NO753955L - - Google Patents
Info
- Publication number
- NO753955L NO753955L NO753955A NO753955A NO753955L NO 753955 L NO753955 L NO 753955L NO 753955 A NO753955 A NO 753955A NO 753955 A NO753955 A NO 753955A NO 753955 L NO753955 L NO 753955L
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- group
- formula
- mononuclear
- alkyl
- Prior art date
Links
- -1 cyano-methyl Chemical group 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 10
- 229930186147 Cephalosporin Natural products 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229940124587 cephalosporin Drugs 0.000 claims description 7
- 150000001780 cephalosporins Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 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
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 claims 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000003831 tetrazolyl group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229910052809 inorganic oxide Inorganic materials 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 3
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 101100328518 Caenorhabditis elegans cnt-1 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
. Fremgangsmåte for fremstilling av. Method of manufacture of
cephalosporiner-.cephalosporins-.
I IN
Foreliggende oppfinnelse-angår en fremgangsmåte for fremstilling av cephalosporir.er. _ The present invention relates to a method for the production of cephalosporins. _
Norsk patentansøkning nr. 751.781 innsendt av foreliggende søker beskriver' blant annet 3-acylamino-2$-thiohydrazoazetidinoner med følgende formel: hvor V kan være hydrogen eller et alifatisk, aromatisk, aryl-alifatisk eller acylisk residiium, da spesielt et av de følgende residua: Norwegian patent application no. 751,781 submitted by the present applicant describes, among other things, 3-acylamino-2$-thiohydrazoazetidinones with the following formula: where V can be hydrogen or an aliphatic, aromatic, aryl-aliphatic or acyl residue, then in particular one of the following residues :
hvor R. er valgt fra gruppen bestående av hydrogen, alkyl med fra 1 til 4' karbonatomer og fra følgende grupper: cyano-metyl, thieny1-metyl, furyl-metyl, nafty1-mety1, fenyl-metyl, fenoksy- where R. is selected from the group consisting of hydrogen, alkyl with from 1 to 4' carbon atoms and from the following groups: cyano-methyl, thienyl-methyl, furyl-methyl, naphthy-1-methyl, phenyl-methyl, phenoxy-
1 1
metyl, fenyl-isopropyl, fenoksy^isoprppyl, pyridyl-4-thio-metyl, tetrazolyl-l-metyl methyl, phenyl-isopropyl, phenoxy^isopropyl, pyridyl-4-thio-methyl, tetrazolyl-1-methyl
og hvor R"*- er valgt fra gruppen bestående av: hydroksyl, alkoksyl med fra 1 til 4 karbonatomer, triklor-etoksy, benzyloksy, p-metoksybenzyloksy, p-nitrobenzyloksy, benzhydryloksy, trifenylmetoksy, fenacyloksy, p-halofenacyloksy. and where R"*- is selected from the group consisting of: hydroxyl, alkoxy with from 1 to 4 carbon atoms, trichloroethoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, triphenylmethoxy, phenacyloxy, p-halophenacyloxy.
