DE2052531A1 - 3 halomethyl delta to the power of 3 cephalosporin esters - Google Patents
3 halomethyl delta to the power of 3 cephalosporin estersInfo
- Publication number
- DE2052531A1 DE2052531A1 DE19702052531 DE2052531A DE2052531A1 DE 2052531 A1 DE2052531 A1 DE 2052531A1 DE 19702052531 DE19702052531 DE 19702052531 DE 2052531 A DE2052531 A DE 2052531A DE 2052531 A1 DE2052531 A1 DE 2052531A1
- Authority
- DE
- Germany
- Prior art keywords
- phosphorus
- tert
- amino
- butyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 cephalosporin esters Chemical class 0.000 title claims description 36
- 229940124587 cephalosporin Drugs 0.000 title claims description 13
- 229930186147 Cephalosporin Natural products 0.000 title claims description 8
- 125000004970 halomethyl group Chemical group 0.000 title 1
- 238000000034 method Methods 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 14
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 2
- AYLIEDQYYJIGDP-UHFFFAOYSA-N [C]1=CC=CS1 Chemical group [C]1=CC=CS1 AYLIEDQYYJIGDP-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000003018 phosphorus compounds Chemical class 0.000 claims description 2
- 239000000126 substance Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 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 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical class N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical group CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 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
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- ZMBYOEUVJPYYFU-QHDYGNBISA-N tert-butyl (6R)-3-(bromomethyl)-7-formamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C(=O)NC1[C@@H]2N(C(=C(CS2)CBr)C(=O)OC(C)(C)C)C1=O ZMBYOEUVJPYYFU-QHDYGNBISA-N 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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
ü .v; U::■ Z H -ι. ;%j 2 3ü .v; U :: ■ Z H -ι. ;% j 2 3
hGi;-it.; j, j?, ϋί, . VuL. 3ö Ü2 36 83 680hGi; -it .; j, j ?, ϋί,. VuL. 3ö Ü2 36 83 680
Eli Lilly and Company, Indianapolis, Indiana, V.St.A.Eli Lilly and Company, Indianapolis, Indiana, V.St.A.
■2■ 2
3~Halogenmethy1~/\ -cephalosporinester3-halomethyl / cephalosporin ester
Zusatz zu Patent P 20 15 317.7Addition to patent P 20 15 317.7
Die Erfindung betrifft die weitere Ausbildung des Gegenstands von Patent P 20 15 317.7.The invention relates to the further development of the object from patent P 20 15 317.7.
Gegenstand der Erfindung sind 3-Halogenmethyl-/\ -cephalosporinester der Formel .. ■.The invention relates to 3-halomethyl- / \ -cephalosporin esters the formula .. ■.
1 R-NH-CH-CII 1 R-NH-CH-CII
CH,CH,
t <t <
CO-N. C-CH0XCO-N. C-CH 0 X
,2, 2
• COOR1
oder• COOR 1
or
ItIt
11 R-NH-CH-CH OH0 11 R-NH-CH-CH OH 0
If I C If I C
COOR1 COOR 1
209808/1866209808/1866
worin R einen C^Cg-Alkanoylrest, einen C2-Cg-Chloralkanoylrest oder eine Acylgruppe der Formelwherein R is a C 1 -C 6 alkanoyl radical, a C 2 -C 6 chloroalkanoyl radical or an acyl group of the formula
H5 H 5
00- ,00-,
E4 ■ ·E 4 ■ ·
worin Ar einen 2-Thienylrest darstellt, m eine ganze Zahl von 0 bis 4 ist, η eine ganze Zahl von 1 bis 4 ist, £ Sauerstoff oder Schwefel oder eine chemische Bindung be-where Ar is a 2-thienyl radical, m is an integer from 0 to 4, η is an integer from 1 to 4, £ oxygen or sulfur or a chemical bond is
3 4···
deutet, R und R Wasserstoffatome oder Methylreste sind,
oder, wenn R ein Wasserstoffatom istf R auch eine
N-geschützte Aminogruppe, nämlich eine N-tert.-Butoxycarbonyl)amino-,N-(Benzyloxycarbonyl)amino-,
N-(Allyloxycarbonyl)amino-, N-(Cyclopentyloxycarbonyl)amino- oder
N-(2-methoxycarbonyl-1-methylvinyl)aminogruppe sein
kann und η den Wert 1 haben kann und/oder, wenn R die N-geschützte Aminogruppe bedeutet, Ar auch eine Gruppe
der Pormel ' .3 4 ···
indicates that R and R are hydrogen atoms or methyl radicals, or, when R is a hydrogen atom, f R is also an N-protected amino group, namely an N-tert.-butoxycarbonyl) amino, N- (benzyloxycarbonyl) amino, N- (allyloxycarbonyl ) amino, N- (cyclopentyloxycarbonyl) amino or N- (2-methoxycarbonyl-1-methylvinyl) amino group and η can have the value 1 and / or, if R denotes the N-protected amino group, Ar also a group the formula '.
