GB2033390A - Process for the Preparation of 7-aminothiazolylacetamido- cephalosporanic Acid Derivatives - Google Patents
Process for the Preparation of 7-aminothiazolylacetamido- cephalosporanic Acid Derivatives Download PDFInfo
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- GB2033390A GB2033390A GB7935808A GB7935808A GB2033390A GB 2033390 A GB2033390 A GB 2033390A GB 7935808 A GB7935808 A GB 7935808A GB 7935808 A GB7935808 A GB 7935808A GB 2033390 A GB2033390 A GB 2033390A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 36
- -1 mesyl ion Chemical class 0.000 claims abstract description 213
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 239000002253 acid Substances 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 150000003254 radicals Chemical class 0.000 claims description 68
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims description 34
- 125000006239 protecting group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000004185 ester group Chemical group 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 8
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- 150000001340 alkali metals Chemical group 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000005544 phthalimido group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 229940126062 Compound A Drugs 0.000 claims description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical compound O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- DUAJIKVIRGATIW-UHFFFAOYSA-N trinitrogen(.) Chemical compound [N]=[N+]=[N-] DUAJIKVIRGATIW-UHFFFAOYSA-N 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- RYVZYACBVYKUHD-UHFFFAOYSA-N Alk5 Natural products CC#CC#CCCCCC=CC(=O)NCC(C)C RYVZYACBVYKUHD-UHFFFAOYSA-N 0.000 claims 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 abstract description 9
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract 3
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 150000004714 phosphonium salts Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 22
- 238000013019 agitation Methods 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- IHFZSFMOJYFAHV-VCHQGTEKSA-N (6R)-3-(acetyloxymethyl)-7-[[2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C(C)(=O)OCC=1CS[C@H]2N(C=1C(=O)O)C(C2NC(C(=NOC)C=1N=C(SC=1)NC(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)=O)=O IHFZSFMOJYFAHV-VCHQGTEKSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- PKPGSMOHYWOGJR-UHFFFAOYSA-N 2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid Chemical compound CON=C(C(O)=O)C1=CSC(NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 PKPGSMOHYWOGJR-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
- AGPORCHKBPLKKN-UHFFFAOYSA-M 4-methylbenzenesulfonate tris(dimethylamino)-[2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]oxyphosphanium Chemical compound S(=O)(=O)([O-])C1=CC=C(C)C=C1.C(C1=CC=CC=C1)(C1=CC=CC=C1)(C1=CC=CC=C1)NC=1SC=C(N1)C(C(=O)O[P+](N(C)C)(N(C)C)N(C)C)=NOC AGPORCHKBPLKKN-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 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
- 230000005587 bubbling Effects 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 2
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 2
- 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 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000004522 1,3,4-thiadiazol-5-yl group Chemical group S1C=NN=C1* 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229920005557 bromobutyl Polymers 0.000 description 1
- 125000005998 bromoethyl group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 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
- 125000006351 ethylthiomethyl group Chemical group [H]C([H])([H])C([H])([H])SC([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 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
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Syn 7-[2-(2-protected-amino-4- thiazolyl)-2-substituted-imino- acetamido]-ceph-3-em-4-carboxylic acid derivatives, which have pharmacological activity or may be used in the preparation of pharmacologically-active compounds, are prepared by reacting a syn 2-(2- protected-amino-4-thiazolyl)-2- substituted-imino-acetic acid or salt thereof with a compound of the general formula: <IMAGE> (wherein Y represents a tosyl or mesyl ion and Z represents a halogen ion, Y and Z each represent a tosyl ion, or Y and Z each represent a mesyl ion) and optionally treating the product with a base, so as to obtain the corresponding syn 2-(2-protected- amino-4-thiazolyl)-2-substituted- iminoacetoxy-tris(dimethylamino)- phosphonium salts, which salt is thereafter treated, optionally in the presence of a base, with an optionally 3/4 substituted 7-amino- cephalosporanic acid, or S-oxo or S,S- dioxo derivative, or a salt or ester thereof, and then treated with an acid. The acylation of the phosphonium salt is preferably carried out in an organic solvent below 0 DEG C, or in an aqueous solvent at ambient temperature.
Description
SPECIFICATION
Process for the Preparation of 7-aminothiazolyl-acetamido-cephalosporanic Acid Derivatives
This invention concerns a new process for the preparation of 7-aminothiazolyl-acetamidocephalosporanic acid derivatives.
This invention provides a process for the preparation of syn isomer compounds of the general formula:
(wherein R represents a protecting group for the amino radical; n, is 0, 1 or 2; R1 represents:
a) a protecting group for the hydroxy group;
b) a saturated or unsaturated, aliphatic hydrocarbyl radical having from 1 to 4 carbon atoms;
c) a radical
in which R' and R", which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms, and R5 represents:
i) a Co2Re radical in which R8 represents an alkyl radical having from 1 to 3 carbon atoms or a
removable ester group,
ii) a nitrile group, or
iii) a carbamoyl radical;
d) a radical -C(=X)-R7 in which X represents a sulphur or oxygen atom and R, represents::
i) an alkyl or alkoxy radical having from 1 to 4 carbon atoms,
ii) a phenyl radical, or
iii) a radical (CH2)nNR8R9 in which n is O or an integer from 1 to 4 and R8 and R9, which may
be the same or different, each represent a protecting group for the amino group, a hydrogen
atom, or an alkyl radical having from 1 to 4 carbon atoms, or R8 and R9, together with the
intervening nitrogen atom, represent a piperidino, morpholino or phthalimido group, with the
proviso that R8 and R9 do not both represent an atom of hydrogen;
e) a radical
in which A' represents a removable ester group, R10 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms and R" represents a phenyl or nitril radical,
f) a v-lactone of the formula::
g) a radical(CH2)n,R,2 in which n' is an integer from 1 to 4 and R,2 represents: i) an alkoxy or
radical having from 1 to 4 carbon atoms, n's being 0, 1 or 2,
ii) a radicalNR,3R,4 in which R13 and Rid, which may be the same or different, each represent a
hydrogen atom, a protecting group for the amino radical, or an alkyl radicalkavinflfrom 1 to
4 carbon atoms, with the proviso that R,3 and R,4 do not both represent a hydrogen atom, or
