NO147839B - PROCEDURE FOR THE PREPARATION OF CEPHALOSPORIN COMPOUNDS - Google Patents
PROCEDURE FOR THE PREPARATION OF CEPHALOSPORIN COMPOUNDS Download PDFInfo
- Publication number
- NO147839B NO147839B NO744088A NO744088A NO147839B NO 147839 B NO147839 B NO 147839B NO 744088 A NO744088 A NO 744088A NO 744088 A NO744088 A NO 744088A NO 147839 B NO147839 B NO 147839B
- Authority
- NO
- Norway
- Prior art keywords
- methoxy
- cephem
- reaction
- solution
- water
- Prior art date
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- -1 CEPHALOSPORIN COMPOUNDS Chemical class 0.000 title claims description 37
- 238000000034 method Methods 0.000 title claims description 26
- 229940124587 cephalosporin Drugs 0.000 title claims description 18
- 229930186147 Cephalosporin Natural products 0.000 title claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000002808 molecular sieve Substances 0.000 claims description 15
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 12
- 239000010457 zeolite Substances 0.000 claims description 11
- 229910021536 Zeolite Inorganic materials 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 5
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000036571 hydration Effects 0.000 claims description 4
- 238000006703 hydration reaction Methods 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000003776 cleavage reaction Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 230000007017 scission Effects 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 150000001780 cephalosporins Chemical class 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- AJYXPNIENRLELY-UHFFFAOYSA-N 2-thiophen-2-ylacetyl chloride Chemical compound ClC(=O)CC1=CC=CS1 AJYXPNIENRLELY-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 150000001356 alkyl thiols Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- GNWUOVJNSFPWDD-VHCCSVTPSA-M sodium;(6r)-3-(carbamoyloxymethyl)-7-methoxy-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].S([C@@H]12)CC(COC(N)=O)=C(C([O-])=O)N1C(=O)C2(OC)NC(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-VHCCSVTPSA-M 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-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
- 230000032683 aging Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000005171 halobenzenes Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000005924 transacylation reaction Methods 0.000 description 2
- GUSVHTGHWCRLNP-UHFFFAOYSA-N 2-(furan-2-yl)acetyl chloride Chemical compound ClC(=O)CC1=CC=CO1 GUSVHTGHWCRLNP-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229910017090 AlO 2 Inorganic materials 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000004448 titration Methods 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
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved frem- The present invention relates to a method by producing
stilling av 70-(2-fenylacetamido)-, 70-(2-thienylacetamido)- og 73-(2-furylacetamido)-7-methoxy-3-carbamoyloxymethyl- resp. position of 70-(2-phenylacetamido)-, 70-(2-thienylacetamido)- and 73-(2-furylacetamido)-7-methoxy-3-carbamoyloxymethyl- resp.
-3-acetoxymethyl-3-cefem-4-carboxylsyre og deres estere som an- -3-acetoxymethyl-3-cephem-4-carboxylic acid and their esters as an-
gitt i kravet, i forbedret utbytte. given in the claim, in improved yield.
Foreliggende oppfinnelse er en forbedring av acyleringsfremgangsmåten for fremstilling av 7-acylamido-cefalosporiner ifølge norsk patent 146 601 og 145 883. The present invention is an improvement of the acylation method for the production of 7-acylamido-cephalosporins according to Norwegian patents 146 601 and 145 883.
Fremgangsmåten ifølge norsk patent 145 883 omfatter frem- The method according to Norwegian patent 145 883 comprises
stilling av det analoge 7-aminocefalosporin, som så acyleres for å danne det ønskede produkt. Denne fremgangsmåte lider av den ulempe at det er nødvendig først å isolere og rense 7-aminocefalosporin-mellomproduktet. Andre fremgangsmåter har følgelig position of the analogous 7-aminocephalosporin, which is then acylated to form the desired product. This method suffers from the disadvantage that it is necessary to first isolate and purify the 7-aminocephalosporin intermediate. Consequently, other methods have
vært søkt, som ville unngå behovet for fremstilling av 7-amino-cef alosporansyre. been sought, which would avoid the need for the production of 7-amino-cephalosporanic acid.
Fremgangsmåten ifølge norsk utlegningsskrift 146 601 angår transacylering av en acylgruppe i 7-stillingen på et cefalosporin ved anvendelse av et acylhalogenid i nærvær av et tri-laverealkyl-silylderivat, hvorefter diacylderivatet behandles for å The method according to Norwegian explanatory document 146 601 concerns the transacylation of an acyl group in the 7-position of a cephalosporin using an acyl halide in the presence of a tri-lower alkyl silyl derivative, after which the diacyl derivative is treated to
spalte av den N-beskyttende gruppe og bevirke selektiv avspalt- cleave off the N-protecting group and cause selective cleavage
ning av aminoadipoyl-sidekjeden ved spontan ringslutning til lactam. Den N-beskyttende gruppe må være lett fjernbar, og sterisk hindring må ikke hindre at ringslutningen til et lactam kan finne sted. ning of the aminoadipoyl side chain by spontaneous cyclization to lactam. The N-protecting group must be easily removable, and steric hindrance must not prevent cyclization to a lactam from taking place.
Transacyleringen ifølge foreliggende oppfinnelse utføres The transacylation according to the present invention is carried out
ved behandling med et acyleringsmiddel, i nærvær av molekylsikter, by treatment with an acylating agent, in the presence of molecular sieves,
av et cefalosporin hvori aminosubstituenten og carboxy- of a cephalosporin in which the amino substituent and the carboxy-
gruppene er blokkert for å danne det diacylerte mellomprodukt. Det meste av den dannede saltsyre bindes av molekylsiktene, men tilstrekkelig saltsyre blir tilbake i reaksjonsblandingen til å bevirke avspaltning av den blokkerte aminoadipoyl-sidekjede. Ifølge foreliggende oppfinnelse er det således ikke nødvendig med et ekstra trinn for å fjerne den N-beskyttende gruppe for å få en fri aminogruppe som så initierer groups are blocked to form the diacylated intermediate. Most of the hydrochloric acid formed is bound by the molecular sieves, but sufficient hydrochloric acid remains in the reaction mixture to effect cleavage of the blocked aminoadipoyl side chain. According to the present invention, there is thus no need for an additional step to remove the N-protecting group to obtain a free amino group which then initiates
den selektive avspaltning av aminoadipoyl-sidekjeden ved spontan the selective cleavage of the aminoadipoyl side chain by spontaneous
ringslutning til et lactam som ifølge norsk patent 146 6Ci. cyclization to a lactam which according to Norwegian patent 146 6Ci.
Ved foreliggende oppfinnelse kan den N-beskyttende gruppe In the present invention, the N-protecting group can
som anvendes, være en gruppe som ikke er lett å fjerne senere i prosessen. Dette er en økonomisk fordel ved foreliggende oppfinnelse da N-beskyttende grupper som ikke er lett å fjerne, which is used, be a group that is not easy to remove later in the process. This is an economic advantage of the present invention as N-protecting groups which are not easy to remove,
ofte er billigere og lettere å behandle ved fremstilling i stor målestokk på grunn av at de er mere stabile. are often cheaper and easier to process when manufactured on a large scale because they are more stable.
Det har nylig vist seg at cefalosporiner med en methoxy-substituent istedenfor hydrogenet på C-7 dannes av forskjellige mikroorganismer. Disse cefalosporiner inneholder en aminoadipoyl-sidekjede som fortrinnsvis fjernes for å få nye 7a-methoxy-cefalosporiner med øket antibiotisk aktivitet. It has recently been shown that cephalosporins with a methoxy substituent instead of the hydrogen at C-7 are formed by various microorganisms. These cephalosporins contain an aminoadipoyl side chain which is preferably removed to obtain new 7a-methoxy-cephalosporins with increased antibiotic activity.