Z er valgt fra gruppen bestående av hydrogen, hydroksyl, -0-Z is selected from the group consisting of hydrogen, hydroxyl, -0-
alkyl, -0-CO-alkyl eller fra residua -Br, -I, -N^, -NHg, alkyl, -O-CO-alkyl or from residues -Br, -I, -N^, -NHg,
-0-CO-CH^, 0-C0-NH2 og en S-mononukleær nitrogenheterocyklisk ; ring. E og 8 J er like eller kan være forskjellige og— representerer en lavere alkyl, en mononukleær aryl, CN-gruppe, en mononukleær heterocyklisk ring eller radikalene -COR^, -CONHR^ eller Rp og R^kan til sammen danne et av de -0-CO-CH^, 0-C0-NH2 and an S-mononuclear nitrogen heterocyclic; ring. E and 8 J are the same or may be different and— represents a lower alkyl, a mononuclear aryl, CN group, a mononuclear heterocyclic ring or the radicals -COR^, -CONHR^ or Rp and R^ can together form one of the
følgende residua: the following residues:
hvor<!.>T representerer ^.CH2, - R^ og hvor R^* er en lavere alkylgruppe, en mononukleær aryl og en mononukleær heterocyklisk ring eller lignende. Man har nå overraskende funnet, og dette funn utgjør et grunnlag for den foreliggende oppfinnelse, at nevnte 3-acylamino-2P-thiohydrazoazetidinoner kan d£sacyleres til de tilsvarende 3-°S 20-thiohydrazoazetidinoner med formelen IV ved en suksessiv behandling med et halogeneringsmiddel, en lavere alifatisk alkohol og et hydrolysemiddel vod h-jolp av— ligningen: where<!.>T represents ^.CH2, - R^ and where R^* is a lower alkyl group, a mononuclear aryl and a mononuclear heterocyclic ring or the like. It has now been surprisingly found, and this finding constitutes a basis for the present invention, that said 3-acylamino-2P-thiohydrazoazetidinones can be deacylated to the corresponding 3-°S 20-thiohydrazoazetidinones with the formula IV by successive treatment with a halogenating agent , a lower aliphatic alcohol and a hydrolyzing agent vod h-jolp of— the equation:
hvor R, R2, R^ samt V har samme betydning som angitt ovenfor. Man har også overraskende funnet" at hvis nevnte 3-amino-2P-thiohydrazoazetidinoner hvor substituenten V representerer residuet where R, R2, R1 and V have the same meaning as stated above. It has also surprisingly been found" that if the aforementioned 3-amino-2P-thiohydrazoazetidinones where the substituent V represents the residue
omsettes mdd uorganiske oksyder eller baser i overensstemmelse med de betingelser som er beskrevet i forannevnte norske patent-søknad nr. 751.781, så vil de cykliseres til derivater av 7-ACAy eller 7-ACDA som angitt ved hjelp av ligningen: '" are reacted with inorganic oxides or bases in accordance with the conditions described in the aforementioned Norwegian patent application no. 751,781, then they will be cyclized to derivatives of 7-ACAy or 7-ACDA as indicated by means of the equation: '"
hvor R<1>, R<2>, R^ og Z har samme betydning som angitt ovenfor. Denne prosess som mer detaljert vil bli beskrevet i det etter-følgende, representerer en ny og overraskende fremgangsmåte for where R<1>, R<2>, R^ and Z have the same meaning as stated above. This process, which will be described in more detail in the following, represents a new and surprising method for
fremstilling av derivater av 7-amino-cephalosporaninsyre (7-ACA)production of derivatives of 7-amino-cephalosporanic acid (7-ACA)
og 7-amino-desacetoksy-cephalosporaninsyre (7-AØCA), som er viktige mellomprodukter for fremstillingen av en rekke varierende cephalosporiner. and 7-amino-desacetoxy-cephalosporanic acid (7-AØCA), which are important intermediates for the production of a number of varying cephalosporins.