R,3 and Rid, together with the intervening nitrogen atom, represent a phthalimido or 1
pyridinyl group,
iii) when n' is other than 1, a nitrile radical,
iv) a radical -C(=X')-NH2 in which X' represents a sulphur atom or, when n' is other than 1, an
oxygen atom,
v) a 4-methyl- or 4-amino-1 ,3-thiazol-2-yl radical,
vi) a 1 ,2,3,4-tetrazol-5-yl radical,
vii) an azido radical,
viii) an acyl radical having from 2 to 4 carbon atoms,
ix) a halogen atom,
x) a radical --SS-R,, in which R15 represents a phenyl radical or a 5- or 6-membered, heterocylic
aromatic ring comprising from 1 to 4 heteroatoms selected from sulphur, nitrogen and
oxygen atoms, which phenyl or heterocyclic ring may optionally be substituted by one or
more radicals selected from nitrile, amino, nitro and alkyl radicals having from 1 to 4 atoms
of carbon;
R2 represents a hydrogen atom or a removable ester group; and either R3 represents a hydrogen atom and R4 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R4 represents a hydrogen atom and R3 represents:
a) a chloro or methoxy radical;
b) an alkyl, cycloalkyl or alkyithio radical having at most 5 carbon atoms;
c) a radical -CH2-S-R16 in which R16 represents an optionally-substituted nitrogen-containing heterocyclic radical, an acyl radical having from 2 to 4 carbon atoms, a 2-oxo(3H)-thiazolin-4-ylcarbonyl radical or a 3-methyl-i ,2-oxazol-5-yl-carbonyl radical;
d) an acetoxymethyl or a carbamoyloxymethyl radical;
e) a radical -NH-C0-Alk8 in which Alka is an alkyl radical having from 1 to 4 carbon atoms; or
f) [when R, represents either a protecting group for the hydroxy radical, a saturated or unsaturated aliphatic hydrocarbyl radical having 1 to 4 carbon atoms, a radical (CH2)nR11 in which Ra1 represents i) a radical --CO,R,, in which Rea represents a removable ester, ii) a radical -NHR131 in which R138 represents a protecting group for the amino radical, or iii) a benzoyl radical] R3 represents an azidomethyl radical, with the proviso that R1 does not represent a protecting group for the hydroxy radical, a saturated or unsaturated, aliphatic hydrocarbyl radical having from 1 to 4 carbon atoms or a radical CR'R"R5 when R3 represents a radical -cH2-S-R16 in which R1e represents a 2-oxo(3H)thiazolin-4-yl-carbonyl radical or a 3-methyl- 1 ,2-oxazol-2-yl-carbonyl radical) in which process a syn isomer compound of the general formula:
is treated, optionally in the presence of a base, with a compound of the general formula:
(wherein R'2 represents R2, an alkali metal atom or a substituted ammonium group) and then with an acid to yield a product of general formula 1.
The compound of general formula Ill may itself be prepared by reacting a syn isomer compound of the general formula:
(wherein Ad represents a hydrogen atom, alkali-metal atom or a substituted ammonium group) with a compound of the general formula:
(wherein Y represents a tosyl or mesyl ion and Z represents a halide ion, orY and Z each represent a tosyl ion, or Y and Z each represents a mesyl ion) and optionally treating the product with a base, so as to obtain a product of general formula Ill.
The general formulae and their substituents referred to hereinafter are as first defined, unless otherwise indicated.
R represents a protecting group for the amino group and may be an alkyl radical having from 1 to 6 carbon atoms, and preferred alkyl radicals are the t-butyl or t-amyl radicals.
R may also represent an aliphatic acyl group, an aromatic or heterocyclic acyl group or a carbamoyl group. Suitable aliphatic alkyl groups include lower alkanoyl groups such as the formyl, acetyl, propionyl, butynyl, isobutynyl, valeryl, isovaleryl, oxalyi, succinyl and pivaloyl radicals, and alkoxy- or cycloalkoxy-carbonyl groups such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 -cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, t-pentoxycarbonyl and hexyloxycarbonyl radicals. Aromatic acyl groups include the benzoyl, toluyl, naphthoyl, phthaloyl, mesyl, phenyl-acetyl and phenylpropionyl radicals and arylalkoxycarbonyl groups such as the benzyloxycarbonyl radical.
These acyl groups may be substituted, for example by an atom of chlorine, bromine, iodine or fluorine, and examples of substituted acyl groups are the chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl and bromoacetyl radicals.
The substituent R may represent a lower aralkyl group such as a benzyl, 4-methoxybenzyl, phenylethyl, trityl, 3,4-dimethoxybenzyl or benzhydryl radical, or a haloalkyl group such as a trichloroethyl radical.
Further examples of protecting groups which may be represented by substituent R are the chlorobenzoyl, p-nitrobenzoyl, p-(t-butyl)-benzoyl, phenoxyacetyl, caprylyl, n-decanoyl, acryloyl and trichloroethoxycarbonyl groups, as well as the methylcarbamoyl, phenylcarbamoyl and naphthylca rba moyl groups, and the corresponding thiocarbamoyls.
The above list is not intended to be exhaustive and other amine protecting groups will be obvious to one skilled in the art. In particular, other protecting groups known as being useful in the chemistry of the peptides, may equally be used.
When R, represents a protecting group for the hydroxy radical, this may be chosen from known hydroxy-protecting groups, and examples include acyl groups such as the formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoyl formyl and p-nitrobenzoyl radicals.Further protecting groups which may be used are the ethoxyca rbonyl, methoxcarbonyl, propoxycarbonyl, p -trichloroethoxycarbonyl, benzyloxycarbonyl, tbutoxycarbonyl, 1 -cyclopropylethoxyca rbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl, benzyl, 4-methoxybenzyl, benzhydryl, trichloroethyl, 1 -methyl-1 - methoxyethyl and phthaloyl radicals, as well as other acyl groups such as the propionyl, butyryl, isobutyryl, a valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, p-nitrobenzoyl, p-(t-butyl)-benzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylacarbamoyl and naphthylcarbamoyl radicals.
When R1 represents a hydrocarbyl radical, this may be, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, vinyl, allyl, propargyl, ethynyl or butenyl radical.
When R1 represents a radical --CR'R"R,, the substituents R' and R" may be for example, methyl, ethyl, propyl or isopropyl radicals. When R5 represents a -C02fl6 radical, R, may be an alkyl radical such as methyl, ethyl, propyl or isopropyl, but it is preferably a removable ester group. Such removable ester groups are well-known, being groups which form an ester by replacing the hydrogen atom or a carboxy group and which are readily cleaved to free the acid group. Examples of such removable ester groups include alkyl radicals such as the butyl, isobutyl, butyl, pentyl and hexyl radicals.In addition Re may represent an acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-mesylethyl, 2-iodoethyl, ,9-trichloroethyl, vinyl, allyl, ethynyl, propynyl, benzyl, 4-methoxy-benzyl, 4-nitrobenzyl, phenylethyl, trityl, diphenylmethyl, 3 ,4-dimethoxybenzyl, phenyl, 4-chlorophenyl, tolyl or tertiary-butylphenyl esterforming group.