I henhold til foreliggende oppfinnelse har det vist seg at cefalosporinforbindelser kan omvandles som følger: According to the present invention, it has been found that cephalosporin compounds can be converted as follows:
hvor where
A er carbamoyloxy eller acetoxy; og A is carbamoyloxy or acetoxy; and
R^ er fenyl, thienyl eller furyl; og R 1 is phenyl, thienyl or furyl; and
R" er en lett fjernbar esterblokkerende gruppe, og B er en blokkert aminoadipoylgruppe. R" is an easily removable ester blocking group, and B is a blocked aminoadipoyl group.
I ovenstående prosesskjerna overføres cefalosporinforbindelsen I med et acyleringsmiddel, R^CP^-CO-Cl, hvor R^ er som ovenfor angitt, i nærvær av en syntetisk aluminiumsilikat-zeolitt av typen 4A, 5A eller 12A inneholdende 0-30 vekt% hydratiseringsvann til 7-diacylimido-cefalosporinforbindelsen (II). In the above process core, the cephalosporin compound I is transferred with an acylating agent, R^CP^-CO-Cl, where R^ is as indicated above, in the presence of a synthetic aluminosilicate zeolite of type 4A, 5A or 12A containing 0-30% by weight of hydration water to The 7-diacylimido-cephalosporin compound (II).
Under reaksjonen avspaltes acylgruppen B under dannelse av den nye 7-acylamido-cefalosporinforbindelse (III). During the reaction, the acyl group B is split off to form the new 7-acylamido-cephalosporin compound (III).
Reaksjonen utføres best ved å bringe cefalosporinforbindelsen I i intim kontakt med acyleringsmidlet i et passende opp-løsningsmiddelmedium i nærvær av molekylsikten. Temperaturen ved hvilken reaksjonen utføres, er ikke særlig kritisk, og temperaturer fra -20°C til 100°C er i alminnelighet tilfredsstillende, skjønt det foretrekkes å utføre reaksjonen ved en temperatur fra 50° til 90°C. Oppløsningsmidler som ikke inneholder aktivt hydrogen, som kloroform, acetonitril, methylenklorid, dioxan, benzen, halogenbenzen, carbontetraklorid og diethylether, er passende medier for utførelse av denne reaksjon. The reaction is best carried out by bringing the cephalosporin compound I into intimate contact with the acylating agent in a suitable solvent medium in the presence of the molecular sieve. The temperature at which the reaction is carried out is not particularly critical, and temperatures from -20°C to 100°C are generally satisfactory, although it is preferred to carry out the reaction at a temperature from 50° to 90°C. Solvents that do not contain active hydrogen, such as chloroform, acetonitrile, methylene chloride, dioxane, benzene, halobenzene, carbon tetrachloride and diethyl ether, are suitable media for carrying out this reaction.
Molekylsiktene som anvendes ved denne oppfinnelse, er syntetiske aluminiumsilikat-zeolitter. En syntetisk zeolitt fremstilles fra en kombinasjon av basiske oxyder (A102, Si00, ^£0, 1^0, etc.) i et vandig system for å få en hydratisert eller halvhydratisert krystallinsk struktur. Efter oppvarmningsbehand-ling kan zeolittene betraktes som i det vesentlige vannfrie. Syntetiske zeolitter kjennetegnes og klassifiseres hovedsakelig ved røntgenpulver-diffraksjonsmetoder. Skjønt man mangler en systematisk kjemisk metode for å sette navn på syntetiske, kom-plekse aluminiumsilikater, gies hver ny syntetisk zeolitt historisk en vilkårlig bokstav eller gruppe av bokstaver og nummere. Betydningen av disse vilkårlige symboler er vel kjent av fagfolk. The molecular sieves used in this invention are synthetic aluminum silicate zeolites. A synthetic zeolite is prepared from a combination of basic oxides (AlO 2 , SiO 2 , ^£0, 1^0, etc.) in an aqueous system to obtain a hydrated or semi-hydrated crystalline structure. After heating treatment, the zeolites can be considered essentially anhydrous. Synthetic zeolites are characterized and classified mainly by X-ray powder diffraction methods. Although a systematic chemical method for naming synthetic, complex aluminosilicates is lacking, historically each new synthetic zeolite was given an arbitrary letter or group of letters and numbers. The meaning of these arbitrary symbols is well known to those skilled in the art.
Det har vist seg at. syntetiske zeolitter av A-typen kan anvendes ved acyleringsfremgangsmåten beskrevet ovenfor. Pore-størrelsen av zeolittene kan variere fra 3 til 15 Å. Zeolittene kan være i det vesentlige vannfrie eller inneholde noe hydratiseringsvann. Vektmengden av vann i zeolitten kan være fra 0 til 30% . It has been shown that. synthetic zeolites of the A type can be used in the acylation process described above. The pore size of the zeolites can vary from 3 to 15 Å. The zeolites can be essentially anhydrous or contain some water of hydration. The weight amount of water in the zeolite can be from 0 to 30%.
Reaksjon I—>II sem er vist skjematisk ovanfor, er en like-vekstreaksjon. Et overskudd av acyleringsmidlet (inneholdende gruppen R^-CI^-CO-) anvendes for å øke utbyttet av det ønskede sluttprodukt III. Diacyl-mellomproduktat II må spaltes for å fjerne gruppen B for å danne sluttproduktet III. Denne spaltning kan utføres på flere måter. For det første finner spontan spaltning sted (i nærvær av et molekylært overskudd av acyleringsmidlet, •CH^•CO-Cl) ved bare å forlenge reaksjonstiden. For det annet, når vann er tilstede i molekylsiktene, virker vannet som et spaltningsmiddel, og det endelige acylamido-produkt utvinnes i høyt utbytte. Begge disse metoder kan betegnes som "passive" i den forstand at der ikke behøver å tilsettes et spesielt "spaltningsmiddel" til reaksjonsblandingen. Reaction I—>II, which is shown schematically above, is an equal-growth reaction. An excess of the acylating agent (containing the group R^-CI^-CO-) is used to increase the yield of the desired end product III. Diacyl intermediate II must be cleaved to remove group B to form final product III. This cleavage can be carried out in several ways. First, spontaneous cleavage takes place (in the presence of a molecular excess of the acylating agent, •CH^•CO-Cl) by simply prolonging the reaction time. Second, when water is present in the molecular sieves, the water acts as a cleavage agent and the final acylamido product is recovered in high yield. Both of these methods can be described as "passive" in the sense that there is no need to add a special "dissolving agent" to the reaction mixture.
En tredje spaltningsmetode fåes ved tilsetning av benzylalkohol, en alkanol eller en laverealkyl-thiol, med 1-6 carbon-atomer. Saltsyre kan også tilsettes som spaltningsmiddel, som et fjerde middel. A third cleavage method is obtained by adding benzyl alcohol, an alkanol or a lower alkyl thiol, with 1-6 carbon atoms. Hydrochloric acid can also be added as a splitting agent, as a fourth agent.
Acyleringsmidlene som anvendes ved foreliggende fremgangsmåte, har den generelle formel:: The acylating agents used in the present method have the general formula:
hvor R^ er som ovenfor angitt. where R^ is as indicated above.
Acyleringsmidlet anvendes i mengder i molekylært overskudd over det av cefalosporin-utgangsmaterialet, fortrinnsvis fra 2 The acylating agent is used in amounts in molecular excess over that of the cephalosporin starting material, preferably from 2
til 6 ganger så meget acyleringsmiddel som cefalosporin. to 6 times as much acylating agent as cephalosporin.