bedeuten kann, worin Y Wasserstoff oder Fluor, Chlor, Brom, Jod, C-|-C2-Alkylreste, Cj-C2-Alkyloxyreste, N-geschützte alpha-Amino-C^-Cj-alkylreate, Butoxycarbonylreste, Nitrogruppen, Cyangruppen oder Trifluormethylreste als Substituenten an'den Phenylringkohlenatoffatomen und w eine ganze Zahl von 1 bis 2 bedeutet, X Chlor, Fluor oder Jod und R einen 2,2,2-Trichloräthyl-, C.-Gg-tert.-Alkyl-, Cc-C,-tert.-Alkenyl-, Cc-C7-tert.-Alkinyl-, Benzyl-, Methoxybenzyl-, Nitrobenzyl-, Phenacyl-, Phthalimidoaethyl- oder Succinimidoaethylrest bedeutet. may mean in which Y is hydrogen or fluorine, chlorine, bromine, iodine, C- | -C2-alkyl radicals, Cj-C2-alkyloxy radicals, N-protected alpha-amino-C ^ -Cj-alkyl create, butoxycarbonyl radicals, nitro groups, cyano groups or trifluoromethyl radicals as substituents on the phenyl ring carbon atoms and w is an integer from 1 to 2, X is chlorine, fluorine or iodine and R is 2,2,2-trichloroethyl, C.-Gg-tert.-alkyl, Cc-C, -tert-alkenyl, Cc-C 7 -tert-alkynyl, benzyl, methoxybenzyl, nitrobenzyl, phenacyl, phthalimidoaethyl or succinimidoaethyl radical.
20 9 80 8/18.6 620 9 80 8 / 18.6 6
Das Verfahren zur Herstellung dieser Verbindungen ■ist dadurch gekennzeichnet, daß man eine der folgenden PhosphorverbindungenThe process for the preparation of these compounds is characterized in that one of the following Phosphorus compounds
(1) Phosphortrichlorid oder Phosphortribromid oder(1) phosphorus trichloride or phosphorus tribromide or
(2) Phosphorpentachlorid, Phosphorpentabromid, Phoaphoroxychlorid oder Phosphoroxybromid;(2) phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or phosphorus oxybromide;
•ar• ar
mit einem 3-HydroxymethyI-A -cephaloaporinaulfoxidester in Gegenwart eines tertiären Amins in einem praktisch wasserfreien flüssigen Verdünnungsmittel bei einer Temperatur von etwa -75 Grad \Q bis etwa 50 Grad C umsetzt und als Produkt den entsprechendenwith a 3-HydroxymethyI- A -cephaloaporinaulfoxidester in the presence of a tertiary amine in a practically anhydrous liquid diluent at a temperature of about -75 degrees \ Q to about 50 degrees C and the product is the corresponding
■2■ 2
(1) 3-Halogenmethyl~/\L -cephalosporinester bei Anwendung einer äquiaolaren Menge Phoephortrlchlorid oder Phosphortribromid und von Temperaturen oberhalb etwa -25 Grad C oder(1) 3- Halomethyl ~ / \ L -cephalosporin ester when using an equiaolar amount of phosphorus chloride or phosphorus tribromide and temperatures above about -25 degrees C or
(2) 3-Halogenmethyl-A -CQPhaloBporinsulfoxidester bei Anwendung einer etwa äquimaloren Menge Phosphortribromid oder Phosphortrichlorid und von Temperaturen unterhalb etwa -25 Grad C oder(2) 3-Halomethyl-A -CQPhaloBporine sulfoxide ester when using an approximately equal amount of phosphorus tribromide or phosphorus trichloride and from temperatures below about -25 degrees C or
(3) 3-Halogenmethyl-A-cephaloeporinsulfoxidester bei Anwendung von Phosphorpentachlorid, Phosphorpentabromid, Phosphoroxychlorid oder Phosphoroxybroaid erzeugt.(3) 3-halomethyl-A-cephaloeporine sulfoxide ester generated when using phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or phosphorus oxybroaid.