When R1 represents a --CXX-R, radical, this may be, for example, an acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or t-valeryl radical, as well as the corresponding sulphur derivatives of these radicals such as a thioacetyl radical. Further, R1 may represent a benzoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tbutoxycarbonyl radical, as well as the corresponding sulphur derivatives of these radicals such as a methoxythiocarbonyl radical.Additional examples of R1 (when this represents a radical X-R7 and R7 is a radical (CH2)nNR5Rg) include the N-methylcarbamoyl, N,N-dimethylcarbamoyl, dimethylaminoacetyl, methylaminopropionyl, dimethylaminopropionyl, aminovaleryl, dimethylaminovaleryl, N-piperidinocarbonyl, N-piperidinoacetyl, N-piperidinopropionyl, N phthalimidocarbonyl, N-phthalimidoacetyl and N-phthalimidopropionyl radicals.
When R8 or fig represents a protecting group for the amino group, this group can be chosen from among those set out hereinbefore for R.
When R1 represents a -CR10fl11-C02A' radical, A' preferably is a removable ester group as listed hereinbefore in relation to Re. Rio preferably is a saturated alkyl group such as exemplified previously in relation to R1.
Among possible groups represented by R1 as a(CH2)n,R12 radical, the following are worthy of particular mention: methoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, methylthiomethyl, methylthioethyl, ethylthiomethyl and ethylthioethyl radicals, as well as the oxidised forms of these sulphur-containing radicals such as methylsulphinylmethyl and methylsuiphonylmethyl radicals.
Further examples of(CH2)n,R12 radicals include: protected aminoethyl radicals, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, phthalimidomethyl, phthalimidoethyl, phenylimidopropyl;; N-pyridinylmethyl, N-pyridinyiethyl, N-pyridinylpropyl, carbamoylmethyl, thiocarbamoylmethyl, carbamoylethyl, carbamoyipropyl, thiocarbamoylethyl, 4-amihothiazol-2-yl-methyl, 4-methylthiazol-2-yl-methyl, 1 ,2,3,4,-tetrazol-5-yl-methyl, 1,2,3,4tetrazol-5-yl-ethyl, acetylmethyi, acetylethyl, propionylmethyl, propionylethyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, chioromethyl, chloroethyl, chloropropyl and chlorobutyl radicals, as well as the branched halogenated derivatives corresponding to the halogenopropyl or halogeno-butyl radicals.
When R,2 represents a radical the the substituent flis may be, for example, a phenyl radical or a 1,2,3-, or 1,2,5-, 1,2,4 or 1 3,4-thiadiazolyl radical, 1-H-tetrazolyl or 1 ,3-thiazolyl radical, a 1,2,3-, 1,2,4- or 1 ,3,4-triazolyl radical, a 1,2,3-, 1,2,4-, 1,2,5- or 1 3,4-oxadazolyl radical, these radicals being optionally substituted by one or more substitutents chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, nitro and amino radicals.
When R2 represents a removable ester group this is preferably one of those cleavable esterforming groups described hereinbefore in relation to substituent Re.
Preferred removable ester groups R2 are those listed hereinbefore in relation to R.
When Rs represents a group CH2SRie, the substituent R1e may, for example, be one of those nitrogen-containing heterocyclic radicals listed hereinbefore in relation to R16, which heterocycles may be substituted by an alkoxy radical having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy. R16 may alternatively represent an acyl group such as an acetyl, propionyl or butyryl radical.
Preferred substituents R16 include the acetyl, 1-methyltetrazolyl, 2methyl1 ,3,4-thiadiazolyl, 3methyl- 1 ,2,4-thiadiazolyl-5-yl, 3-methoxy-1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazol-5-yl, 2-amino- 1 3,4thiadiazol-5-yl, 3-hydroxycarbonylmethyl- 1 ,2,4-thiadiazol-5-yl, 5-methoxy- 1 ,2,4-thiadiazol-3-yl, 4methyl-5-hydroxycarbonyl methyl- 1 ,3-thiazol-2-yl and 1 -dimethylaminoethyl- 1 ,2,3,4-tetrazol-5-yl radicals.
When Z represents a halogen ion this may be a chlorine, bromine, iodine or fluorine ion, and the chlorine ion is preferred.
Ad can represent a hydrogen atom or an alkali metal atom such as a sodium or potassium atom.
Ad can also represent a substituted ammonium group--that is, a salt-forming cation derived from an organic amine base, and preferably from a trialkylamine such as triethylamine. Nevertheless Ad represents preferably a hydrogen atom, and in that case the reaction of the compound A with the compound ll is followed by treatment with a base such as triethylamine or another trialkylamine. When for example Ad represents a substituted ammonium group, this addition of base is not necessary.
R'2 preferably is a group as described hereinbefore for substituent R2 or Ad.
In a preferred aspect the invention provides a process for the preparation of compounds of the general formula:
(wherein R1a represents:
a) a protecting group for the hydroxy radical,
b) a saturated or unsaturated, aliphatic hydrocarbyl radical having from 1 to 4 carbon atoms,
c) a radical--CH2--CO2R8a in which R6a represents a removable ester group, or
d) a radical (CH2)naNR in which n'a is an integer from 1 to 4, one of R13a and R14a represents a hydrogen atom, and the other of R13a and R14a represents a protecting group for the amino radical; R3a represents:: a) a methyl radical,
b) an acetoxymethyl or a carbamoyloxymethyl radical,
c) a radical -CH2-S-R15 in which R1 > represents an acetyl radical, a 1-methyltetrazolyl or a 2 methyl ,3,4-thiadiazol-5-yl radical, or
d) an azidomethyl radical; and n'5 is O or 1) in which process a compound of the general formula:
is treated with a compound of general formula A and then with a base to obtain a product of the general formula:
which product of general formula 111a is treated, in the presence of a base, with a compound of the general formula:
and thereafter with an acid to form the desired product of general formula I In another preferred aspect the invention provides a process for the preparation of compounds of the general formula::
(wherein R1b represents a protecting group for the hydroxy radical, a methyl radical or a radical --CH2--CO2--R6a and R3b represents an acetoxymethyl, 1 -methyltetrazol-5-yl-thiomethyl or a 2-methyl1 ,3,4-thiadiazol-5-yl-thiomethyl radical) in which process a compound of the general formula llb:
is treated by a product according to the formula:
(wherein Yb represents a tosyl ion and Zb represents a tosyl or a chloride ion) and thereafter by a base to obtain a product of the general formula:
which product of general formula 111b is treated, in the presence of a base, with a compound of general formula IVb::
and thereafter with an acid to form the desired product or general formula lb.