Den anvendte molekylsikt er en syntetisk aluminiumsilikat-zeolitt av typen 4A, 5A eller 12A som er lett kommersielt til-gjengelig . Fortrinnsvis anvendes en syntetisk zeolitt med regulær krystallstruktur og jevn porestørrelse. De mest alminne-lig tilgjengelige sikter, type 4A, 5A og 12A, kan alle anvendes ifølge oppfinnelsen. Disse sikter har porestørrelser på 3 - 15 Å. The molecular sieve used is a synthetic aluminosilicate zeolite of type 4A, 5A or 12A which is readily commercially available. A synthetic zeolite with a regular crystal structure and uniform pore size is preferably used. The most commonly available sieves, type 4A, 5A and 12A, can all be used according to the invention. These sieves have pore sizes of 3 - 15 Å.
Siktene er tilgjengelige i i det vesentlige vann.fri form, og de kan anvendes i denne form eller dehydratiseres ytterligere, til 0% vann 1 2% vann , ved oppvarmning til høye temperaturer ( 500°C eller høyere) før anvendelse, eller de kan anvendes når de inneholder opptil 30 vekt% hydrat iseringsvann. De hydrat iserte sikter fremstilles ved å la dem stå i et kammer eller omgivelser med høy fuktig-het eller ved å oppslemme dem i vann og derpå innstille det ønskede fuktighetsinnhold ved vakuumtørring eller tørring ved værelsetemperatur eller ved forhøyet temperatur. The sieves are available in essentially water-free form, and they can be used in this form or further dehydrated, to 0% water 1 2% water, by heating to high temperatures (500°C or higher) before use, or they can be used when they contain up to 30% by weight of water of hydration. The hydrated sieves are produced by leaving them in a chamber or environment with high humidity or by slurping them in water and then setting the desired moisture content by vacuum drying or drying at room temperature or at an elevated temperature.
I alminnelighet tar denne tørring 2-5 timer, skjønt dette ikke er en kritisk tidsgrense. Fuktighetsinnholdet kan måles ved anvendelse av Karl Fischers metode, en vanlig godtatt metode eller andre tilgjengelige metoder. In general, this drying takes 2-5 hours, although this is not a critical time limit. The moisture content can be measured using Karl Fischer's method, a commonly accepted method or other available methods.
Trinnet for å overføre den beskyttede cefalosporinforbindelse til det diacylerte produkt utføres fortrinnsvis ved å The step of transferring the protected cephalosporin compound to the diacylated product is preferably carried out by
bringe cefalosporinforbindelsen i intim kontakt med acyleringsmidlet i et passende oppløsningsmiddelmedium i nærvær av den ønskede molekylsikt. Temperaturen ved hvilken denne reaksjon utføres, er ikke kritisk, og temperaturer fra -20°C til 100°C er i alminnelighet tilfredsstillende. Da reaksjonen imidlertid synes å være temperaturavhengig, og forløper hurtigere ved høyere temperaturer, foretrekkes det å utføre reaksjonen ved temperaturer fra 50°C til 90°C. Forskjellige oppløsningsmidler som ikke inneholder et aktivt hydrogen, som kloroform, acetonitril, methylenklorid, dioxan, benzen, halogenbenzen, carbontetraklorid, 1,2-diklorethan og diethylether, er meget vel egnet som medier for reaksjonsblandingen. Det er viktig å holde suspensjonen i bevegelse ved omrøring eller ryst ing under reaksjonen. bringing the cephalosporin compound into intimate contact with the acylating agent in a suitable solvent medium in the presence of the desired molecular sieve. The temperature at which this reaction is carried out is not critical, and temperatures from -20°C to 100°C are generally satisfactory. However, as the reaction appears to be temperature dependent, and proceeds faster at higher temperatures, it is preferred to carry out the reaction at temperatures from 50°C to 90°C. Various solvents which do not contain an active hydrogen, such as chloroform, acetonitrile, methylene chloride, dioxane, benzene, halobenzene, carbon tetrachloride, 1,2-dichloroethane and diethyl ether, are very well suited as media for the reaction mixture. It is important to keep the suspension moving by stirring or shaking during the reaction.
Mengden av sikter som er nødvendig for utbytningsreaksjonen, kan varieres for å passe til de valgte operasjonsbetingelser. I alminnelighet - foret rekkes det å anvende omtrent like vektmengder av utgangsmaterialet og siktene, skjønt det er mulig å anvende et vekt-forhold av utgangsforbindelse til sikter på 1:0,5 til 1:2. The amount of sieves required for the yield reaction can be varied to suit the chosen operating conditions. In general, it is recommended to use roughly equal weight amounts of the starting material and the sieves, although it is possible to use a weight ratio of starting compound to sieves of 1:0.5 to 1:2.
Som nevnt ovenfor, avspaltes den opprinnelige acylgruppe på As mentioned above, the original acyl group is cleaved on
en rekke forskjellige måter. Ganske enkel elding av reaksjonsblandingen er tilstrekkelig i noen tilfelle, f.eks. når siktene inneholder 10 - 30% vann, i fra 30 minutter til 30 timer. En alkanol, laverealkylthiol eller benzylalkohol kan tilsettes efter en kortere eldingsperiod?. Alkanolen eller laverealkylthiolen kan ha 1 - 6 car-bonatomer, og er fortrinnsvis methanol, ethanol, isopropanol eller t-butanol. Saltsyre kan også tilsettes for å bevirke spaltning. Under acyleringsreaksjonen inntrer noe "spontan" spaltning av amino-adipoylgruppen på grunn av reaksjonens 1ikevektsnatur, avhengig av a number of different ways. Fairly simple aging of the reaction mixture is sufficient in some cases, e.g. when the sieves contain 10 - 30% water, for from 30 minutes to 30 hours. An alkanol, lower alkyl thiol or benzyl alcohol can be added after a shorter aging period?. The alkanol or lower alkyl thiol can have 1-6 carbon atoms, and is preferably methanol, ethanol, isopropanol or t-butanol. Hydrochloric acid can also be added to effect cleavage. During the acylation reaction, some "spontaneous" cleavage of the amino-adipoyl group occurs due to the equilibrium nature of the reaction, depending on
de betingelser under hvilke acyleringen utføres. Lengre oppvarmning av reaksjonsblandingen fører til spaltning av aminoadipoy1-gruppen og fremstillingen av den ønskede 7-acylert cefalosporinforbindelse, særlig når siktene inneholder over 10% vann. the conditions under which the acylation is carried out. Longer heating of the reaction mixture leads to cleavage of the aminoadipoyl group and the production of the desired 7-acylated cephalosporin compound, especially when the sieves contain more than 10% water.
Fjernelse av den beskyttende eller blokkerende gruppe på car-boxyfunksjonen kanoppnåes ved velkjente metoder. Således fjernes f.eks. methoxymethylgruppen ved anvendelse av saltsyre ved 0 - 10°C, og triklorethoxycarbonylgruppen fjernes ved omsetning med zink og eddiksyre; og t-butoxycarbonyl- og benzhydrylgruppene fjernes ved omsetning med trifluoreddiksyre. Andre fjernelser utføres med til-svarende letthet. Removal of the protecting or blocking group on the carboxy function can be achieved by well-known methods. Thus, e.g. the methoxymethyl group using hydrochloric acid at 0 - 10°C, and the trichloroethoxycarbonyl group is removed by reaction with zinc and acetic acid; and the t-butoxycarbonyl and benzhydryl groups are removed by reaction with trifluoroacetic acid. Other removals are carried out with corresponding ease.
