active IP Right Cessation
- 1975-12-23 PL PL1975185927A patent/PL114521B1/pl unknown
- 1975-12-23 HU HU75EI662A patent/HU177431B/hu unknown
- 1975-12-23 AR AR261750A patent/AR220505A1/es active
- 1975-12-24 RO RO7594622A patent/RO74273A/ro unknown
- 1975-12-24 BG BG036782A patent/BG31072A4/xx unknown
- 1975-12-24 FR FR7539714A patent/FR2333804A1/fr active Granted
- 1975-12-24 NL NLAANVRAGE7515069,A patent/NL182880C/xx not_active IP Right Cessation
- 1975-12-24 RO RO7584303A patent/RO68478A/ro unknown
- 1975-12-24 BG BG031908A patent/BG27236A3/xx unknown
-
1976
- 1976-05-04 FR FR7613230A patent/FR2300080A1/fr active Granted
-
1977
- 1977-04-15 ES ES457884A patent/ES457884A1/es not_active Expired
-
1979
- 1979-08-17 SE SE7906899A patent/SE444810B/sv not_active IP Right Cessation
-
1980
- 1980-11-21 CH CH862880A patent/CH626604A5/de not_active IP Right Cessation
-
1981
- 1981-04-24 CH CH271381A patent/CH628620A5/de not_active IP Right Cessation
- 1981-08-26 YU YU02064/81A patent/YU206481A/xx unknown
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