In a further particularly preferred aspect the invention provides a process for the preparation of compounds of the general formula:
in which a compound of the general formula:
is treated with a compound of the general formula A, and thereafter by a base to obtain a compound of the general formula:
which product of general formula Illc is treated, in the presence of a base, with the compound of formula:
and thereafter with an acid to form the desired product of general formula ic.
The invention is concerned in particular with the preparation of products of general formulae I, lat 1t, and lc, in which R is a protecting group chosen from the formyl, acetyl, ethoxycarbonyl, tpentoxycarbonyl, t-butoxycarbonyl, chloroacetyl, trifluoroacetyl, trityl and trichloroethoxycarbonyl radicals, as well as the preparation of the products of general formulae 1, a and It, in which I R1, Ia or R,b is a protecting group chosen from the formyl, tetrahydropyranyl, trityl, 1 -methyl-1 -methoxyethyl, acetyl and chloroacetyl radicals.
In the process of the invention reaction of compound Ill with compound IV is preferably carried out in the presence of a base. This may be an organic base such as triethylamine, tributylamine, Nmethyl-morpholine, pyridine or a picoline, or an inorganic base such as a carbonate or bicarbonate of sodium or potassium.
The preferred bases are triethylamine, N-methyl-morpholine, pyridine and sodium and potassium carbonate and bicarbonate, with triethylamine and sodium bicarbonate being especially preferred.
The acid used to isolate the product of general formula I (and thus lat It, or lc) is preferably an organic carboxylic acid such as acetic, formic or trifluoroacetic acid or a mineral acid such as hydrochloric or dilute sulphuric acids. Acetic or hydrochloric acid is highly preferred.
The reaction of compound Ill with compound IV has been found to be significantly influenced by the temperature and the nature of the solvent utilised. It has been discovered that when carried out in an organic solvent, and preferably then in one or more of acetone, methylene chloride, N,Ndimethylformamide and tetrahydrofuran, the reaction temperature is very preferably below OOC, and most preferably well below that temperature in the region of from -900C to -400C.
By contrast, when the reaction is conducted in an aqueous solvent, the reaction can be conducted at ambient temperature-that is to say, at about 200C. By aqueous solvent is meant either water or a mixture of water with a miscible solvent such as acetone, hexamethylphosphorotriamide or dimethylformamide.
The reaction of the compound of general formula A with the compound of general formula II (and thus, A with lla, A, with lit, and A, with llc) is advantageously carried out in an organic solvent, such as acetone, methylene chloride, N,N-dimethylformamide or tetrahydrofuran, or in a mixture of these solvents. Other solvents may be used, such as dioxan, acetonitrile, chloroform, dichloroethane or ethyl acetate. The reaction can equally take place in an excess of hexamethylphosphorotriamide.
This reaction to form the compound Ill is preferably carried out at a temperature of from OOC to +200C.
The starting materials of general formula II wherein R1 represents a protecting group for the hydroxy radical or a saturated or unsaturated aliphatic hydrocarbyl radical can be prepared according to the process described in Belgian Patent 850,662.
The other compounds of general formula II may be prepared by reacting a syn isomer compound of the general formula:
either with a compound of the general formula
in which Hal represents a halogen atom;
or with a functional derivative, such as an acid halide or acid anhydride, of the acid of the general formula HO--CXX-R', in which R'7 represents an alkyl, alkoxy or phenyl radical, or a radical -(CH2)-NR8R9; or with a compound of the general formula
in which Y represents a halogen, a sulphate or a sulphonate group;
or with a compound of the general formula:
or with a compound of the general formula Y(CH2)n,R',2 in which R',2 represents a halogen atom or an acyl, alkylthio or alkoxy radical.
The compounds of the general formula:
which may be obtained by reacting a compound of the general formula Hal(CH2)ni-1al with a compound of general formula K, may then be converted into corresponding compounds of general formula II by treatment with pyridine, an alkali metal azide, an amine of the general formula NHR,3R,4, or a mercaptan of the general formula HS-R15.
The compound of general formula K may also be reacted with a compound of the general formula Y(CH2)nCN to obtain a product of the general formula:
which product may thereafter be converted, by conventional methods, into products of general formula
II in which R12 represents a radical -CX-NH2. This latter product may in turn be converted into products in which R12 represents a 4-methyl- or 4-amino-1 ,3-thiazol-2-yl radical, by reaction with a compound of the general formula:
in which R'7 is methyl or amino and Hal is a halogen.
The product M may also be treated with an azide to prepare the products of general formula II in which R12 is a 1,2,3,4-tetrazol-5-yl radical.
The starting materials of general formula A may be prepared according to the method described in JACS 91, 20 (1 969); examples of such preparations are set out hereinafter.
Compounds of general formula Ill in which R4 represents a hydrogen atom and R3 represents a chloro, methoxy, alkyl, cycloalkyl, alkylthio, acetoxymethyl, carbamoyloxymethyl or NH-CO-Alk radical are known in the literature or can easily be prepared according to the methods analogous to those given in the literature.
Similarly compounds of general formula Ill in which R3 represents CH2SRie can easily be prepared by a nucleophilic exchange reaction starting with 7-amino-cephalosporanic acid by means well known in the art.
Compounds of general formula Ill in which R3 represents a hydrogen atom and R4 represents an alkyl radical can be prepared according to the process of German Patent No. 2,412,51 3, while compounds in which R3 and R4 each represent a hydrogen atom are described in the published German
Patent Application No, 2,151,567, and compounds in which ns is other than 0 can be prepared according to the process described in published Dutch Application No. 73-09918.
The products of general formula I have useful pharmacological activity or may be used as intermediates in the preparation of pharmacologically-active compounds.
The following Examples are now given, though only by way of illustration, to show certain aspects of the invention in more detail.
Example 1: 3-acetoxymethyl-7-[2(2-trityla mino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-em-4 carboxylic acid, syn isomer.
Stage A: 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetoxy-tris (dimethylamino)phosphonium tosylate, syn isomer.
34 g of 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetic acid were added to 120 cm3 of methylene chloride under nitrogen. 30 cm3 of methylene chloride were distilled off at ordinary pressure. The mixture was cooled to about OOC and to the suspension obtained there was added, over 5 minutes, a solution prepared by agitating 64.6 g hexamethylphosphorotriamide in 12.9 g of tosyl chloride for about 1 5 minutes at 150--200C. The orange-coloured solution obtained was agitated under nitrogen at about OOC for a further thirty minutes.