Eksempel 1 Example 1
3-carbamoyloxymethyl-7-methoxy-7|3-thienylacetamido-3-cef em-4-carboxylsy re 3-carbamoyloxymethyl-7-methoxy-7|3-thienylacetamido-3-cef em-4-carboxylic acid
Trinn A: 7(3 - (D-5-tosylamino~5-carboxy val eramido) -3~ca rbamoyl - Step A: 7(3 - (D-5-tosylamino~5-carboxy val eramido)-3~ca rbamoyl -
oxymethyl- 7- methoxy- 3- cefem- 4- carboxylsyre oxymethyl- 7- methoxy- 3- cephem- 4- carboxylic acid
45,0 ml av en 49,5 mg/ml vandig oppløsning av mononatriumsaltet av 7(3 - (D-5 -amino-5-ca rboxy va ler am ido ) - 3-ca rbamoyloxymeth yl-7-methoxy - 3-cefem-4-carboxylsyre blandes med 450 ml aceton og 450 ml vann. Blandingens pH innstilles på 9,5 - 9,6 med 50%-ig natriumhydroxyd-oppløsning og 19 g tosylklorid i lOO ml aceton tilsettes i porsjoner. pH holdes ved 9,5 - 9,6 ved hyppig tilsetning av natronlut. Efter 15 ~ 20 minutter blir pH stabil, og sulfonyleringen fortsettes i til-sammen 1 time. Temperaturene av oppløsningen er 20 - 23°C, under hele reaksjonsperioden. 45.0 ml of a 49.5 mg/ml aqueous solution of the monosodium salt of 7(3- (D-5-amino-5-carboxy valeramido)-3-ca rbamoyloxymeth yl-7-methoxy-3- Cepheme-4-carboxylic acid is mixed with 450 ml of acetone and 450 ml of water. The pH of the mixture is adjusted to 9.5 - 9.6 with a 50% sodium hydroxide solution and 19 g of tosyl chloride in 100 ml of acetone is added in portions. The pH is kept at 9 .5 - 9.6 by frequent addition of caustic soda. After 15 ~ 20 minutes, the pH becomes stable, and the sulfonylation is continued for a total of 1 hour. The temperature of the solution is 20 - 23°C, during the entire reaction period.
Efter dette avkjøles oppløsningen i et isbad, og pH senkes til 7 ved tilsetning av 1:1 saltsyre (iskold). Oppløsningen ekstraheres under anvendelse av ethylacetat. Ethylacetatskiktet vaskes tilbake med lOO ml 5%-ig nat riumkloridoppløsning. Det organiske skikt kastes, og de vandige skikt sammen med 500 ml ethylacetat innstilles igjen på pH 2,5, og skiktene skilles. Det vandige skikt ekstraheres igjen med 3 x 500 ml ethylacetat. Ethylacetatskiktet vaskes tilbake med lOO ml mettet nat riumkloridoppløsning. Ekstraktene tørres med natriumsulfat, og oppiøsningsmidlet inndampes til lite volum. After this, the solution is cooled in an ice bath, and the pH is lowered to 7 by adding 1:1 hydrochloric acid (ice cold). The solution is extracted using ethyl acetate. The ethyl acetate layer is washed back with 100 ml of 5% sodium chloride solution. The organic layer is discarded, and the aqueous layers together with 500 ml of ethyl acetate are again adjusted to pH 2.5, and the layers are separated. The aqueous layer is extracted again with 3 x 500 ml of ethyl acetate. The ethyl acetate layer is washed back with 100 ml saturated sodium chloride solution. The extracts are dried with sodium sulphate, and the solvent is evaporated to a small volume.
(Temperatur 30°C). (Temperature 30°C).
Den konsentrerte oppløsning oppløses så i 200 ml isopropanol, oppvarmes til 4o - 45°C, og 5,8 ml eddiksyre og 21,6 ml dicyclohexyl-amin tilsettes. The concentrated solution is then dissolved in 200 ml of isopropanol, heated to 40-45°C, and 5.8 ml of acetic acid and 21.6 ml of dicyclohexylamine are added.
Denne suspensjon tillates å avkjøle langsomt og eldes over natten ved værelsetemperatur. Produktet f rafiltreres, vaskes med lOO ml isopropanol og tørres over natten ved værelsetemperatur under høyvakuum. This suspension is allowed to cool slowly and aged overnight at room temperature. The product is filtered, washed with 100 ml isopropanol and dried overnight at room temperature under high vacuum.
Produkt et, 76 -(D-5-tosylamino-5-ca rboxyvaleramido)-3-ca rbamoy1-oxy met hyl-7-methoxy-3-cef em-4~carboxylsy re-dicyclohexylaminsalt , fåes i et utbytte på 44,5 g; Product one, 76 -(D-5-tosylamino-5-ca rboxyvaleramido)-3-ca rbamoyl-oxy methyl-7-methoxy-3-cef em-4~carboxylsy re-dicyclohexylamine salt, is obtained in a yield of 44, 5 g;
uv: (pH 7,0 puffer) uv: (pH 7.0 buffer)
X maks. 2620 E% 94,7 X max. 2620 E% 94.7
Ekvivalentvekt (HCIO^ titrering) 481,5 (teoretisk 481,5) Equivalent weight (HCIO^ titration) 481.5 (theoretical 481.5)
Anal. beregn, for C^H^N^-^: C 58,60; H 7,74; N 8,72; Anal. calculate, for C^H^N^-^: C 58.60; H 7.74; N 8.72;
Funnet: C 58,29; H 7,29; N 8,73- Found: C 58.29; H 7.29; N 8.73-
Trinn B: Dimethoxymethylester av 7(3-(D-5-tosylamino-5-carb>xy-valeramido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4- carboxylsyre 20 g av tosylsaltet fra trinn A innføres i en 3-halset kolbe. 200 ml methylenklorid tilsettes, og oppslemningen avkjøles til 0°c i et isbad under nitrogen. 4,1 ml klormethy1-methylether i 30 ml methylenklorid tilsettes til reaksjonsblandingen i løpet av 90 minutter under god omrøring og isavkjøling. Efter 1 times tilsetnings-tid innrøres en oppløsning av 1,58 ml collidin i 5 ml methylenklorid. Step B: Dimethoxymethyl ester of 7(3-(D-5-tosylamino-5-carb>xy-valeramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid 20 g of the tosyl salt from step A are introduced into a 3-necked flask. 200 ml methylene chloride is added, and the slurry is cooled to 0°c in an ice bath under nitrogen. 4.1 ml chloromethyl-1-methyl ether in 30 ml methylene chloride is added to the reaction mixture over 90 minutes with good stirring and ice-cooling. After 1 hour addition time, a solution of 1.58 ml of collidine in 5 ml of methylene chloride is stirred in.
Efter tilsetningene omrøres blandingen i ytterligere 2 timer, filtreres, og filterkaken vaskes med tørt methylenklorid. Efter ekstraksjon med vandig fosforsyre, nat riumklorid, natriumbicarbonat og natriumkloridoppløsninger, vaskes filterkaken med methylenklorid. Det organiske skikt tørres, filtreres, inndampes til lite volum og krystalliseres. Produktet, dimethoxymethylesteren av 7(3-(D-5-tosyl-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4-carboxylsyre, fåes i en mengde av 9,6 g (utbytte 83,5%). Både ultrafiolett og tynnskiktskromatografi viser bare en enkelt forbindelse i produktet. After the additions, the mixture is stirred for a further 2 hours, filtered and the filter cake is washed with dry methylene chloride. After extraction with aqueous phosphoric acid, sodium chloride, sodium bicarbonate and sodium chloride solutions, the filter cake is washed with methylene chloride. The organic layer is dried, filtered, evaporated to a small volume and crystallized. The product, the dimethoxymethyl ester of 7(3-(D-5-tosyl-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid, is obtained in an amount of 9.6 g (yield 83 .5%) Both ultraviolet and thin-layer chromatography show only a single compound in the product.