Det er videre en hensikt ved foreliggende oppfinnelseThere is a further purpose of the present invention
å fremstille cephalosporiner med formel III idet man går ut fra de forannevnte forbindelser med formel IV<*>, og hvor disse sist-nevnte omsettes med en R-CO-X-forbindelse, og hvor man i første to prepare cephalosporins of formula III starting from the aforementioned compounds of formula IV<*>, and where these last-mentioned are reacted with an R-CO-X compound, and where in the first
. trinn får 3-acylamino-23-thiohydrazo-azetidinoner med formel II<f>, som deretter omsettes med uorganiske oksyder eller baser slik det er angitt i forannevnte norske patentsøknad nr. 751»7&L»hvorved : . man får cephalosporiner med formel III. Dette er vist ved den etterfølgende ligning: . step obtains 3-acylamino-23-thiohydrazo-azetidinones of formula II<f>, which are then reacted with inorganic oxides or bases as stated in the aforementioned Norwegian patent application no. 751"7&L"whereby: . you get cephalosporins with formula III. This is shown by it following equation:
hvor R, R1, R<2>, R^ og Z har samme betydning som angitt ovenfor, where R, R1, R<2>, R^ and Z have the same meaning as stated above,
og X<*>representerer klor, brom, et hydroksyl, gt acyl radial med fra 1 til 4 karbonatomer eller residuet q - C H and X<*>represents chlorine, bromine, a hydroxyl, gt acyl radial with from 1 to 4 carbon atoms or the residue q - C H
I første trinn blir 3-acylamino-2P-thiohydrazoazetidinoner om-dannet til et imino-halogenid ved at det omsettes med et fosfor-halogenid f.eks. som fosforpentaklorid i et egnet oppløsnings-middel ved temperaturer mellom -10°C og +100°C i nærvær av et tertiært amin såsom pyridin. Etter avdampning av oppløsnings- In the first step, 3-acylamino-2P-thiohydrazoazetidinones are converted into an imino halide by reacting with a phosphorus halide, e.g. as phosphorus pentachloride in a suitable solvent at temperatures between -10°C and +100°C in the presence of a tertiary amine such as pyridine. After evaporation of the solvent
midlet under vakuum, ble residuet oppløst ved 0°C i en lavere alifatisk alkohol, fortrinnsvis metanol, og så hensatt et par timer ved romtemperatur. Man får dpå denne måten dannet en tilsvarende iminoeter. Oppløsningsmidlet blir eliminert ved for-dampning til tørrhet, og residuet blir gjenoppløst:i et vandig oppløsningsmiddel som tetrahydrcifuran/vann for å hydrolysere . \ iminoeteren til aminet med formel IV.. ; the agent under vacuum, the residue was dissolved at 0°C in a lower aliphatic alcohol, preferably methanol, and then left for a couple of hours at room temperature. In this way, a corresponding iminoether is formed. The solvent is eliminated by evaporation to dryness, and the residue is redissolved in an aqueous solvent such as tetrahydrofuran/water to hydrolyze. \ the iminoether of the amine of formula IV.. ;
Reaksjonsproduktet ble hensatt ved romtemperatur, V"" og oppløsningsmidlet ble fordampet under vakuum, hvoretter vann, natriumklorid og et oppløsningsmiddel som er ublandbart med vann, tilsatt og hele blandingen ble ristet. The reaction product was left at room temperature, V"" and the solvent was evaporated under vacuum, after which water, sodium chloride and a solvent immiscible with water were added and the whole mixture was shaken.
( Det forønskede produkt med formel IV vil gå over i det vandige lag hvorfra det kan ekstraheres ved svak alkalisering (The desired product of formula IV will pass into the aqueous layer from which it can be extracted by weak alkalization
og ekstraksjon med et oppløsningsmiddel som er ublandbart med . vann. and extraction with a solvent immiscible with . water.
Cykliseringen av mellomproduktene med formel IV<f>The cyclization of the intermediates of formula IV<f>
til derivater av 7-ACA eller 7-ADCA (V) utgjør som nevnt oven-to derivatives of 7-ACA or 7-ADCA (V) constitutes, as mentioned above,
for en ny og overraskende fremgangsmåte for en praktisk fremstilling av 7—-amino-cephalosporaninsyre og l- amlno- åesacetokBy- » cephalosporaninsyrev for a new and surprising method for a practical preparation of 7--amino-cephalosporanic acid and l-amlno-åesacetokBy- » cephalosporanic acid
Mellomproduktet med IV omsettes i et egnet oppløs-ningsmiddel ved temperaturer mellom -100°C og + 120°C med /uorga- ... niske oksyder såsom AlgO^, Fe20^, Cr20^, Si02 eller uorganiske eller organiske baser såsom KOH, NagCO^, NH^OH, alkalimetall-alkoholater, alifatiske, aromatiske og heterocykliske aminer, alkylammoniumbaser og basiske harpikser. The intermediate product with IV is reacted in a suitable solvent at temperatures between -100°C and +120°C with /inorganic oxides such as AlgO^, Fe20^, Cr20^, SiO2 or inorganic or organic bases such as KOH, NagCO^, NH^OH, alkali metal alcoholates, aliphatic, aromatic and heterocyclic amines, alkylammonium bases and basic resins.