Then, under agitation and in an atmosphere of nitrogen at OOC, 12.6 cm3 of triethylamine were introduced during five minutes. Agitation under nitrogen was continued at OOC for a further thirty minutes.
Stage B: 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamidoj-ceph3 em-4-carboxylic acid, syn isomer:
The solution from Stage A was cooled to about -700C and, under nitrogen and while agitating, over a period of about fifteen minutes there was added the following solution, prepared extemporaneously under nitrogen at OOC from:
12.27 g of 7-aminocephalosporanic acid 1 85 cm3 of methylene chloride
19 cm3 of triethylamine.
After the introduction of the solution the mixture was agitated for a further hour at 700 C. Then all at once 20 cm3 of pure acetic acid were added and the temperature was allowed to rise. The formed mixture was agitated under nitrogen and the internal temperature was raised to OOC. Then the reaction mixture was poured into 500 cm3 of demineralised water, agitated and separated. The aqueous phase was re-extracted with 100 cm3 of methylene chloride. All of the chloromethylenic phases were washed four times with 250 cm3 of demineralised water. The organic phase was then concentrated to dryness at reduced pressure in a bath at 200 to 250C.
The dry extract, in the form of a resin, was taken up with 500 cm3 of demineralised water, and agitated at about 200C until the resin was transformed into a crystalline suspension. After agitation for a further thirty minutes at about 200C, the liquid was separated off. The product was washed five times with 100 cm3 of demineralised water, then dried under reduced pressure at about 300C to yield a crude product, containing from 2 to 4% of water.
Example 2: 3-acetoxy-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-em-4-carboxylic acid, syn isomer.
Stage A: 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetoxy-tris(dimethylamino)phosphonium tosylate, syn isomer.
Under nitrogen, 42.1 g of 2-(2-tritylamino-4-thiazolyí)-2-methoxyimino-acetic acid were added to 100 cm3 of pure acetone and 1 8 cm3 of dimethylformamide. The formed suspension was taken to 00j20C while being agitated under pressure of nitrogen, and during fifteen minutes at 00+20C a solution of 76.7 cm3 of hexamethylphosphorotriamide and 1 5.75 g of tosyl chloride was added. Then during fifteen minutes at 00+20C, 1 5.3 cm3 of triethylamine were added, and the mixture was agitated for thirty minutes at 00+20C under nitrogen.
Stage B: 3-acetoxymethyl-7-[2-(2-tritylaminoA-thiazolyl)-2-methoxyimino-acetamidoj-ceph-3- em-4-carboxylic acid, syn isomer.
The solution from Stage A was cooled to a temperature of -700C and during fifteen minutes 55.5 cm3 of dimethylformamide, 1 5 g of 7-aminocephalosporanic acid and 23 cm3 of triethylamine were introduced. The mixture was agitated for one hour at -700+20C under nitrogen, then still at -700+20C, 24 cm3 of acetic acid were added and the agitation was continued for fifteen minutes at -700+20C. 30 cm3 of demineralised water were then added and the temperature was raised to from --120 to -1 50C. Precipitation was brought about in 1800 cm3 of demineralised water containing 360 g of sodium chloride. After agitation for thirty minutes at 200C, the precipitate was separated from the liquid, washed with water and dried under vacuum to obtain the required product.
Example 3: 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-em-4- carboxylic acid, syn isomer.
Stage A: 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetoxy- tris(dimethylamino)phosphonium tosylate, syn isomer.
Under nitrogen pressure 25.8 g of tosyl chloride were added to 126 cm3 of hexamethylphosphorotriamide and the mixture was agitated for thirty minutes at 180--200C, then taken to 00+20C. 61 cm3 of dimethylformamide and 69 g of 2-(2-tritylamino-4-thiazolyl)-2methoxyimino-acetic acid were added, and after agitation for fifteen minutes at 00+20C, 25.2 cm3 of triethylamine were added over 10 minutes at 00+20C to the formed solution. The mixture was agitated for thirty minutes at 00+20C under nitrogen.
Stage B: 3-acetoxymethyl-7-[2-(2-'trityle mino-4-thiazolyl)-2-methoxyimino-acetamidojceph-3- em-4-carboxylic acid, syn isomer.
The solution obtained in Stage A was introduced under agitation, at from --650 to -700C, into a mixture made up of 86 cm3 of dimethylformamide, 24.6 g of 7-aminocephalosporanic acid and 38 cm3 of triethylamine. After agitation for two hours at 650 to -700C under nitrogen pressure, and at the same temperature, 40 cm3 of acetic acid were added. The mixture was agitated for fifteen minutes then at -650C, 50 cm3 of demineralised water were added. The temperature was raised to from -120 to -1 50C and a precipitate induced in a mixture made up of 1.9 l of demineralised water and 390 g of sodium chloride.After agitation for 30 minutes at 200 C, the precipitate was separated from the liquid and washed with demineralised water to obtain 383 g of a damp product. This product was crushed into 664 cm3 of water containing 30% of acetone and left for one night at 200 C. The solid material was again separated from the liquid, washed with demineralised water and dried under vacuum at 200C in the presence of potassium hydroxide to obtain the required product.
Example 4: 3-acetoxymethyl-7-[2-(2-trityla mino-4-thiazolyl )-2-methoxyimino-acetamido]-ceph-3-em-4carboxylic acid, syn isomer.
Stage A: 2-(2-tritylam ino-4-thiazolyl )-2-methoxyimino-acetoxy-tris(dimethylamino)- phosphonium tosylate, syn isomer.
At 200+20C, 640 cm3 of anhydrous hexamethylphosphorotriamide were mixed with 77 g of tosyl chloride, then maintained under nitrogen at 180--200C for thirty minutes while being agitated.
With the temperature still at 180 to 200 C, 206 g of 87% pure 2-(2-tritylamino-4-thiazolyl)-2methoxyimino-acetic acid were sprinkled into the mixture. A solution was obtained which was maintained for ten minutes under agitation and under nitrogen at 180--200C. Then during fifteen minutes, and while maintaining at 1 80--200C, 56.2 cm3 of triethylamine were added and the formed solution was left for thirty minutes under agitation and under nitrogen at 180--200C.
Stage B: 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3- em-4-carboxylic acid, syn isomer.
