CA1337522C - Syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for the preparation thereof - Google Patents

Info

Publication number

CA1337522C

CA1337522C CA000272430A CA272430A CA1337522C CA 1337522 C CA1337522 C CA 1337522C CA 000272430 A CA000272430 A CA 000272430A CA 272430 A CA272430 A CA 272430A CA 1337522 C CA1337522 C CA 1337522C

Authority

CA

Canada

Prior art keywords

formula

group

amino

compound

methyl

Prior art date

1976-04-12

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

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• -1 3,7-disubstituted-3-cephem-4-carboxylic acid compounds Chemical class 0.000 title claims abstract description 494
• 238000000034 method Methods 0.000 title claims description 164
• 230000008569 process Effects 0.000 title claims description 144
• 238000002360 preparation method Methods 0.000 title claims description 55
• 150000001875 compounds Chemical class 0.000 claims abstract description 309
• 150000003839 salts Chemical class 0.000 claims abstract description 204
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 145
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 134
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 70
• 150000002367 halogens Chemical group 0.000 claims abstract description 69
• 125000004423 acyloxy group Chemical group 0.000 claims abstract description 65
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 58
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 50
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 50
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 37
• 239000001257 hydrogen Substances 0.000 claims abstract description 36
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 34
• 125000001424 substituent group Chemical group 0.000 claims abstract description 34
• 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 24
• 125000005042 acyloxymethyl group Chemical group 0.000 claims abstract description 21
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 21
• 125000001931 aliphatic group Chemical group 0.000 claims abstract description 20
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 19
• 125000004442 acylamino group Chemical group 0.000 claims abstract description 18
• 238000006243 chemical reaction Methods 0.000 claims description 132
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 121
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 99
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 78
• 239000002253 acid Substances 0.000 claims description 77
• 125000003342 alkenyl group Chemical group 0.000 claims description 48
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
• 125000006239 protecting group Chemical group 0.000 claims description 35
• 125000002252 acyl group Chemical group 0.000 claims description 31
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
• 238000003379 elimination reaction Methods 0.000 claims description 30
• 230000007062 hydrolysis Effects 0.000 claims description 29
• 238000006460 hydrolysis reaction Methods 0.000 claims description 29
• 239000003795 chemical substances by application Substances 0.000 claims description 28
• 239000002585 base Substances 0.000 claims description 26
• 125000004432 carbon atom Chemical group C* 0.000 claims description 26
• 125000003118 aryl group Chemical group 0.000 claims description 25
• 229910052783 alkali metal Inorganic materials 0.000 claims description 24
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 23
• 125000003277 amino group Chemical group 0.000 claims description 19
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 17
• 125000005110 aryl thio group Chemical group 0.000 claims description 17
• 125000004104 aryloxy group Chemical group 0.000 claims description 17
• 125000000623 heterocyclic group Chemical group 0.000 claims description 16
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 238000004519 manufacturing process Methods 0.000 claims description 13
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
• QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical group [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 claims description 11
• 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 9
• 125000001589 carboacyl group Chemical group 0.000 claims description 9
• 239000000460 chlorine Substances 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 150000001340 alkali metals Chemical class 0.000 claims description 8
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 8
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 230000007935 neutral effect Effects 0.000 claims description 8
• 125000001544 thienyl group Chemical group 0.000 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
• UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims description 5
• 150000001342 alkaline earth metals Chemical class 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
• PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
• 239000012948 isocyanate Substances 0.000 claims description 4
• 230000001590 oxidative effect Effects 0.000 claims description 4