Einer der besonderen Vorteile von /\ -Desacetoxycephalosporin-Verbindungen liegt darin, daß sie nach dem Verfahren der USA-Patentschrift 3 275 626 aus Penicillinsulfoxidestern hergestellt werden können.One of the particular advantages of / \ -desacetoxycephalosporin compounds is that they can be prepared from penicillin sulfoxide esters by the process of US Pat. No. 3,275,626.
209808/1866209808/1866
•χ• χ
Die erfindungagemäßen 3-Halogenmethyl-A -cephalosporinester sind vorteilhafte Zwischenprodukte zur· Herstellung von neuen und bekannten stickstoff- und schwefelhaltigen 3-(Nuceliophil-methyl)-/\ -cephalosporinantibiotica und können zur Erzeugung vonThe 3-halomethyl-A-cephalosporin esters according to the invention are advantageous intermediates for the production of new and known nitrogen and Sulfur-containing 3- (Nuceliophil-methyl) - / \ -cephalosporin antibiotics and can be used to generate
•z• z
3-(Nucleophilmethyl)-/\ -cephalosporinen eingeaetzt werden, ohne daß Oxydations- und Reduktionsbedingungen angewandt werden müssen.3- (Nucleophilmethyl) - / \ -cephalosporinen incorporated without the need to apply oxidation and reduction conditions.
Durch das erfindungsgemäße Verfahren werden die Schwierigkeiten umgangen oder vermieden, die sich in manchen Fällen nach der Umwandlung., eines 3-Brommethyl-,A -The method according to the invention eliminates the difficulties circumvented or avoided, which in some cases after the conversion., of a 3-bromomethyl-, A-
cephalosporinester in einen 3-(Nucleophil-methyl)-^\ cephalosporinester ergeben können, wenn die nukleophile Gruppe ein oxydierbares Stickstoff- oder Sohwefelantom enthält.cephalosporin ester into a 3- (nucleophile-methyl) - ^ \ cephalosporin ester can result if the nucleophilic group is an oxidizable nitrogen or sulfur atom contains.
Das erfindungsgemäße Verfahren wird im einzelnen in der gleichen Weise durchgeführt, wie es im Hauptpatent beschrieben ist. .,The process according to the invention is carried out in detail in the same way as in the main patent is described. .,
Falls 7-Aminocephalosporansäure (7-ACA) als Ausgangsstoff verwendet werden soll, werden 7-Aminosohutzgruppen bevorzugt, die sich nicht nur leicht mit dem 7-Aminostickstoff verbinden,"sondern sich auch leicht entfernen lassen, nachdem die gewünschte Folge von Reaktionen an der Methylgruppe in 3-Stellung beendet ist. In solchen Fällen kann die bevorzugte 7-Aminoschutzgruppe eine einfache Cj-Cg-Alkanoylgruppe, zum Beispiel eine Formyl-, Aaetyl-, Propionyl-, Butanoyl- oder Hexanoylgruppe, ader eine C^-Og-Chloralkanoylgruppe, besondere eine alpha-Chloralkanoylgruppe, sum Beispiel eine 2-Chloracetylgruppe, sein. Diese Gruppen werden durch Umsetzung von 7-AOA alt dem entsprechenden Säurtohlorid If 7-aminocephalosporanic acid (7-ACA) is to be used as the starting material, preference is given to 7-amino protecting groups, which not only combine easily with the 7-amino nitrogen, but can also be easily removed after the desired sequence of reactions on the methyl group In such cases, the preferred 7-amino protective group can be a simple Cj-Cg -alkanoyl group, for example a formyl, aetyl, propionyl, butanoyl or hexanoyl group, or a C 1-6 chloroalkanoyl group, in particular an alpha-chloroalkanoyl group, for example a 2-chloroacetyl group, These groups are converted into the corresponding acid chloride by the reaction of 7-AOA
2 09808/ 1 8.6 62 09808/1 8.6 6
angebracht. Wenn der gewählte Gesamtverfahrensweg au dem Cephalosporinaritibioticum eine Acylierung von 7-ACA, eines Esters von 7-AGA, von 7~ACA~aulfoxid oder eines 7-AGA-sulfoxidesters mit der endgültigen Acy!gruppe erfordert, kann man beiunieloweise mit einer aktiviertenappropriate. If the chosen overall procedural route on the Cephalosporinaritibioticum an acylation of 7-ACA, an ester of 7-AGA, of 7-ACA-sulfoxide or one of them 7-AGA sulfoxide ester with the final Acy! Group requires, you can use an activated
; Form von N-geschütztera Pheny!glycin acylieren. Eine.; Acylate form of N-protected phenyl glycine. One.