Trinn C: 3-carbamoyloxymethy1-7-methoxy-73-thienylacetamido-3~ cefem -4- ca rboxylsyre Step C: 3-carbamoyloxymethy1-7-methoxy-73-thienylacetamido-3~ cephem -4- ca rcarboxylic acid
Til en omrørt suspensjon av 6,9 g tosyl-methoxymethylester fra trinn B og 7,5 g av type 4A pulveriserte molekylsikter (6oO mesh, hydratisert til 17% t 2% vann) i 85 ml 1,2-diklorethan ble tilsatt 5 ml destillert 2-thienyl icety2 klorid. Den omrørte suspensjon ble To a stirred suspension of 6.9 g of tosyl-methoxymethyl ester from step B and 7.5 g of type 4A powdered molecular sieves (600 mesh, hydrated to 17% t 2% water) in 85 ml of 1,2-dichloroethane was added 5 ml distilled 2-thienyl icety2 chloride. The stirred suspension was
oppvarmet ved 65°C i l6 timer under nitrogen. heated at 65°C for 16 hours under nitrogen.
Reaksjonen følges ved anvendelse ved tynnskiktskromatografi. Efter den angitte tid er hovedbestanddelen av reaksjonsblandingen The reaction is monitored using thin-layer chromatography. After the specified time, the main component of the reaction mixture
den ønskede mellomproduktforbindelse. 0,8 ml methanol tilsettes så, og suspensjonen eldes i ytterligere 2 timer. På dette tidspunkt er 4-methoxymethylesteren av det ønskede produkt den fremherskende forbindelse i suspensjonen. the desired intermediate compound. 0.8 ml of methanol is then added, and the suspension is aged for a further 2 hours. At this point, the 4-methoxymethyl ester of the desired product is the predominant compound in the suspension.
Esteren hydrolyseres ved å avkjøle ovenstående oppløsning til 25°C, filtrere og vaske med kold methanol. Filtratet og vaskevæsken forenes og avkjøles til 0°C. En 0°C oppløsning av 20,8 ml konsentrert saltsyre og 23,6 ml methanol tilsettes, og oppløsningen oppvarmes til 15°C og omrøres ved 15°C i 2 timer og 40 minutter. En tynnskiktskromatografisk analyse utføres på dette tidspunkt. Blandingens pH innstilles ved først -å boble inn ethylenklorid efter behov for å innstille pH mellom 2 og 2,5, og derpå bringes pH til mellom 5 og 6 ved tilsetning av fast nat riumhydroxyd. Blandingen filtreres, og diklorethanskiktet fraskilles. Det kolde vandige skikt inneholder natriumsaltet av produktet. Dette skikt renses under anvendelse av kolonnekromatografi, under anvendelse av IRA-68-harpiks i nitrat - formen, og elueringsmidtet er 0,02M fosfatpuffer pH 7,0. Sluttutbyttet av produkt er 1,74 g som viser en enkelt flekk ved tynnskiktskromatografi. Dreiningsvinkelen er 192°. Produktets identitet bekreftes ved anvendelse av NMR, og produktet er den ønskede 3-carbamoyloxy-met hyl -7-methoxy-7(3-thienylacetamido-3-cef em-4-carboxylsyre , smp. 165 - 167°C. The ester is hydrolyzed by cooling the above solution to 25°C, filtering and washing with cold methanol. The filtrate and washing liquid are combined and cooled to 0°C. A 0°C solution of 20.8 ml of concentrated hydrochloric acid and 23.6 ml of methanol is added, and the solution is warmed to 15°C and stirred at 15°C for 2 hours and 40 minutes. A thin-layer chromatographic analysis is performed at this point. The pH of the mixture is adjusted by first bubbling in ethylene chloride as needed to set the pH between 2 and 2.5, and then the pH is brought to between 5 and 6 by adding solid sodium hydroxide. The mixture is filtered and the dichloroethane layer is separated. The cold aqueous layer contains the sodium salt of the product. This layer is purified using column chromatography, using IRA-68 resin in the nitrate form, and the eluent is 0.02M phosphate buffer pH 7.0. The final yield of product is 1.74 g which shows a single spot by thin layer chromatography. The turning angle is 192°. The product's identity is confirmed using NMR, and the product is the desired 3-carbamoyloxy-methyl-7-methoxy-7(3-thienylacetamido-3-cef em-4-carboxylic acid, m.p. 165 - 167°C.
Utgangsmaterialet , mononat riumsaltet av 7(3 - (D-5-amino-5~ The starting material, the monosodium salt of 7(3 - (D-5-amino-5~
carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4-carboxylsyre, som anvendes i det foregående eksempel, kan fremstilles ifølge norsk patent 134 219. carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid, which is used in the preceding example, can be prepared according to Norwegian patent 134,219.
Eksempel 2 Example 2
3-carbamoyloxymethy1-7-methoxy-76-fenylacetamido-3-cefem-4-carboxy1-syre 3-carbamoyloxymethy1-7-methoxy-76-phenylacetamido-3-cephem-4-carboxy1-acid
Trinn A: Dimethoxymethylester av 7(3-; (D-5-tosylamino-5-carboxy-valeryl)-feny1acetylamido J-3-carbamoyloxymethyl-7-methoxy- 3- cefem- 4- carboxylsyre Step A: Dimethoxymethyl ester of 7(3-; (D-5-tosylamino-5-carboxy-valeryl)-phenylacetylamido J-3-carbamoyloxymethyl-7-methoxy- 3- cephem- 4- carboxylic acid
En oppløsning av 9,3 g (IO mmol) av dimethoxymethylesteren av 73-(D-5-tosylamino-5-carboxyvaleramido)-3-carbamoyloxymethy1-7-methoxy-3-cef em-4-carboxylsyre10,8 9 type 12A pulveriserte molekyl- A solution of 9.3 g (10 mmol) of the dimethoxymethyl ester of 73-(D-5-tosylamino-5-carboxyvaleramido)-3-carbamoyloxymethy1-7-methoxy-3-cef em-4-carboxylic acid10.8 9 type 12A powdered molecular
sikter (hydratisert til 20% t 2% vann) og 5,3 ml (40 mmol) fenyl-acetylklorid i 50 ml acetonitril oppvarmes til 40°C i 20 timer. sieves (hydrated to 20% t 2% water) and 5.3 ml (40 mmol) of phenylacetyl chloride in 50 ml of acetonitrile are heated to 40°C for 20 hours.
Derefter avkjøles blandingen til værelsetemperatur og filtreres. The mixture is then cooled to room temperature and filtered.
Filtratet inndampes til tørrhet og tritureres med hexan. Det uopp- The filtrate is evaporated to dryness and triturated with hexane. The unexplained
løselige residuum inneholdende dimethoxymethylesteren av 73~[(D-5-tosylamino-5-carboxyvaleryl)-feny1acetylamino]-3-carbamoyloxymethyl-7-methoxy-3-cefem-4-carboxylsyre, anvendes uten rensning i det neste trinn. soluble residue containing the dimethoxymethyl ester of 73-[(D-5-tosylamino-5-carboxyvaleryl)-phenylacetylamino]-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid is used without purification in the next step.
Trinn B: 3-carbamoyloxymethyl-7-methoxy-73-fenylacetamido-3-cefem- 4- carboxylsyre Step B: 3-carbamoyloxymethyl-7-methoxy-73-phenylacetamido-3-cephem-4-carboxylic acid
Råproduktet fra trinn A oppløses i 50 ml 1,2-diklorethan. The crude product from step A is dissolved in 50 ml of 1,2-dichloroethane.