Man får på denne måten fremstilt derivatet med formel V, som så kan isoleres og renses på vanlig kjent måte. '" iT In this way, the derivative of formula V is produced, which can then be isolated and purified in a conventional manner. '" iT
Oppfinnelsen angår også en modifikasjon av den ":i fremgangsmåte for fremstilling av cephalosporiner med formel III, The invention also relates to a modification of the ":i process for the production of cephalosporins of formula III,
som er beskrevet i forannevnte norske patentsøknad nr. J^ l. fQl innsendt av foreliggende søker: which is described in the aforementioned Norwegian patent application no. J^ l. fQl submitted by the present applicant:
hvor man går ut fra et 3-afflino-2S-thiohydrazoazetidinon med for- where one starts from a 3-afflino-2S-thiohydrazoazetidinone with for-
mel IV<*>slik det er beskrevet ovenfor. Denne forbindelse acyleres med aminogruppen i stilling 3 ved at den omsettes med en forbindelse R-CO-X<*>, hvorved man får 3-acylamino-2|3-thiohydrazoazetidinoner flour IV<*>as described above. This compound is acylated with the amino group in position 3 by reacting it with a compound R-CO-X<*>, whereby 3-acylamino-2|3-thiohydrazoazetidinones are obtained
med formel II<*>. Disse mellomprodukter som er beskrevet i foran- v nevnte patentsøknad blir så cykllsert ved samme fremgangsmåte ved at de behandles med uorganiske oksyder eller baser og man får til slutt cephalosporiner med forannenvnte formel III, hvor R, R og Z har samme betydning som angitt ovenfor, og X<*>representerer with formula II<*>. These intermediate products which are described in the above-mentioned patent application are then cyclized by the same method by treating them with inorganic oxides or bases and finally cephalosporins with the aforementioned formula III are obtained, where R, R and Z have the same meaning as stated above, and X<*>represents
klor. brom. et hvdroksvl. et acvloksvradikal med fra 1 til 4. kar-chlorine. bromine. a hvdroksvl an acvloxvradical with from 1 to 4. car-
w w «r ~ 1 m w w «r ~ 1 m
bonatomer, eller residuet bonatoms, or the residue
De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
EKSEMPEL 1 EXAMPLE 1
Metyl- 2g- thiohydrazodikarbok3yetyl- tt- i80propenyl- 4- oxo- 3B-amino- l- azetidin- acetat<1>Methyl- 2g- thiohydrazodicarbox3yethyl- tt- i80propenyl- 4- oxo- 3B-amino- l- azetidine- acetate<1>
1,05 g PCl^ble tilsatt en oppløsning av 2,2 g metyl-2B-thiohydrazodikarboksyetyl-a-isopropenyl-4-oxo-3P-fénoksy- • 1.05 g of PCl^ was added to a solution of 2.2 g of methyl-2B-thiohydrazodicarboxyethyl-α-isopropenyl-4-oxo-3P-phenoxy- •
acetamido-l-aaetidin-acetat i 100 ml vannfri benzen inneholdende 1,5 ml vannfri pyridin, og blandingen ble holdt på 50°C i 60 minutter. Oppløsningsmidlet ble avdampet, og residuet ble av-kjølt til 0°C og gjenoppløst i kald metanol og hensatt ved romtemperatur i to timer. Oppløsningsmidlet ble fordampet, og resi- V duet gjenoppløst under avkjøling, ved hjelp av tetrahydrofuran og vann {1:1, volum/volum) og så hensatt i 30 minutter ved romtemperatur. Tetrahydrofuranen ble avdampet under vakuum t - og man tilsatte salt, vann og etylacetat under røring. Det forønskede acetamido-1-aaethidine acetate in 100 ml of anhydrous benzene containing 1.5 ml of anhydrous pyridine, and the mixture was kept at 50°C for 60 minutes. The solvent was evaporated, and the residue was cooled to 0°C and redissolved in cold methanol and left at room temperature for two hours. The solvent was evaporated, and the residue redissolved under cooling, using tetrahydrofuran and water (1:1, volume/volume) and then left for 30 minutes at room temperature. The tetrahydrofuran was evaporated under vacuum t - and salt, water and ethyl acetate were added while stirring. The desired
produkt vil gå totalt over i den vandige fase hvorfra det kan bli product will completely pass into the aqueous phase from which it can become
ekstrahert ved alkalisering med NaHCO^og ekstraheringiflére extracted by alkalization with NaHCO^ and extraheringiflere
ganger med etylacetat. Man fikk på denne måten 1,1 g av det for-ønskede produkt. times with ethyl acetate. In this way, 1.1 g of the desired product was obtained.