•; solche aktivierte Form kunn aus dem gemischten Anhydrid bestehen, das durch Umsetzung von Isobutylchlorformiat und 2-^-(tert.-Butoxyoarboriyl)amino^~2~phenyles8lgsäure entsteht.• ; such an activated form can consist of the mixed anhydride which is formed by the reaction of isobutyl chloroformate and 2 - ^ - (tert-butoxyoarboryl) amino ^ 2 ~ phenyl-phenylgic acid.
Das Symbol R in den oben angegebenen FormelnI und II bedeutet eine Estergruppe), wie aie im Hauptpatent definiert ist.The symbol R in formulas I and II given above means an ester group), as defined in the main patent is.
Die erhaltenen 3-Halogenmethyl-^Λ,-cephaloaporlnester der Formel I sind als Zwischenprodukte zur direkten Herstellung von antibiotischen Gephalosporinverbindungen durch Entfernung der Estergruppe nach verschiedenen bekannten Methoden vorteilhaft, wie bereits im Hauptpatent angegeben ist. . .The 3-halomethyl- ^ Λ, -cephaloaporlnester obtained of formula I are available as intermediates for direct production of antibiotic gephalosporin compounds advantageous by removing the ester group by various known methods, as in the main patent is specified. . .
Die Verbindungen der Formel I und II sind hauptsächlich für die Herstellung bekannter und neuer antibiotisch aktiver Cephalosporinverbindungen von Bedeutung, wie bereits im Hauptpatent erläutert wurde.The compounds of formula I and II are mainly used for the production of known and new antibiotic active cephalosporin compounds of importance, as already explained in the main patent.
Durch die folgenden Beispiele, die die Durchführung des Verfahrens und typische Herstellungsweisen der neuen Verbindungen aeigen, wird die Erfindung näher erläutert.·Through the following examples showing the implementation of the process and typical manufacturing methods of the new Compounds, the invention is explained in more detail.
209808/186 6209808/186 6
Beispiel 1example 1
A 'A '
* *z * * z
7-Aoetamido-3-acetoxymethyl-A -cephem^-carbonsäure wird durch Umsetzung von 7-Aminocephalosporansäure (7-AGA) mit Acetylchlorld'hergestellt. Die 7-Acetamido-• 3-acetoxymethyl-^ -cephem-4-oarbonsäure wird durch Be-7-Aoetamido-3-acetoxymethyl-A -cephem ^ -carboxylic acid is produced by reacting 7-aminocephalosporanic acid (7-AGA) with Acetylchlorld '. The 7-acetamido • 3-acetoxymethyl- ^ -cephem-4-oarboxylic acid is
}■ handlung mit Oxalylchlorid in Gegenwart einer kleinen Menge Ν,Ν-Dimethylformamid in das entsprechende Säurechlorid übergeführt. Dieses Säurechlorid von 7-Acetamido-3-acetoxymethyl-^ -oephem-4-carbonsäure wird in Methylenchlorid gelöst, und die Lösung wird mit tert.-Butanol } ■ treatment with oxalyl chloride in the presence of a small amount of Ν, Ν-dimethylformamide converted into the corresponding acid chloride. This acid chloride of 7-acetamido-3-acetoxymethyl- ^ -oephem-4-carboxylic acid is dissolved in methylene chloride and the solution is treated with tert-butanol
^ und Triäthylamin behandelt,, um den tert.-Butyl-7-acetamido-3-acetoxymethyl-^ -cephem^-carboxylatester zu erzeugen.^ and triethylamine treated, to the tert-butyl-7-acetamido-3-acetoxymethyl- ^ -cephem ^ -carboxylate ester.