A solution was prepared extemporaneously by cooling 1,000 cm3 of methylene chloride to from --150 to -1 00C and introducing 100 g of 7-aminocephalosporanic acid. While maintaining this at the same temperature, 1 53 cm3 of triethylamine were added. After complete dissolution, the solution was cooled to 700 to 720C, and over thirty to forty minutes the solution prepared in Stage A was poured into the foregoing solution containing 7-amino-cephalosporanic acid, while the temperature was maintained at -700+20C. The mixture was maintained for one hour at this temperature with agitation and under nitrogen, and still at that temperature, 100 cm3 of acetic acid were added and the mixture agitated for fifteen minutes.Then while the temperature was allowed to rise to about -600C, 200 cm3 of demineralised water were introduced. Following agitation for fifteen minutes under nitrogen, the mixture was taken to from --200 to -1 50C, poured into 4,000 cm3 of demineralised water maintained at from 180 to 200C, separated and extracted with 200 cm3 of methylene chloride, then washed with water. The methylene chloride was evaporated under vacuum and the required product was obtained.
Example 5: 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-em-4- carboxylic acid, syn isomer.
Carbon dioxide was bubbled for five minutes into 1,000 cm3 of demineralised water at 200+20C, and 61.7 g of sodium bicarbonate were added. After complete dissolution, the bubbling of carbon dioxide was maintained for five minutes at 200+20C, then 100 g of 7-aminocephalosporanic acid was sprinkled into the solution. The formed mixture was maintained for about fifteen minutes under agitation and with continued bubbling of carbon dioxide at 200+20C, until complete dissolution was obtained, then immediately, over thirty to thirty five minutes at 200+20C and after having halted the introduction of carbon dioxide, the activated ester solution prepared in Stage A of Example 4 was added.After agitation at 200+20C for sixteen hours the suspension was poured into an agitated solution of 4,000 cm3 of distilled water and 1 ,200 g of sodium chloride. A suspension was thus obtained which was maintained for thirty minutes under agitation at 200+20C, then adjusted to pH 2 by the addition of 70 cm3 of hydrochloric acid diluted to half strength with water. The precipitate was separated from the liquid immediately, and washed by crushing five times in 300 cm3 of demineralised water.
The product obtained was introduced into a mixture of 1,200 cm3 of demineralised water and 400 cm3 of ethanol and agitated for sixteen hours at 200+20C. The product was then washed by crushing first in 400 cm3 of water with 20% of ethanol, then three times in 400 cm3 of demineralised water, and finally dried to yield 276 g of crude product containing 2.7% of water. This product was purified; the 276 g of product were sprinkled at from 1 80 to 200C into 512 cm3 of pure acetone, then re-crystallised after partial distillation. The solid matter was left for five hours under agitation at 180--200C, separated from the liquid, crushed twice in 256 cm3 of acetone and dried at 250 to 300C under vacuum to obtain the required product.
Example 6: 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxvimino-acetamido]-ceph-3-em-4- carboxylic acid, syn isomer.
Stage A: 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetoxy tris(dimethylamino)phosphoniumtosylate. syn isomer.
228 g of tosyl chloride were introduced, at 200+20C and during two to three minutes, into 1,600 cm3 of anhydrous hexamethyl phosphorotriamide. The formed solution was cooled to from 0 to +20C under nitrogen and, still maintained at this temperature, 595 g of 89% pure 2-(2-tritylamino-4thiazolyl)-2-methoxyimino-acetic acid were sprinkled into the solution which was agitated at 0 to +20C until complete dissolution was obtained. Over twenty to twenty five minutes and at OOC, 165 cm3 of triethylamine were added. The solution obtained was maintained under agitation and under nitrogen at this temperature.
Stage B: 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3- em-4-carboxylic acid, syn isomer.
This Stage was carried out in the manner described in Stage B of Example 4, starting with a solution of 250 g of 7-aminocephalosporanic acid in 2,500 cm3 of methylene chloride.
Claims (17)
1. A process for the preparation of syn isomer compounds of the general formula:
(wherein R represents a protecting group for the amino radical; na is 0, 1 or 2: R, represents:
a) a protecting group for the hydroxy group;
b) a saturated or unsaturated, aliphatic hydrocarbyl radical having from 1 to 4 carbon atoms;
c) a radical
in which R' and R't, which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms, and R5 represents::
i) a CO2R6 radical in which R6 represents an alkyl radical having from 1 to 3 carbon atoms or a
removable ester group,
ii) a nitrile group, or
iii) a carbamoyl radical;
d) a radical -C(=X)-fi7 in which X represents a sulphur or oxygen atom and R7 represents::
i) an alkyl or alkoxy radical having from 1 to 4 carbon atoms,
ii) a phenyl radical, or
iii) a radical (CH2)NRgRg in which n is O or an integer from 1 to 4 and R8 and R9, which may
be the same or different, each represent a protecting group for the amino group, a hydrogen
atom, or an alkyl radical having from 1 to 4 carbon atoms, or R8 and fig, together with the
intervening nitrogen atom, represent a piperidino, morpholino or phthalimido group, with the
proviso that Re and fig do not both represent an atom of hydrogen;;
e) a radical
in which A' represents a removable ester group, R10 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms and fill represents a phenyl or nitril radical,
f) a y-lactone of the formula:
g) a radical(CH2)n,R12 in which n' is an integer from 1 to 4 and R12 represents: i) an alkoxy or
radical having from 1 to 4 carbon atoms, n'5 being 0, 1 or 2,
ii) a radical-- NR13R14 in which R,3 and R,4, which may be the same or different, each represent a
hydrogen atom, a protecting group for the amino radical, or an alkyl radical having from 1 to
4 carbon atoms, or R,3 and R,4, together with the intervening nitrogen atom, represent a
phthalimido or 1 -pyridinyl group, with the proviso that R,3 and Rr4 do not both represent a
hydrogen atom,
iii) when n' is other than 1, a nitrile radical,
iv) a radical -C(=X')-NH2 in which X' represents a sulphur atom or, when n' is other than 1, an
oxygen atom,
v) a 4-methyl- or 4-amino-1 ,3-thiazol-2-yl radical,
vi) a 1 ,2,3,4-tetrazol-5-yl radical,
vii) an azido radical,
viii) an acyl radical having from 2 to 4 carbon atoms,
ix) a halogen atom,
x) a radical -S-fl15 in which R1s represents a phenyl radical or a 5- or 6-membered,
heterocyclic aromatic ring comprising from 1 to 4 heteroatoms selected from sulphur,
nitrogen and oxygen atoms, which phenyl or heterocylic ring may optionally be substituted
by one or more radicals selected from nitrile, amino, nitro and alkyl radicals having from 1 to 4
atoms of carbon or nitrile;
R2 represents a hydrogen atom or a removable ester group; and either R3 represents a hydrogen atom and R4 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R4 represents a hydrogen atom and R3 represents:
a) a chloro or methoxy radical;
b) an alkyl, cycloalkyl or alkylthio radical having at most 5 carbon atoms;
c) a radical -CH2-S-fi15 in which R16 represents an optionally-substituted nitrogen-containing heterocyclic radical, an acyl radical having from 2 to 4 carbon atoms, a 2-oxo(3H)-thiazolin-4-ylcarbonyl radical or a 3-methyl-1,2-oxazol-5-yl-carbonyl radical;
d) an acetoxymethyl or a carbamoyloxymethyl radical;
e) a radical -NH-C0-Alk5 in which Alk5 is an alkyl radical having from 1 to 4 carbon atoms; or
f) [when R, represents either a protecting group for the hydroxy radical, a saturated or unsaturated aliphatic hydrocarbyl radical having 1 to 4 carbon atoms, a radical (CH2)nR51 in which Ra1 represents i) a radical -C02fi55 in which R6a represents a removable ester, ii) a radical -NHR135 in which R13a represents a protecting group for the amino radical, or iii) a benzoyl radical] an azidomethyl radical, with the proviso that R, does not represent a protecting group for the hydroxy radical, a saturated or unsaturated, aliphatic hydrocarbyl radical having from 1 to 4 carbon atoms or a radical CR'R"R5 when R3 represents a radical -CH2-S-fi15 in which R,6 represents a 2-oxo(3H)-thiazolin-4-yl-carbonyl radical or a 3-methyl-1 ,2-oxazol-5-yl-carbonyl radical) in which process a syn isomer compound of the general formula:
is treated, optionally in the presence of a base, with a compound of the general formula:
(wherein R'2 represents R2, an alkali metal atom or a substituted ammonium group) and then with an acid to yield a product of general formula I.