I.R.- (CHgClg): 34OO cnT1(NH og NH2)I.R.- (CHgClg): 34OO cnT1(NH and NH2)
I76O cm"1 (CK) p lactam)I76O cm"1 (CK) p lactam)
1735 cm"<1>(00 ester og karbonater) 1735 cm"<1>(00 ester and carbonates)
EKSEMPEL 2 EXAMPLE 2
Metyl- 28- thiohydrazodikarboksyetyl- a- i3opropylidin- 4- oxo- 33-amino- l- azetidin- acetat Methyl- 28- thiohydrazodicarboxyethyl- α- i3opropylidine- 4- oxo- 33-amino- 1- azetidine- acetate
2,3 g fosforpentaklorid ble tilsatt en oppløsning ar 5,0 g metyl-23-thiohydrazodikarboksyetyl-a-isopropyliden-4^oxo--3B-fenoksyacetamido-l-azetidin-acetat i 2$ 0 ml vannfri benzen inneholdende 3 ral vannfri pyridin, og blandingen ble i 90 minutter holdt på 50°C«Benzenen ble fordampet, og vannfri metanol ble tilsatt ved 0 C hvoretter blindingen ble hensatt ved romtemperatur i 90 minutter. Metanolen ble fordampet, og tétra-hydrofuran/vann (1:1, volum/volum) ble tilsatt under kontinuer—* lig røring. Blandingen ble hensatt i 40 minutter ved romtemperatur, hvoretter tetrahydftbfuranen ble fordampet under vakuum, 2.3 g of phosphorus pentachloride was added to a solution of 5.0 g of methyl-23-thiohydrazodicarboxyethyl-α-isopropylidene-4^oxo--3B-phenoxyacetamido-1-azetidine-acetate in 2$0 ml of anhydrous benzene containing 3 ral of anhydrous pyridine , and the mixture was kept at 50°C for 90 minutes. The benzene was evaporated, and anhydrous methanol was added at 0°C, after which the blank was left at room temperature for 90 minutes. The methanol was evaporated, and tetrahydrofuran/water (1:1, v/v) was added with continuous stirring. The mixture was allowed to stand for 40 minutes at room temperature, after which the tetrahydrofuran was evaporated under vacuum,
og man tilsatte saltvann og etylacetat. Produktet gikk over i den vandige fase som så ble alkalisert med NaHCO^og gjentatte ganger ekstrahert med etylacetat. Man fikk på denne måten 3, 0 g . av produktet. and salt water and ethyl acetate were added. The product passed into the aqueous phase which was then alkalized with NaHCO 3 and repeatedly extracted with ethyl acetate. 3.0 g was obtained in this way. of the product.