Der tert.-Butyl-7-acetamido-3-acetoxymethyl-/\ -cephem-4-carboxylat wird mit einer Persäure, zum Beispiel m-Chlorperbenzoesäure in einer Mischung aus Isopropanol und Methylenchlorid zu dem tert.-Butyl-7-acetamido-3-acetoxymethyl-^ -cephem-4-carboxylat-i-oxid oxydiert.The tert-butyl-7-acetamido-3-acetoxymethyl - / \ -cephem-4-carboxylate is with a peracid, for example m-chloroperbenzoic acid in a mixture of isopropanol and methylene chloride to the tert-butyl-7-acetamido-3-acetoxymethyl- ^ -cephem-4-carboxylate-i-oxide oxidized.
Das tert.-Butyl-7-aoetamido-3-acetoxymethyl-A -cephem-4-carboxylat-1-oxid wird nach bekannten Methoden mit Citrusacetyleateraee behandelt, um tert.-Butyl-7-acetamido-3-hvdroxymethyl-/\ -cephem^-carboxylat-i-oxid zu erhalten·The tert-butyl-7-aoetamido-3-acetoxymethyl-A -cephem-4-carboxylate-1-oxide is treated according to known methods with Citrusacetyleateraee to tert-butyl-7-acetamido-3-hydroxymethyl - / \ - to obtain cephem ^ -carboxylate-i-oxide
Das tert.-Butyl-7-acetamido-3-hvdroxymethyl-A -oephem-4-carboxylat-1-oxid wird mit Phosphortribromid nach der Arbeitsweise von Beispiel 7 des Hauptpatente behandelt, wodurch als· Produkt tert.-Butyl^-aoetamidoO-brommethyl- -cephem-4-carbpxylat-i-oxid erhalten wird.The tert-butyl-7-acetamido-3-hydroxymethyl-A-oephem-4-carboxylate-1-oxide is treated with phosphorus tribromide according to the procedure of Example 7 of the main patent, whereby the product tert-butyl ^ -aoetamidoO-bromomethyl- -cephem-4-carbpxylate-i-oxide is obtained.
209808/186 6209808/186 6
Dieses Produkt kann als Zwischenprodukt zur Herstellung verschiedener bekannter und neuer Cepha-4 losporinantibiotica verwendet werden. Beispielsweise kann dieses Produkt durch Behandlung mit Methanol in das 3-Methoxymethylanaloge oder mit Methylmercaptan in das 3-Methylthiomethylanaloge übergeführt werden. Solche Verbindungen können dann zum Sulfidzustand reduziert, zur Abspaltung der 7-Acetylgruppe in bekannter Weise mit PClc/CH^OH/HgO behandelt und mit"einer beliebigen Acylgruppe, die bekanntermaßen der erhaltenen /\ -Cephalosporinsäure gute Aktivität verleiht, wieder acyliert werden. Beispielsweise kann die tert.-Butyl-7-amino-3-methylthiomethyl-/y-cßphem—4-carboxylate8ter"kern"verbindung mit einem gemischten Alkylanhydrid eines N-D-(tert.-Butoxycarbonylamido)phenylglycins acyliert werden, und anschließend können die tert.-Butoxycarbonylschutzgruppe und die tert.-Butylestergruppen nach bekannten Methoden entfernt werden, wodurch das 3-Methylthiomethy1-7-^0-2'-amino-2 *-pheny!acetamido ^7-/\ -cephem-4-carbonsäurezwitterion (inneres SaI^, ein bekanntes Antibioticum, erhalten wird. This product can be used as an intermediate for the production of various known and novel Cepha- 4 losporinantibiotica. For example, this product can be converted into the 3-methoxymethyl analogue by treatment with methanol or into the 3-methylthiomethyl analogue with methyl mercaptan. Such compounds can then be reduced to the sulfide state, treated in a known manner with PClc / CH ^ OH / HgO to split off the 7-acetyl group and acylated again with any acyl group known to give the cephalosporic acid obtained. For example the tert-butyl-7-amino-3-methylthiomethyl- / y-cβphem-4-carboxylate8ter "core" compound can be acylated with a mixed alkyl anhydride of an ND- (tert-butoxycarbonylamido) phenylglycine, and then the tert. -Butoxycarbonyl protective group and the tert-butyl ester groups are removed by known methods, whereby the 3-Methylthiomethy1-7- ^ 0-2'-amino-2 * -pheny! Acetamido ^ 7 - / \ -cephem-4-carboxylic acid zwitterion (inner SaI ^, a well-known antibiotic, is obtained .