2. A process as claimed in claim- 1, in which the compound of general formula Ill is prepared by reacting a syn isomer compound of the general formula:
(wherein Ad represents a hydrogen atom, alkali-metal atom or a substituted ammonium group) with a compound of the general formula:
(wherein Y represents a tosyl or mesyl ion and Z represents a halide ion, orY and Z each represent a tosyl ion, or Y and Z each represent a mesyl ion), and optionally treating the product with a base, so as to obtain a product of general formula Ill.
3. A process as claimed in claim 2 for the preparation of sun isomer compounds of the general formula:
(wherein R1a represents: a) a protecting group for the hydroxy radical, b) a saturated or unsaturated, aliphatic hydrocarbyl radical having from 1 to
4 carbon atoms,
c) a radical -CH2-C02fl85 in which R6a represents a removable ester group, or
d) a radical(CH2)n'a--R13aR14a in which nta is an integer from 1 to 4, one of R13a and R14a represents a hydrogen atom, and the other of R135 and R14a represents a protecting group for the amino radical; R3a represents: : a) a methyl radical,
b) an acetoxymethyl or a carbamoyloxymethyl radical, c) a radical -CH2-S-R15 in which R1s represents an acetyl radical, a 1 -methyltetrazolyl or a 2methyl-1 ,3,4-thiadiazol-5-yl radical, or d) an azidomethyl radical; and n'5 is O or 1) in which process a compound of the general formula:
is treated with a compound of general formula A and then with a base to obtain a product of the general formula:
which product of general formula 111a is treated, in the presence of a base, with a compound of the general formula:
and thereafter with an acid to form the desired product of general formula I 4.A process as claimed in claim 2 for the preparation of syn isomer compounds of the general formula:
(wherein fi1t, represents a protecting group for the hydroxy radical, a methyl radical or a radical --CH2--CO2--R6a and fi3t, represents an acetoxymethyl, 1 -methyltetrazol-5-yl-thiomethyl or a 2-methyl 1 ,3,4-thiadiazol-5-yl-thiomethyl radical) in which process a compound of the general formula lIt,:
is treated by a product according to the formula:
(wherein Yt, represents a tosyl ion and Z, represents a tosyl or a chloride ion) and thereafter by a base to obtain a product of the general formula::
which product of general formula lIlt, is treated, in the presence of a base, with a compound of general formula lit,:
and thereafter with an acid to form the desired product of general formula It,.
5. A process as claimed in claim 2 for the preparation of syn isomer compounds of the general formula:
in which a compound of the general formula:
is treated with a compound of the general formula A, and thereafter by a base to obtain a compound of the general formula:
which product of general formula 111 is treated, in the presence of a base, with the compound of formula:
and thereafter with an acid to form the desired product of general formula lc.
6. A process as claimed in any of the preceding claims, in which R is a protecting group chosen from the formyl, acetyl, ethoxycarbonyl, t-pentoxycarbonyl, t-butoxycarbonyl, chloroacetyl, trifluoroacetyl, trityl and trichloroethoxycarbonyl radicals.
7. A process as claimed in any of the preceding claims, in which R1, R15 or R1b is a protecting group chosen from the formyl, tetrahydropyranyl, trityl, 1-methyl-1-methoxyethyl, acetyl and chloroacetyl radicals.
8. A process as claimed in any of the preceding claims, in which the reaction of the compound III, Illa, lilt, or Illc with the compound IV, Viva, IV, or IVc respectively is carried out in the presence of a triethylamine, N-methyl-morpholine, pyridine, sodium or potassium carbonate, or sodium or potassium bicarbonate.
9. A process as claimed in any of the preceding claims in which the reaction of the compound III, ills, lIlt, or Illc with the compound IV, IV,, IV, or IVe respectively is carried out in an organic solvent at a temperature below OOC.
10. A process as claimed in claim 9, in which the organic solvent comprises one or more of acetone, methylene chloride, N,N-dimethyl-formamide and tetrahydrofuran.
11. A process as claimed in claim 9 or claim 10, in which the reaction temperature is from -900C to -400C.
12. A process as claimed in any of claims 1 to 8, in which the reaction of the compound 111,111 lilt, or 111c with the compound IV, Viva, IV, or IVc respectively is carried out in an aqueous solvent at ambient temperature.
13. A process as claimed in claim 12, in which the aqueous solvent is water or a mixture of water with acetone, hexamethylphosphorotriamide or dimethylformamide.
14. A process as claimed in any of claims 2 to 13, in which the reaction of the compound A with the compound II or lla, or the reaction of the compound A, with the compound lIt, or liC, is carried out in an organic solvent comprising one or more of acetone, methylene chloride, N,N-dimethylformamide and tetrahydrofuran.