I.R. (CH2C12): 34OO cm"1(NH)I.R. (CH2C12): 34OO cm"1(NH)
1755 cm"1 (C-0 B-lactam)1755 cm"1 (C-0 B-lactam)
1725 cm"<1>(0*0 ester og karbonater)1725 cm"<1>(0*0 ester and carbonates)
EKSEMPEL 3 EXAMPLE 3
2 * , 2', 2'- trikloretyl^ g- thiohydrazodikarboksyetyl- a- isopropenyl-4- QXO- 3S- amino- l- azetidin- acetat 2 * , 2', 2'- trichloroethyl^ g- thiohydrazodicarboxyethyl- a- isopropenyl-4- QXO- 3S- amino- l- azetidine- acetate
3 ml vannfri pyridin og 2,5 g PCI,- ble tilsatt en.... oppløsning av 6,55 g 2',2f,2 Vtrikloretyl^B-thiohydrazodikar-boksyletyl-a-isopropenyl^-oxo^B-fenoksyacetamido-l-azetidin-acetat i 200 ml vannfri benzen, og blandingen ble holdt på 50°C 3 ml of anhydrous pyridine and 2.5 g of PCI,- were added to a... solution of 6.55 g of 2',2f,2Vtrichloroethyl^B-thiohydrazodicarboxylethyl-a-isopropenyl^-oxo^B-phenoxyacetamido- 1-azetidine acetate in 200 ml of anhydrous benzene, and the mixture was kept at 50°C
i 90 minutter. Benzenen ble fordampet, og vannfri metanol ble tilsatt under avkjøling, hvoretter blandingen ble hensatt ved for 90 minutes. The benzene was evaporated, and anhydrous methanol was added with cooling, after which the mixture was set at
romtemperatur i en time. Oppløsningsmidlet ble igjen fordampet, room temperature for one hour. The solvent was again evaporated,
. og residuet ble etter avkjøling oppløst i en blanding av tetra- O hydrofuran og vann (1:1, volum/volum). Blandingen ble hensatt i 30 minutter ved romtemperatur, hvoretter tetrahydrofuranen ble . and the residue, after cooling, was dissolved in a mixture of tetra-O hydrofuran and water (1:1, volume/volume). The mixture was left for 30 minutes at room temperature, after which the tetrahydrofuran was
fordampet og man tilsatte saltvann og etylacetat. Den vandige fase ble utskilt og alkalisert med NaHCO^og ekstrahert flere ganger med etylacetat, noe som ga 3»7g av det forønskede produkt. I.R. (CH2C12): 34OO cm"<1>(NH og NH2) evaporated and brine and ethyl acetate were added. The aqueous phase was separated and alkalized with NaHCO 3 and extracted several times with ethyl acetate, yielding 3.7 g of the desired product. I.R. (CH2C12): 34OO cm"<1>(NH and NH2)
I76Ocm"<1>(C=0 B-lactam)I76Ocm"<1>(C=0 B-lactam)
1735 cm"<1>(C»0 ester og karbonater)1735 cm"<1>(C»0 ester and carbonates)
EKSEMPEL 4 EXAMPLE 4
Metylester av 7- amino- desacetoksycephalosporaninsyreMethyl ester of 7-amino-desacetoxycephalosporanic acid
En 30 f° oppløsning av KOH i vann ble under magnetisk røring tilsatt en oppløsning av 2 g raetyl-28-thiohydrazodi- A 30% solution of KOH in water was added under magnetic stirring to a solution of 2 g of raethyl-28-thiohydrazodi-
i in
)"'■ karboksyetyl-a-isopropen7l-^-pxo-3P-amino-l-az)"'■ carboxyethyl-a-isopropene7l-^-pxo-3P-amino-1-az
100 ml benzen, og blandingen ble.hensatt ved romtemperatur i en time. Det organiske lag ble utskilt og vasket flere ganger med 100 ml of benzene, and the mixture was left at room temperature for one hour. The organic layer was separated and washed several times with