Die Aminogruppe von 7-Aminocephalosporansäure (7-ACA) wird mit einer Formylgruppe durch Umsetzung von 7-ACA mit dem gemischten Anhydrid, das durch Addition von Ameisensäure an Acetanhydrid entsteht, unter Bildung der 7-Pormamido-3-acetoxymethyl-/\-cephem-4-carbonaäure geschützt. Dieses N-geschützte 7-ACA wird in der in Beispiel 1 beschriebenen Weise unter Bildung dee tert.-Bitty1-7-formamido-3-acetoxymethyl-/\ -cephem-4-oarboxylatesterB vtreetert. Dieser ^\ -Cephaloeporin- The amino group of 7-aminocephalosporanic acid (7-ACA) is reacted with a formyl group by the reaction of 7-ACA with the mixed anhydride formed by addition of formic acid to acetic anhydride, to give the 7-Pormamido-3-acetoxymethyl - / \ - cephem -4-carbonic acid protected. This N-protected 7-ACA is converted in the manner described in Example 1 with the formation of the tert-Bitty 1-7-formamido-3-acetoxymethyl- / \ -cephem-4-carboxylate ester. This ^ \ -Cephaloeporin-
209 808/ 1 86 6209 808/1 86 6
ester wird wie in Beispiel 1 beschrieben zu tert,-Butyl-T-formamido-J-acetoxymethyl-/^ -cephem-4-carboxylat-1-oxid oxydiert. Dieser /\ -Cephalosporinsulfoxidester wird mit Citrusacetylesterase zu tert.-Butyl-7-formamido-3-hydroxymethyl-A -cephem-4-oarboxylat-1—oxid hydrolysiert, das als Ausgangsstoff für das erfindungsgemäße Verfahren dient.Ester is oxidized as described in Example 1 to tert -butyl-T-formamido-J-acetoxymethyl - / ^ -cephem-4-carboxylate-1-oxide. This / \ -Cephalosporinsulfoxidester is with Citrusacetylesterase to tert-butyl-7-formamido-3-hydroxymethyl-A -cephem-4-oarboxylat-1-oxide hydrolyzed, which serves as starting material for the novel process.
Nach der Arbeitsweise von Beispiel' 7 des Hauptpatente wird Phosphortribromid mit tert.-Butyl-T-formamido-J-hydroxymethyi-^y-cephem-^-carboxylat-i-oxid zu erfindungsgemäßem tert.~Butyl-7-formamido-3-brommethyl- -cephem-4-carboxylat umgesetzt.Following the procedure of Example '7 of the main patent Phosphorus tribromide with tert-butyl-T-formamido-J-hydroxymethyi- ^ y-cephem - ^ - carboxylate-i-oxide to tert-butyl-7-formamido-3-bromomethyl- -cephem-4-carboxylate implemented.