1,0 ml methanol tilsettes så, og oppløsningen omrøres i 1 time. Methoxymethylesteren hydrolyseres ved å tilsette en 0°C oppløsning 1.0 ml of methanol is then added, and the solution is stirred for 1 hour. The methoxymethyl ester is hydrolysed by adding a 0°C solution
av 20 ml konsentrert saltsyre i,25 ml methanol og omrøre ved 15°C i 3 timer. Produktet isoleres og renses ved anvendelse av samme gener- of 20 ml of concentrated hydrochloric acid in 25 ml of methanol and stir at 15°C for 3 hours. The product is isolated and purified using the same gen-
elle fremgangsmåte som i eksempel 1. Produktet, 3-carbamoyloxymethyl-7-methoxy-73-:fenylacetamido-3-cef em-4-carboxylsyre, fåes med et smeltepunkt på 159 - l6l°C, og med UV- og NMR-spektra som stemmer med den tilskrevne struktur. ell method as in example 1. The product, 3-carbamoyloxymethyl-7-methoxy-73-:phenylacetamido-3-cef em-4-carboxylic acid, is obtained with a melting point of 159 - 161°C, and with UV and NMR spectra which is consistent with the attributed structure.
Eksempel 3 Example 3
3-ca rbamoy loxymet hyl -7-methoxy ~73-(2-furylacetamido)-3 -cef em-4-ca rboxylsyre 3-ca rbamoyloxymet hyl -7-methoxy ~73-(2-furylacetamido)-3 -cef em-4-ca rboxylic acid
Dimethoxymethylesteren av 73-(D-5-tosylamino-5-carboxyvaler - amido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4-carboxylsyre omsettes med 2-furylacetylklorid i nærvær av 12 g hydratisert type 4A molekylsikter (hydratisert til 15% ± 2% vann), ved å følge de nettopp be- The dimethoxymethyl ester of 73-(D-5-tosylamino-5-carboxyvaler-amido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid is reacted with 2-furylacetyl chloride in the presence of 12 g of hydrated type 4A molecular sieves (hydrated to 15% ± 2% water), by following the just be-
skrevne fremgangsmåter. Sidekjeden og den esterblokkerende gruppe fjernes også ved de beskrevne fremgangsmåter. Det erholdte produkt er 3-carbamoyloxymethyl-7-methoxy-73-(2-furylacetamido)-3-cefem-4-carboxylsyre, smp. 156 - l6l°C, UV (pH 7,0 puffer) X maks. 265 nm. written procedures. The side chain and the ester blocking group are also removed by the methods described. The product obtained is 3-carbamoyloxymethyl-7-methoxy-73-(2-furylacetamido)-3-cephem-4-carboxylic acid, m.p. 156 - l6l°C, UV (pH 7.0 buffer) X max. 265 nm.
£7200 og med IR og NMR som stemmer med strukturen. £7200 and with IR and NMR consistent with the structure.
Eksempel Example
Nat rium-7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethy1-3-cef em- 4- ca rboxy lat Sodium 7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethy1-3-cef em- 4- ca rboxy lat
Trinn A: 73-(D-5-benzoylamino-5-carboxyvaleramido)-3-carbamoy1-oxymethyl-7-methoxy-3-cefem-4-carboxylsyre-dinat rium-salt Step A: 73-(D-5-benzoylamino-5-carboxyvaleramido)-3-carbamoyl-oxymethyl-7-methoxy-3-cephem-4-carboxylic acid disodium salt
Til 500 ml av en vandig oppløsning inneholdende 48,5 mmol mononat rium-73-(D-5-amino-5-carboxyvaleramido)-3-carbamoyloxymethy1-7-methoxy-3-cefem-4-carboxylat tilsettes nok 50%-ig nat riumhydroxyd til å bringe pH til 9,5. Til denne oppløsning tilsettes 15 ml Add sufficient 50% sodium hydroxide to bring the pH to 9.5. 15 ml is added to this solution
(128 mmol) benzoylklorid under kraftig røring. pH holdes ved 9,5 i (128 mmol) of benzoyl chloride with vigorous stirring. The pH is maintained at 9.5 in
30 minutter ved tilsetning av nat riumhydroxyd efter behov. 30 minutes by adding sodium hydroxide as needed.
Oppløsningens pH innstilles så på 4,0 med konsentrert saltsyre, og oppløsningen vaskes to ganger med ethylacetat. The pH of the solution is then adjusted to 4.0 with concentrated hydrochloric acid, and the solution is washed twice with ethyl acetate.
Vannfasen avkjøles til 0°C, og 200 ml isopropanol og 300 ml ethylacetat tilsettes under omrøring. pH innstilles på 2,0 med saltsyre. Den organiske fase kastes, og vannfasen ekstraheres igjen 3 ganger med ethylacetat. De forenede ekstrakter vaskes med natrium-kloridoppløsning, tørres med natriumsulfat og inndampes i vakuum, hvorved man får 43,0 g av en mørk olje. The water phase is cooled to 0°C, and 200 ml of isopropanol and 300 ml of ethyl acetate are added while stirring. The pH is adjusted to 2.0 with hydrochloric acid. The organic phase is discarded, and the aqueous phase is extracted again 3 times with ethyl acetate. The combined extracts are washed with sodium chloride solution, dried with sodium sulfate and evaporated in vacuo, whereby 43.0 g of a dark oil is obtained.
Oljen oppløses i 200 ml ethanol, og en oppløsning av 30 g 2-ethylhexansyre-natriumsalt tilsettes. Suspensjonen avkjøles til 0°C, filtreres, vaskes med ethanol og tørres i vakuum, hvorved man får 28,8 g (102%) dinatrium-73"(D~5-benzoylamino-5-carboxyvaler-amido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4-carboxylat som var 67% rert ved kromatografisk sammenligning med en ren standard. The oil is dissolved in 200 ml of ethanol, and a solution of 30 g of 2-ethylhexanoic acid sodium salt is added. The suspension is cooled to 0°C, filtered, washed with ethanol and dried in vacuo, whereby 28.8 g (102%) of disodium-73"(D~5-benzoylamino-5-carboxyvaler-amido)-3-carbamoyloxymethyl- 7-methoxy-3-cephem-4-carboxylate which was 67% purified by chromatographic comparison with a pure standard.
Trinn B: Dimethoxymethylester av 73"(D-5-benzoylamino-5-ca rboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3- cefem- 4- carboxylsyre Step B: Dimethoxymethyl ester of 73"(D-5-benzoylamino-5-ca rboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4- carboxylic acid
Til en oppslemning av 20 g dinatrium-73~(D-5-benzoylamino-5-ca rboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4~carbox-ylat i 200 ml acetonitril ved 0°C tilsettes dråpevis 16 ml 6m klor-methyl-methylether i løpet av 90 minutter. Efter 1 times tilsetnings - tid tilsettes 6 ml S-collidin. Suspensjonen omrøres i ytterligere 2 timer ved 0°C Blandingen fortynnes så med 500 ml methylenklorid og vaskes to ganger med fortynnet fosforsyrc, en gang med fortynnet natriumbicarbonat og en gang med 5%-ig nat riumklor id, Vannfasene tilbakevaskes med 50 ml methylenklorid. Den organiske fase tørres med natriumsulfat og inndampes i vakuum til ca. 100 ml. To a slurry of 20 g of disodium 73~(D-5-benzoylamino-5-ca rboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4~carbox-ylate in 200 ml of acetonitrile at 0°C is added dropwise 16 ml of 6m chloro-methyl-methyl ether during 90 minutes. After 1 hour's addition time, 6 ml of S-collidine is added. The suspension is stirred for a further 2 hours at 0°C. The mixture is then diluted with 500 ml of methylene chloride and washed twice with diluted phosphoric acid, once with diluted sodium bicarbonate and once with 5% sodium chloride. The aqueous phases are backwashed with 50 ml of methylene chloride. The organic phase is dried with sodium sulfate and evaporated in vacuo to approx. 100 ml.