15. A process as claimed in claim 14, in which the reaction to form the compound ill is carried out at a temperature of from 0 C to +200C.
16. A process for the preparation of compounds of general formula I substantially as described herein with reference to any one of the Examples.
17. A syn isomer compound of general formula I whenever prepared by a process as claimed in any of the preceding claims.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7830053A FR2439785A1 (en) | 1978-10-23 | 1978-10-23 | NEW PROCESS FOR THE PREPARATION OF PRODUCTS DERIVED FROM 7-AMINO-THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2033390A true GB2033390A (en) | 1980-05-21 |
| GB2033390B GB2033390B (en) | 1982-12-08 |
Family
ID=9214034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7935808A Expired GB2033390B (en) | 1978-10-23 | 1979-10-16 | Process for the preparation 7 - aminothiazolylacetamido - cephalosporanic acid derivatives |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5557593A (en) |
| AT (1) | AT370418B (en) |
| CA (1) | CA1124232A (en) |
| CH (1) | CH643847A5 (en) |
| DE (1) | DE2942797A1 (en) |
| DK (1) | DK160312C (en) |
| ES (1) | ES484639A1 (en) |
| FR (1) | FR2439785A1 (en) |
| GB (1) | GB2033390B (en) |
| HU (1) | HU182572B (en) |
| IT (1) | IT1188860B (en) |
| NL (1) | NL7907789A (en) |
| PT (1) | PT70316A (en) |
| SE (1) | SE438679B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0377987A2 (en) * | 1988-12-27 | 1990-07-18 | Eli Lilly And Company | Acylation process for obtaining cephalosporin derivatives |
| EP0620228A1 (en) * | 1993-04-10 | 1994-10-19 | Lucky Ltd. | Novel reactive thiophosphate derivatives of thia(dia)zole acetic acid and process for preparing the same |
| EP0628561A1 (en) * | 1993-06-10 | 1994-12-14 | Lucky Ltd. | Process for preparing cephalosporin compounds from reactive organic acid derivatives |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2945248A1 (en) * | 1978-11-13 | 1980-05-22 | Fujisawa Pharmaceutical Co | CEPHEM COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL PHARMACEUTICAL AGENTS CONTAINING THE SAME |
| FR2462439A1 (en) * | 1979-07-26 | 1981-02-13 | Roussel Uclaf | NOVEL PROCESS FOR THE PREPARATION OF PRODUCTS DERIVED FROM 7 - / (2-ARYL) 2-HYDROXYIMINO ACETAMIDO / CEPHALOSPORANIC ACID |
| US4252802A (en) * | 1980-03-13 | 1981-02-24 | E. R. Squibb & Sons, Inc. | Hydroxamic acid derivatives of 7-[(2-amino-4-thiazolyl)-oximino] cephalosporins |
| US5883247A (en) * | 1996-06-10 | 1999-03-16 | Hoffmann-La Roche Inc. | Preparation of cephem and isooxacephem derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5175091A (en) * | 1974-12-24 | 1976-06-29 | Teikoku Hormone Mfg Co Ltd | Sefuarosuhorinkei koseibutsushitsunoseizoho |
-
1978
- 1978-10-23 FR FR7830053A patent/FR2439785A1/en active Granted
-
1979
- 1979-08-06 SE SE7906605A patent/SE438679B/en not_active IP Right Cessation
- 1979-10-02 ES ES484639A patent/ES484639A1/en not_active Expired
- 1979-10-15 PT PT70316A patent/PT70316A/en unknown
- 1979-10-15 IT IT50568/79A patent/IT1188860B/en active
- 1979-10-16 GB GB7935808A patent/GB2033390B/en not_active Expired
- 1979-10-22 HU HU79RO1038A patent/HU182572B/en not_active IP Right Cessation
- 1979-10-22 DK DK443879A patent/DK160312C/en not_active IP Right Cessation
- 1979-10-22 AT AT0687879A patent/AT370418B/en not_active IP Right Cessation
- 1979-10-22 CA CA338,145A patent/CA1124232A/en not_active Expired
- 1979-10-22 CH CH946579A patent/CH643847A5/en not_active IP Right Cessation
- 1979-10-23 NL NL7907789A patent/NL7907789A/en not_active Application Discontinuation
- 1979-10-23 DE DE19792942797 patent/DE2942797A1/en not_active Withdrawn
- 1979-10-23 JP JP13600879A patent/JPS5557593A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0377987A2 (en) * | 1988-12-27 | 1990-07-18 | Eli Lilly And Company | Acylation process for obtaining cephalosporin derivatives |
| EP0377987A3 (en) * | 1988-12-27 | 1991-08-28 | Eli Lilly And Company | Acylation process for obtaining cephalosporin derivatives |
| EP0620228A1 (en) * | 1993-04-10 | 1994-10-19 | Lucky Ltd. | Novel reactive thiophosphate derivatives of thia(dia)zole acetic acid and process for preparing the same |
| US5502200A (en) * | 1993-04-10 | 1996-03-26 | Lucky, Ltd. | Reactive thiophosphate derivatives of thia(dia)zole acetic acid and process for preparing the same |
| EP0628561A1 (en) * | 1993-06-10 | 1994-12-14 | Lucky Ltd. | Process for preparing cephalosporin compounds from reactive organic acid derivatives |
| CN1040001C (en) * | 1993-06-10 | 1998-09-30 | 株式会社乐喜 | Process for preparing cephalosporin compounds from reactive organic acid derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2439785B1 (en) | 1981-07-10 |
| GB2033390B (en) | 1982-12-08 |
| SE7906605L (en) | 1980-04-24 |
| HU182572B (en) | 1984-02-28 |
| AT370418B (en) | 1983-03-25 |
| IT1188860B (en) | 1988-01-28 |
| DK160312C (en) | 1991-07-29 |
| DK160312B (en) | 1991-02-25 |
| IT7950568A0 (en) | 1979-10-15 |
| ATA687879A (en) | 1982-08-15 |
| JPS5557593A (en) | 1980-04-28 |
| FR2439785A1 (en) | 1980-05-23 |
| CH643847A5 (en) | 1984-06-29 |
| ES484639A1 (en) | 1980-06-16 |
| SE438679B (en) | 1985-04-29 |
| DE2942797A1 (en) | 1980-04-30 |
| NL7907789A (en) | 1980-04-25 |
| CA1124232A (en) | 1982-05-25 |
| PT70316A (en) | 1979-11-01 |
| DK443879A (en) | 1980-04-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19931016 |