vann. Produktet ble kromatografert over silisiumdioksyd med benzen-etyleter. Man fikk på denne måten fremstilt 0,800 g av produktet. Smeltepunkt 123-124°C (etyleter). / pette produkt hadde kjemiske og fysiske karakteristika (dvs. smeltepunkt, I.R., N.M.R., og massespektrum) tilsvarende det man fant for et produkt fremstilt på en annen måte;/ water. The product was chromatographed over silica with benzene-ethyl ether. 0.800 g of the product was produced in this way. Melting point 123-124°C (ethyl ether). / pet product had chemical and physical characteristics (i.e. melting point, I.R., N.M.R., and mass spectrum) similar to what was found for a product produced in a different way;/
EKSEMPELEXAMPLE
2 * , 2 *, 2 ^ trikloretylester' av 7- aminodesacetoksycephalosporansyre 2 * , 2 *, 2 ^ trichloroethyl ester' of 7-aminodesacetoxycephalosporanic acid
En 30 # oppløsning av K0H i. vann ble tilsatt en opp-løsning av 2,1 g 2» ,2' ^-trikloretyl^S-thiohydrazodikarboksyetyl-a-isopropenyl-4-oxo-3P-amino-l-azetidin-acetat i 100 ml ben- ~ zen, og blandingen ble under røring hensatt i en time. Det organiske lag ble utskilt og rørt med surgjort vann, slik at produktet gikk over i vannet som et salt. Det organiske lag ble eliminert, og det vandige lag ble gjort alkalisk med NaHCO^og ekstrahert med etylacetat. Man fikk på denne måten 1,3 g av det forønskede produkt. Produktet har de karakteristika som er angitt i litteraturen (J. Org. Chem. 1971, 36, 1259). ®& r dette produkt ble behandlet ved hjelp av kjente fremgangsmåter, ga det f- amino-desacetoksycephalosporaninsyre (7-ADCA). A 30% solution of KOH in water was added to a solution of 2.1 g of 2',2'^-trichloroethyl^S-thiohydrazodicarboxyethyl-α-isopropenyl-4-oxo-3β-amino-1-azetidine acetate in 100 ml of benzene, and the mixture was stirred for one hour. The organic layer was separated and stirred with acidified water, so that the product passed into the water as a salt. The organic layer was eliminated and the aqueous layer was made alkaline with NaHCO 3 and extracted with ethyl acetate. In this way, 1.3 g of the desired product was obtained. The product has the characteristics stated in the literature (J. Org. Chem. 1971, 36, 1259). ®& r this product was treated using known methods, it gave f-amino-desacetoxycephalosporanic acid (7-ADCA).
EKSEMPEL 6 EXAMPLE 6
Metyl- 2P- thlohydrazodikarboksyetyl- a- isopropyliden- 4- oxo- 3P~ ■ fenylacetamido- l- azetidin- acetat v Methyl- 2P- thlohydrazodicarboxyethyl- a- isopropylidene- 4- oxo- 3P~ ■ phenylacetamido- l- azetidine- acetate v
En oppløsning av 2,0 g metyl-2B-thiohydrazodikar-boksyletyl-a-isopropyliden-4-oxo-3S-amino-l-azetidin-acetat i 80 ml benzen ble under røring tilsatt 40 -al av en mettet opp-",J løsning av NaHCO^, og blandingen ble tilsatt 1,5 ml av kloridet av fenyleddiksyre ved 0°C. Blandingen ble rørt ved romtemperatur i en time, hvoretter det organiske lag ble utskilt, tørket over Na2S0^og fordampet. Residuet ble kromatografert over silisiumdioksyd, eluert med benzen-etyl-acetat (70:30, volum/ volum). Man fikk på denne måten 2,1 g av det forønskede pro-^ dukt, A solution of 2.0 g of methyl-2B-thiohydrazodicarboxylethyl-α-isopropylidene-4-oxo-3S-amino-1-azetidine acetate in 80 ml of benzene was added with stirring to 40 μl of a saturated op-", J solution of NaHCO^, and to the mixture was added 1.5 ml of the chloride of phenylacetic acid at 0° C. The mixture was stirred at room temperature for one hour, after which the organic layer was separated, dried over Na2SO^ and evaporated. The residue was chromatographed over silica, eluted with benzene-ethyl acetate (70:30, volume/ volume). In this way, 2.1 g of the desired product was obtained,