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
• DDLWWOLZXHAVNY-PVQCJRHBSA-N (6R)-3-(carbamoyloxymethyl)-7-[[2-(3-hydroxyphenyl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)COC(N)=O)C(=O)O)C1=O)C1=CC(=CC=C1)O DDLWWOLZXHAVNY-PVQCJRHBSA-N 0.000 claims description 3
• QDDMXPSXDJRLNO-LESKNEHBSA-N (6R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)COC(N)=O)C(=O)O)C1=O)C=1N=C(SC=1)N QDDMXPSXDJRLNO-LESKNEHBSA-N 0.000 claims description 3
• DSBFHCFBFBNGPS-LRHAYUFXSA-N (6R)-7-[[2-(3-carbamoyloxyphenyl)-2-methoxyiminoacetyl]amino]-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC2=NN=NN2C)C(=O)O)C1=O)C1=CC(=CC=C1)OC(N)=O DSBFHCFBFBNGPS-LRHAYUFXSA-N 0.000 claims description 3
• NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 3
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 239000003456 ion exchange resin Substances 0.000 claims description 3
• 229920003303 ion-exchange polymer Polymers 0.000 claims description 3
• 150000002540 isothiocyanates Chemical class 0.000 claims description 3
• 125000001425 triazolyl group Chemical group 0.000 claims description 3
• HKFQKFMKQDZYJH-PVQCJRHBSA-N (6R)-3-(carbamoyloxymethyl)-7-[[2-(3-chloro-4-hydroxyphenyl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)COC(N)=O)C(=O)O)C1=O)C1=CC(=C(C=C1)O)Cl HKFQKFMKQDZYJH-PVQCJRHBSA-N 0.000 claims description 2
• LSSBHOQSJVWGJN-LESKNEHBSA-N (6R)-3-(carbamoyloxymethyl)-7-[[2-methoxyimino-2-[2-[(2,2,2-trifluoroacetyl)amino]-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)COC(N)=O)C(=O)O)C1=O)C=1N=C(SC=1)NC(C(F)(F)F)=O LSSBHOQSJVWGJN-LESKNEHBSA-N 0.000 claims description 2
• YSFVFWQKYKNZLS-LESKNEHBSA-N (6R)-3-formyl-7-[[2-methoxyimino-2-[2-[(2,2,2-trifluoroacetyl)amino]-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)C=O)C(=O)O)C1=O)C=1N=C(SC=1)NC(C(F)(F)F)=O YSFVFWQKYKNZLS-LESKNEHBSA-N 0.000 claims description 2
• HJJDBAOLQAWBMH-WCRCJTMVSA-N (6R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound NC=1SC=C(N=1)C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC2=NN=NN2C)C(=O)O)C1=O)=NOC HJJDBAOLQAWBMH-WCRCJTMVSA-N 0.000 claims description 2
• NZIYUPNWNHTHLH-WCRCJTMVSA-N (6R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC=2SC=NN=2)C(=O)O)C1=O)C=1N=C(SC=1)N NZIYUPNWNHTHLH-WCRCJTMVSA-N 0.000 claims description 2
• VIGCKDLYZDIDJJ-LRHAYUFXSA-N (6R)-7-[[2-(3-carbamoyloxyphenyl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC=2SC=NN=2)C(=O)O)C1=O)C1=CC(=CC=C1)OC(N)=O VIGCKDLYZDIDJJ-LRHAYUFXSA-N 0.000 claims description 2
• AGWWTUWTOBEQFE-UHFFFAOYSA-N 4-methyl-1h-1,2,4-triazole-5-thione Chemical compound CN1C=NN=C1S AGWWTUWTOBEQFE-UHFFFAOYSA-N 0.000 claims description 2
• 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 15
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 8
• 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims 7
• 229930186147 Cephalosporin Natural products 0.000 claims 5
• 229940124587 cephalosporin Drugs 0.000 claims 5
• 150000001780 cephalosporins Chemical class 0.000 claims 5
• 150000001242 acetic acid derivatives Chemical class 0.000 claims 4
• ILROLYQPRYHHFG-UHFFFAOYSA-N 1-$l^{1}-oxidanylprop-2-en-1-one Chemical group [O]C(=O)C=C ILROLYQPRYHHFG-UHFFFAOYSA-N 0.000 claims 3
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 3
• 150000002513 isocyanates Chemical class 0.000 claims 3
• 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims 3
• 125000001477 organic nitrogen group Chemical group 0.000 claims 3
• 238000010561 standard procedure Methods 0.000 claims 3
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 2
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
• 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims 2
• 150000003951 lactams Chemical class 0.000 claims 2
• XBIICAOWAWDGEI-LNUXAPHWSA-N (6R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino)acetyl]amino]-8-oxo-3-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C(=O)(O)CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC=2SC=NN=2)C(=O)O)C1=O)C=1N=C(SC=1)N XBIICAOWAWDGEI-LNUXAPHWSA-N 0.000 claims 1
• ILVAWHVUNZGZTN-LRHAYUFXSA-N (6R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-cyclopentyloxyiminoacetyl]amino]-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1(CCCC1)ON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC2=NN=NN2C)C(=O)O)C1=O)C=1N=C(SC=1)N ILVAWHVUNZGZTN-LRHAYUFXSA-N 0.000 claims 1
• FAPNNRBIDHHACF-PVQCJRHBSA-N (6R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-cyclopentyloxyiminoacetyl]amino]-8-oxo-3-(2H-tetrazol-5-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1(CCCC1)ON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC2=NN=NN2)C(=O)O)C1=O)C=1N=C(SC=1)N FAPNNRBIDHHACF-PVQCJRHBSA-N 0.000 claims 1
• 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 1
• 125000001309 chloro group Chemical group Cl* 0.000 claims 1
• 125000006627 ethoxycarbonylamino group Chemical group 0.000 claims 1
• 244000052616 bacterial pathogen Species 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 424
• 241000786363 Rhampholeon spectrum Species 0.000 description 407
• 239000000203 mixture Substances 0.000 description 247