Oppløsningen føres gjennorn 200 mi silicagel G, vaskes med The solution is passed through 200 ml of silica gel G, washed with
200 ml methylenklorid, elueres så med 800 ml ethylacetat. Ethyl-acetateluatene inndampes i vakuum, hvorved man får 18,5 g gul olje. 200 ml of methylene chloride, then eluted with 800 ml of ethyl acetate. The ethyl acetate eluates are evaporated in vacuo, whereby 18.5 g of yellow oil is obtained.
Råproduktet omkrystalliseres fra 50 ml ethylacetat, hvilket gir 10,0 g (67%) av dimethoxymethylesteren av 7(3 - (D-5-benzoylamino-5~ ca rboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cefem-4-carboxy1-syre . The crude product is recrystallized from 50 ml of ethyl acetate, which gives 10.0 g (67%) of the dimethoxymethyl ester of 7(3 - (D-5-benzoylamino-5~ ca rboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4 -carboxyl-acid .
Trinn C : Natrium-7-(2-thienylacetamido)-7-methoxy-3-carba - Step C : Sodium 7-(2-thienylacetamido)-7-methoxy-3-carba -
moyloxymethy1 - 3 - cefem - 4 - carboxylat moyloxymethy1 - 3 - cephem - 4 - carboxylate
En suspensjon inneholdende 192 mg (0,3 mmol) dimethoxymethylester av 7(3-(D-5-benzoylamino-5-carboxyvaleramido) -3-carbamoyloxy-methyl-7-methoxy-3-cefem-4-carboxylsyre, 225 mg pulverisert Linde-type 4A molekylsikter inneholdende 10% ± 2% vann, 0,3 ml 2-thienylacetylklorid og 4 ml diklorethan kokes under tilbakeløp under kraftig omrøring i 4 timer. Blandingen avkjøles til 65°C, og IO ml 0,05M t-butanol i diklorethan tilsettes i løpet av 2 timer, og derpå oppvarmes i ytterligere 1 time ved 65°C. Reaksjonsblandingen avkjøles til 0°C, filtreres og vaskes i 5 ml methanol. Filtratet avkjøles til 0°C under omrøring, derpå tilsettes 1,4 ml 1:1 salt syre :methanol , og den erholdte blanding omrøres ved ca. 15°C i 3 timer. Blandingen helles i 10 ml vann inneholdende 1,6 g natriumbicarbonat. De organiske faser kastes. De vandige faser viser ved analyse et 65% utbytte av produktet, natrium-7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3-cefem-4-carboxylat. A suspension containing 192 mg (0.3 mmol) dimethoxymethyl ester of 7(3-(D-5-benzoylamino-5-carboxyvaleramido)-3-carbamoyloxy-methyl-7-methoxy-3-cephem-4-carboxylic acid, 225 mg powdered Linde type 4A molecular sieves containing 10% ± 2% water, 0.3 ml of 2-thienylacetyl chloride, and 4 ml of dichloroethane are refluxed with vigorous stirring for 4 hours, the mixture is cooled to 65°C, and 10 ml of 0.05M t-butanol in dichloroethane is added over 2 hours, and then heated for a further 1 hour at 65°C. The reaction mixture is cooled to 0°C, filtered and washed in 5 ml of methanol. The filtrate is cooled to 0°C with stirring, then 1.4 ml of 1:1 hydrochloric acid:methanol, and the resulting mixture is stirred at approximately 15°C for 3 hours. The mixture is poured into 10 ml of water containing 1.6 g of sodium bicarbonate. The organic phases are discarded. The aqueous phases show on analysis a 65 % yield of the product, sodium 7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylate.
Trinn D: På analogt vis anvendes p-klorbenzoylklorid, p-nitro-benzoylklorid eller toluolylklorid i trinn A. Sluttutbyttene av det ønskede produkt, nat rium-7-(2-thienylacetamido)-7-methoxy-3-carba-moyloxymethyl-3-cefem-4-carboxylat, er i hvert tilfelle hhv. 70%, Step D: Analogously p-chlorobenzoyl chloride, p-nitro-benzoyl chloride or toluolyl chloride are used in step A. The final yields of the desired product, sodium 7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3 -cephem-4-carboxylate, is in each case resp. 70%,
68% og 72%. 68% and 72%.
Eksempel 5 Example 5
Nat rium-7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethy1-3-cefem - 4j- carboxylat Sodium 7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethy1-3-cephem-4j-carboxylate
En blanding av 2,76 g (4 mmol) dimethoxymethylester av 7(3-(D-5-tosylamino-5-carboxyva leramido)-3-carbamoyloxymethy1-7a-methoxy-3-cefem-4-carboxylat, 3 g tørr Linde-type 4A molekylsikter med under 2% vann, 2 ml (16 mmol) thienylacetylklorid i 34 ml diklorethan om-røres under tilbakeløp i 5 timer, derpå tilsettes 0,38 ml (4 mmol) t-butanol, og omrøringen fortsettes i 2 timer. Ved utløpet av denne tid innføres ytterligere 0,095 ml (1 mmol) t-butanol, og reaksjonsblandingen omrøres under tilbakeløp i ytterligere 0,5 timer. Reaksjonsblandingen avkjøles til 0 - 5°C i et is-vannbad. Molekylsiktene fjernes ved sugefilt rering og vaskes så med 40 ml iskold methanol. Filtratet og vaskevæskene ble forenet og avkjølt til o°C. En iskold oppløsning av 8,3 ml konsentrert saltsyre og 9,5 ml methanol ble tilsatt og oppløsningen oppvarmet til 15°C og omrørt ved 15°C i 2 timer og 40 minutter. Når hydrolysen er fullstendig, stanses reaksjonen ved tilsetning til en suspensjon av 22 g nat riumbicarbonat i 120 ml vann ved 0 - 5°C. To-faseoppløsningen omrøres i 10 minutter. Den sterke saltutfeining som dannes, fjernes ved filtrering og vaskes med en liten mengde 5%-ig natriumkloridoppløsning inneholdende 0,5% nat riumbicarbonat. Diklorethanskiktet fraskilles og ekstraheres med 2 X 20 ml av en oppløsning av 0,5% natriumbicarbonat + 5% natrium-klorid. De vandige fraksjoner forenes og vaskes med 20 ml diklorethan. Natriumbicarbonatoppløsningen ble analysert ved væskekromato-grafi til å inneholde 73% nat rium-7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3-cefem-4-carboxylat og 2,1% uforandret utgangs-materiale. A mixture of 2.76 g (4 mmol) dimethoxymethyl ester of 7(3-(D-5-tosylamino-5-carboxyva leramido)-3-carbamoyloxymethy1-7a-methoxy-3-cephem-4-carboxylate, 3 g dry Linde -type 4A molecular sieves with less than 2% water, 2 ml (16 mmol) thienylacetyl chloride in 34 ml dichloroethane are stirred under reflux for 5 hours, then 0.38 ml (4 mmol) t-butanol is added, and the stirring is continued for 2 hours . At the end of this time, a further 0.095 ml (1 mmol) of t-butanol is introduced, and the reaction mixture is stirred under reflux for a further 0.5 hours. The reaction mixture is cooled to 0 - 5°C in an ice-water bath. The molecular sieves are removed by suction and then washed with 40 ml of ice-cold methanol. The filtrate and washings were combined and cooled to o° C. An ice-cold solution of 8.3 ml of concentrated hydrochloric acid and 9.5 ml of methanol was added and the solution warmed to 15° C and stirred at 15° C for 2 hours and 40 minutes. When the hydrolysis is complete, the reaction is quenched by adding to a suspension of 22 g of sodium bicarbonate in 120 ml of water at 0 - 5°C. The two-phase solution is stirred for 10 minutes. The strong salt solution that forms is removed by filtration and washed with a small amount of 5% sodium chloride solution containing 0.5% sodium bicarbonate. The dichloroethane layer is separated and extracted with 2 X 20 ml of a solution of 0.5% sodium bicarbonate + 5% sodium chloride. The aqueous fractions are combined and washed with 20 ml of dichloroethane. The sodium bicarbonate solution was analyzed by liquid chromatography to contain 73% sodium 7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylate and 2.1% unchanged starting material.