Biese Verbindung ist als Zwischenprodukt für die Herstellung von bekannten und neuen Cephalosporinantibiotica vorteilhaft. Beispielsweise kann diese Verbindung mit Methanol zu tert.-Butyl-^-formamido-O-methoxymethyl- -cephem-4-carboxylat-i-oxid umgesetzt werden, derThis compound is used as an intermediate for the manufacture of known and new cephalosporin antibiotics advantageous. For example, this compound can be combined with methanol to give tert-butyl - ^ - formamido-O-methoxymethyl- -cephem-4-carboxylate-i-oxide are converted, the
Sulfoxidester kann mit· Käliumjodid/Acetylchlorid zuSulphoxide ester can be added with potassium iodide / acetyl chloride
Λ 3Λ 3
tert.-Butyl^-formamido^-brommethyl-/^ -cephem-4-carboxylat
reduziert werden, und die Formylgruppe kann mit
Mineralsäure bei -15 bis 100 Grad G unter Bildung des 7-Amino-3-methoxymethyl-/\i -oepheia-4-carboxylatester-"kerns"
abgespalten werden. Dieser Kernester kann mit einer beliebigen Acylgruppe acyliert werden, die bekanntermaßen
zur Bildung einer Cephalosporinverbindung mit beträchtlicher antibiotisoher Aktivität beiträgt. Beispielsweise
kann der Kernester mit einer aktivierten N-geschützten Form von D-Phenylglycin unter Bildung von tert.-Butyl-7-/D-2-(N-geschütztem
Amino)-2'-phenyl-acetamidoj7"
3-methoxymethyl-^ -cephem-4-carboxylatester acyliert
werden. Die N-Schutzgruppe und die Estergruppe können nach bekannten Methoden unter Bildung der Ί-/Ώ-21 -Amines' -phenylacetamidg7-3-methoxymethyl-/Ni 5-oephem-4-carbonsäure,
eines bekannten Antibioticums, entfernt werden.tert-Butyl ^ -formamido ^ -bromomethyl - / ^ -cephem-4-carboxylate can be reduced, and the formyl group can with
Mineral acid at -15 to 100 degrees G with formation of the 7-amino-3-methoxymethyl- / \ i -oepheia-4-carboxylate ester "nucleus" are split off. This core ester can be acylated with any acyl group known to contribute to the formation of a cephalosporin compound with significant antibiotic activity. For example, the core ester with an activated N-protected form of D-phenylglycine to form tert-butyl-7- / D-2- (N-protected amino) -2'-phenyl-acetamidoj 7 "3-methoxymethyl- ^ The N-protective group and the ester group can be acylated by known methods with formation of the Ί- / Ώ-2 1- amines'-phenylacetamide-7-3-methoxymethyl- / N i 5 -oephem-4-carboxylic acid , a known antibiotic, must be removed.
209808/1866209808/1866
Claims (8)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US062699A US3922268A (en) | 1969-12-08 | 1970-08-10 | 3-Halomethyl-{66 {hu 3-Cephalosporin esters |
Publications (1)
Publication Number | Publication Date |
---|---|
DE2052531A1 true DE2052531A1 (en) | 1972-02-17 |
Family
ID=22044223
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19702065718 Pending DE2065718A1 (en) | 1970-08-10 | 1970-10-26 | PROCESS FOR THE PREPARATION OF 3-CHLORO OR BROMOMETHYL DELTA HIGH 3-CEPHALOSPORINE SULFOXIDE ESTER |
DE19702052531 Pending DE2052531A1 (en) | 1970-08-10 | 1970-10-26 | 3 halomethyl delta to the power of 3 cephalosporin esters |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19702065718 Pending DE2065718A1 (en) | 1970-08-10 | 1970-10-26 | PROCESS FOR THE PREPARATION OF 3-CHLORO OR BROMOMETHYL DELTA HIGH 3-CEPHALOSPORINE SULFOXIDE ESTER |
Country Status (5)
Country | Link |
---|---|
CH (2) | CH589659A5 (en) |
DE (2) | DE2065718A1 (en) |
GB (1) | GB1315379A (en) |
HK (1) | HK54876A (en) |
MY (1) | MY7600286A (en) |
-
1970
- 1970-10-19 GB GB4957870A patent/GB1315379A/en not_active Expired
- 1970-10-23 CH CH1573170A patent/CH589659A5/xx not_active IP Right Cessation
- 1970-10-26 DE DE19702065718 patent/DE2065718A1/en active Pending
- 1970-10-26 DE DE19702052531 patent/DE2052531A1/en active Pending
-
1976
- 1976-04-28 CH CH535876A patent/CH598264A5/xx not_active IP Right Cessation
- 1976-09-08 HK HK54876A patent/HK54876A/en unknown
- 1976-12-30 MY MY7600286A patent/MY7600286A/en unknown
Also Published As
Publication number | Publication date |
---|---|
GB1315379A (en) | 1973-05-02 |
CH589659A5 (en) | 1977-07-15 |
MY7600286A (en) | 1976-12-31 |
HK54876A (en) | 1976-09-17 |
DE2065718A1 (en) | 1975-07-17 |
CH598264A5 (en) | 1978-04-28 |
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