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 176
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 168
• 239000000243 solution Substances 0.000 description 158
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 145
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 130
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 121
• 239000007864 aqueous solution Substances 0.000 description 117
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 105
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 96
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 96
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 86
• 239000002904 solvent Substances 0.000 description 86
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 85
• 229960000443 hydrochloric acid Drugs 0.000 description 82
• 235000011167 hydrochloric acid Nutrition 0.000 description 82
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
• 238000003756 stirring Methods 0.000 description 72
• 238000001816 cooling Methods 0.000 description 69
• 239000010410 layer Substances 0.000 description 64
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 55
• 239000011541 reaction mixture Substances 0.000 description 55
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 48
• 235000019341 magnesium sulphate Nutrition 0.000 description 48
• 230000002829 reductive effect Effects 0.000 description 48
• 239000000284 extract Substances 0.000 description 44
• 238000001914 filtration Methods 0.000 description 44
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 42
• 235000017557 sodium bicarbonate Nutrition 0.000 description 42
• 239000013078 crystal Substances 0.000 description 41
• 239000011780 sodium chloride Substances 0.000 description 37
• 239000000843 powder Substances 0.000 description 36
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
• 239000000706 filtrate Substances 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
• 235000011054 acetic acid Nutrition 0.000 description 29
• 229920006395 saturated elastomer Polymers 0.000 description 29
• 239000003921 oil Substances 0.000 description 28
• 239000000725 suspension Substances 0.000 description 28
• NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 28
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
• 239000007858 starting material Substances 0.000 description 25
• 239000002244 precipitate Substances 0.000 description 23
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 230000001376 precipitating effect Effects 0.000 description 20
• 150000002148 esters Chemical class 0.000 description 19
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
• 230000000875 corresponding effect Effects 0.000 description 17
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
• 238000004440 column chromatography Methods 0.000 description 15
• 239000002198 insoluble material Substances 0.000 description 15
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
• KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 14
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
• 238000007796 conventional method Methods 0.000 description 13
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
• 230000002411 adverse Effects 0.000 description 12
• 229910052799 carbon Inorganic materials 0.000 description 12
• YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
• 229910002027 silica gel Inorganic materials 0.000 description 12
• VGIJLQLDEHZKNU-UHFFFAOYSA-N 2-(3-hydroxyphenyl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CC=CC(O)=C1 VGIJLQLDEHZKNU-UHFFFAOYSA-N 0.000 description 11
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 11
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 11
• 241000699670 Mus sp. Species 0.000 description 11
• 150000001721 carbon Chemical group 0.000 description 11
• 239000011734 sodium Substances 0.000 description 11
• 229910052708 sodium Inorganic materials 0.000 description 11
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• BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
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• RTRCVCSWKHSZJC-LNUXAPHWSA-N (6R)-7-[[2-(2-formamido-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC=2SC=NN=2)C(=O)O)C1=O)C=1N=C(SC=1)NC=O RTRCVCSWKHSZJC-LNUXAPHWSA-N 0.000 description 4
• HGZZXAIQRPGHLO-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-2-oxoacetic acid Chemical compound OC(=O)C(=O)C1=CC=C(O)C(Cl)=C1 HGZZXAIQRPGHLO-UHFFFAOYSA-N 0.000 description 4
• NBDYDHVCTKPDRI-UHFFFAOYSA-N 2-(3-hydroxyphenyl)-2-oxoacetic acid Chemical compound OC(=O)C(=O)C1=CC=CC(O)=C1 NBDYDHVCTKPDRI-UHFFFAOYSA-N 0.000 description 4
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• JZWIECIMQZFZBA-UHFFFAOYSA-N ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate Chemical compound CCOC(=O)C(=NOC)C1=CSC(C)=N1 JZWIECIMQZFZBA-UHFFFAOYSA-N 0.000 description 4
• LULLGGWIEBUSRX-UHFFFAOYSA-N ethyl 4-bromo-2-methoxyimino-3-oxobutanoate Chemical compound CCOC(=O)C(=NOC)C(=O)CBr LULLGGWIEBUSRX-UHFFFAOYSA-N 0.000 description 4