Eksempel <6> - 19 Example <6> - 19
Nat rium-7-(2-thienylacetamido)-7a-methoxy-3-carbamoyloxymethyl-3-cefem- 4- carboxylat Sodium 7-(2-thienylacetamido)-7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylate
Ved å følge den generelle fremgangsmåte angitt i eksempel 5 omsettes 2,8 g (4 mmol) dimethoxymethylester av 73-(D-5-tosylamino-5-carboxyvaleramido)-3-ca rbamoyloxymethyl-7a-methoxy-3-cefem-4-carbox-ylat under anvendelse av de følgende tabularisk angitte mengder av reagenser og reaksjonsbetingelser. Hele reaksjonstiden er i hvert tilfelle ca. 16 timer. De anvendte molekylsikter er i hvert tilfelle Linde-type 4A som oppvarmes til 700°C før reaksjonen, og oppviser et vekttap på ca. 3% ved tørring. Siktene er beregnet å være i det vesentlige vannfrie, med mindre enn 2 vekt% vanninnhold. Reaksjonstemperaturen er i hvert tilfelle 67°C. By following the general procedure indicated in example 5, 2.8 g (4 mmol) of dimethoxymethyl ester of 73-(D-5-tosylamino-5-carboxyvaleramido)-3-ca rbamoyloxymethyl-7a-methoxy-3-cephem-4- carbox-ylate using the following tabulated quantities of reagents and reaction conditions. The entire reaction time is in each case approx. 16 hours. The molecular sieves used in each case are Linde type 4A, which are heated to 700°C before the reaction, and show a weight loss of approx. 3% when drying. The sieves are designed to be essentially water-free, with less than 2% water content by weight. The reaction temperature is in each case 67°C.
Eksempel 13 er et sammenligningseksempel hvor molekylsikter ikke er anvendt. Example 13 is a comparison example where molecular sieves are not used.
Eksempel 20- 24 Example 20-24
Samme generelle fremgangsmåte ble anvendt som i eksempel 5 - 19, unntatt at reaksjonstemperaturen ble forandret som angitt i The same general procedure was used as in Examples 5 - 19, except that the reaction temperature was changed as indicated in
tabellen. Reaksjonsblandingen er 2,8 g (4 mmol) av dimethoxymethy1-esteren av 73 -(D-5-tosylamino-5-carboxyvaleramido)-3-carbamoyloxy-methyl-7a-methoxy-3-cefem-4-carboxylat, 3 9 tørrede Linde-type 4A sikter (mindre enn 2 vekt% vann) og 16 mmol thienylacetylklorid i 34 ml diklorethan. the table. The reaction mixture is 2.8 g (4 mmol) of the dimethoxymethyl ester of 73 -(D-5-tosylamino-5-carboxyvaleramido)-3-carbamoyloxy-methyl-7a-methoxy-3-cephem-4-carboxylate, 3 9 dried Linde type 4A sieve (less than 2 wt% water) and 16 mmol of thienylacetyl chloride in 34 ml of dichloroethane.
Sluttproduktet er i alle tilfelle natrium-73-(2-thienyl-acetamido) -7a-methoxy-3-carbamoyloxymethyl-3-cefem-4-carboxylat. The end product is in all cases sodium 73-(2-thienyl-acetamido)-7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylate.
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DK (1) | DK153154C (en) |
ES (1) | ES432305A1 (en) |
FI (1) | FI60210C (en) |
FR (1) | FR2253022B1 (en) |
GB (1) | GB1480757A (en) |
HU (1) | HU168823B (en) |
IE (1) | IE40122B1 (en) |
IT (1) | IT1043920B (en) |
NL (1) | NL187023C (en) |
NO (1) | NO147839C (en) |
SE (1) | SE432934B (en) |
YU (1) | YU36736B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS56158790A (en) * | 1980-05-14 | 1981-12-07 | Sankyo Co Ltd | Preparation of cephalosporin derivative |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2127225A1 (en) * | 1970-06-12 | 1971-12-16 | Yamanouchi Pharmaceutical Co Ltd , Tokio | New process for making cephalexin |
US3843639A (en) * | 1973-02-08 | 1974-10-22 | Bristol Myers Co | Production of cephalexin via methoxymethyl ester |
-
1974
- 1974-11-13 NL NLAANVRAGE7414820,A patent/NL187023C/en not_active IP Right Cessation
- 1974-11-13 DK DK589474A patent/DK153154C/en not_active IP Right Cessation
- 1974-11-13 SE SE7414249A patent/SE432934B/en not_active IP Right Cessation
- 1974-11-14 NO NO744088A patent/NO147839C/en unknown
- 1974-11-14 FI FI3301/74A patent/FI60210C/en active
- 1974-11-18 IE IE2366/74A patent/IE40122B1/en unknown
- 1974-11-21 YU YU3104/74A patent/YU36736B/en unknown
- 1974-11-25 CA CA214,541A patent/CA1041481A/en not_active Expired
- 1974-11-25 GB GB50969/74A patent/GB1480757A/en not_active Expired
- 1974-11-26 ES ES432305A patent/ES432305A1/en not_active Expired
- 1974-11-27 DD DD182615A patent/DD115125A5/xx unknown
- 1974-11-27 AR AR256686A patent/AR211234A1/en active
- 1974-11-28 IT IT54286/74A patent/IT1043920B/en active
- 1974-11-28 CH CH1580874A patent/CH618443A5/en not_active IP Right Cessation
- 1974-11-28 FR FR7439044A patent/FR2253022B1/fr not_active Expired
- 1974-11-29 DE DE2456528A patent/DE2456528C2/en not_active Expired
- 1974-11-29 HU HUME1803A patent/HU168823B/hu unknown
- 1974-11-30 JP JP49136660A patent/JPS6020393B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPS50105687A (en) | 1975-08-20 |
DK153154C (en) | 1988-10-24 |
DK589474A (en) | 1975-07-28 |
AU7550474A (en) | 1976-05-20 |
FR2253022B1 (en) | 1978-07-07 |
DD115125A5 (en) | 1975-09-12 |
NL187023C (en) | 1991-05-01 |
NO147839C (en) | 1983-06-22 |
FI60210C (en) | 1981-12-10 |
HU168823B (en) | 1976-07-28 |
FI330174A (en) | 1975-05-31 |
YU36736B (en) | 1984-08-31 |
IE40122L (en) | 1975-05-30 |
IT1043920B (en) | 1980-02-29 |
NL7414820A (en) | 1975-06-03 |
NL187023B (en) | 1990-12-03 |
DE2456528C2 (en) | 1986-01-16 |
GB1480757A (en) | 1977-07-27 |
CH618443A5 (en) | 1980-07-31 |
FR2253022A1 (en) | 1975-06-27 |
AR211234A1 (en) | 1977-11-15 |
DE2456528A1 (en) | 1975-06-05 |
JPS6020393B2 (en) | 1985-05-21 |
SE7414249L (en) | 1975-05-31 |
FI60210B (en) | 1981-08-31 |
DK153154B (en) | 1988-06-20 |
YU310474A (en) | 1981-11-13 |
IE40122B1 (en) | 1979-03-14 |
NO744088L (en) | 1975-06-23 |
ES432305A1 (en) | 1977-06-16 |
CA1041481A (en) | 1978-10-31 |
SE432934B (en) | 1984-04-30 |
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