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• DUPFUKBMWBUFJO-UHFFFAOYSA-N methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate Chemical compound CON=C(C(=O)OC)C1=CC=CC(OC)=C1 DUPFUKBMWBUFJO-UHFFFAOYSA-N 0.000 description 4
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• GRNOZCCBOFGDCL-UHFFFAOYSA-N 2,2,2-trichloroacetyl isocyanate Chemical compound ClC(Cl)(Cl)C(=O)N=C=O GRNOZCCBOFGDCL-UHFFFAOYSA-N 0.000 description 3
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
• LLKKDHSXDQIHKK-UHFFFAOYSA-N 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid Chemical compound CON=C(C(O)=O)C1=CSC(C)=N1 LLKKDHSXDQIHKK-UHFFFAOYSA-N 0.000 description 3
• SRXBNGGXTMGKLV-UHFFFAOYSA-N 2-methoxyimino-2-(3-methyl-2-methylsulfonylimino-1,3-thiazol-4-yl)acetic acid Chemical compound CON=C(C(O)=O)C1=CSC(=NS(C)(=O)=O)N1C SRXBNGGXTMGKLV-UHFFFAOYSA-N 0.000 description 3
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• HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
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• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
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• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
• 238000009835 boiling Methods 0.000 description 3
• 230000005587 bubbling Effects 0.000 description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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• HASOOENYFDJEAK-UHFFFAOYSA-N ethyl 2-methoxyimino-3-oxobutanoate Chemical compound CCOC(=O)C(C(C)=O)=NOC HASOOENYFDJEAK-UHFFFAOYSA-N 0.000 description 3
• RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
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• 239000011777 magnesium Substances 0.000 description 3
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• SPUACDWLOLSOQO-UHFFFAOYSA-M methoxyazanium;chloride Chemical compound [Cl-].CO[NH3+] SPUACDWLOLSOQO-UHFFFAOYSA-M 0.000 description 3
• UPUSOGVFGJXYSC-UHFFFAOYSA-N methyl 2-(3-hydroxyphenyl)-2-methoxyiminoacetate Chemical compound CON=C(C(=O)OC)C1=CC=CC(O)=C1 UPUSOGVFGJXYSC-UHFFFAOYSA-N 0.000 description 3
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• 230000036961 partial effect Effects 0.000 description 3
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• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
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• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
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• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 3
• 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
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• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
• FUJHOWWZSJQUCM-XCWJXAQQSA-N (6R)-7-[[2-(3-acetyloxyphenyl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)CSC=2SC=NN=2)C(=O)O)C1=O)C1=CC(=CC=C1)OC(C)=O FUJHOWWZSJQUCM-XCWJXAQQSA-N 0.000 description 2
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• RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
• QRPUJGHNWVVHLZ-GUNDQUCTSA-M sodium;(6r)-7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].S1CC(CO)=C(C([O-])=O)N2C(=O)C(N)[C@H]21 QRPUJGHNWVVHLZ-GUNDQUCTSA-M 0.000 description 1
• 239000007787 solid Substances 0.000 description 1
• 238000001179 sorption measurement Methods 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 125000004434 sulfur atom Chemical group 0.000 description 1
• DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 239000003826 tablet Substances 0.000 description 1
• 238000003419 tautomerization reaction Methods 0.000 description 1
• MXJGKTHZWIGRJG-UHFFFAOYSA-N tert-butyl 2-aminooxyacetate Chemical compound CC(C)(C)OC(=O)CON MXJGKTHZWIGRJG-UHFFFAOYSA-N 0.000 description 1
• CZJIOLXNSPBYNA-UHFFFAOYSA-N tert-butyl 2-aminooxypropanoate Chemical compound NOC(C)C(=O)OC(C)(C)C CZJIOLXNSPBYNA-UHFFFAOYSA-N 0.000 description 1
• CVAWKJKISIPBOD-UHFFFAOYSA-N tert-butyl 2-bromopropanoate Chemical compound CC(Br)C(=O)OC(C)(C)C CVAWKJKISIPBOD-UHFFFAOYSA-N 0.000 description 1
• IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
• 150000003536 tetrazoles Chemical class 0.000 description 1
• 125000001984 thiazolidinyl group Chemical group 0.000 description 1
• 125000000335 thiazolyl group Chemical group 0.000 description 1
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
• YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
• 125000005425 toluyl group Chemical group 0.000 description 1
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• 150000003852 triazoles Chemical class 0.000 description 1
• YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
• IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
• 239000001974 tryptic soy broth Substances 0.000 description 1
• 108010050327 trypticase-soy broth Proteins 0.000 description 1
• 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 230000003442 weekly effect Effects 0.000 description 1
• 238000005303 weighing Methods 0.000 description 1
• 238000009736 wetting Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 125000005023 xylyl group Chemical group 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1