IR (CHCl^): 3420 cm"<1>(N-H)IR (CHCl^): 3420 cm"<1>(N-H)
1765 cm"1 (00 B-lactam)1765 cm"1 (00 B-lactam)
I725 cm"<1>(OO ester og karbamater)I725 cm"<1>(OO ester and carbamates)
1670 ca"<1>(OO amid)1670 ca"<1>(OO amide)
NMR (CDCl^): 1,14 og 1,17 (to t, 6H, 2 CH^(H2)-), 2,02~og ' ' NMR (CDCl^): 1.14 and 1.17 (two t, 6H, 2 CH^(H2)-), 2.02~ and ' '
2,19 (to s, 6H, 2 CH3-é»), 3,57 (s, 2H, C6(H5)--CH2-C0-), 3,67 (s, 3H, C00CH3), 4,08 (q, 4H, 2 CH2-C(H3) ), 4,88 (dd, 1H, C(3)H), 5,70 (d, 1H, C(4)H ) og 6,5-7.4 d(m, 7H, 2 CONH og C^)<.>2.19 (two s, 6H, 2 CH3-é»), 3.57 (s, 2H, C6(H5)--CH2-C0-), 3.67 (s, 3H, C00CH3), 4.08 (q, 4H, 2 CH2-C(H3) ), 4.88 (dd, 1H, C(3)H), 5.70 (d, 1H, C(4)H ) and 6.5-7.4 d (m, 7H, 2 CONH and C^)<.>
EKSEMPEL 7 EXAMPLE 7
Metyl- 2B- thiohydrazodikarboksyetyl- a- lsopropenyl- 4- oxo- 3S-fenyl- acetamido- l- azetidin- acetat Methyl- 2B- thiohydrazodicarboxyethyl- a- alsopropenyl- 4- oxo- 3S- phenyl- acetamido- l- azetidine- acetate
Dette produkt ble fremstilt som angitt i eksempel 6. Det fremstilte produkt ble behandlet med baser på kjent måte, og ga da det tilsvarende desacetoksycephalosporin med karakteristika som tilsvarer det man finner i en prøve fremstilt på en annen måte, og i overensstemmelse med de data som er angitt i litteraturen, (J. Chem. Soc. 1971, 3540). This product was prepared as indicated in Example 6. The prepared product was treated with bases in a known manner, and then gave the corresponding desacetoxycephalosporin with characteristics corresponding to those found in a sample prepared in a different manner, and in accordance with the data which is stated in the literature, (J. Chem. Soc. 1971, 3540).
EKSEMPEL 8 EXAMPLE 8
2% 2T , 2t- trlkloretyl- 23- thiohydra2odikarboksyetyl- a- isopropenyl-4- QX0- 36-/ M-( ter- butoksykarbonyl)- D- a- fenylglycinamido/-— 1- azetidin- acetat 2% 2T , 2t- trlchloroethyl- 23- thiohydra2odicarboxyethyl- a- isopropenyl-4- QX0- 36-/ M-( ter-butoxycarbonyl)- D- a- phenylglycinamido/-— 1- azetidine- acetate
En oppløsning av 1,1 g karboterbutoksyfenylglycin A solution of 1.1 g of carboterbutoxyphenylglycine
og 0,62 ml trietylamin i 10 ml metylenklorid ble ved -15°C under røring tilsatt 0,4 ml etylklorformat oppløst i 10 ml vannfri metylenklorid. Blandingen ble hensatt i 3° minutter under nevnte betingelser. Man tilsatte deretter en oppløsning av 1,7 g 2',2f-21-trikloretyl-23-thiohydrazodikarboksyetyl-a-isopropenyl-4-oxo-3P-amino-l-azetidin-acetat i 30 ml CHgClg under langsom tilset-ning og røring. Blandingen ble hensatt i 3 timer ved -10°C, hvoretter man^tilsatte vann og CHgClg. Det organiske lag ble utskilt, det vandige lag ble igjen ekstrahert med CHgClg, og de vandige lag ble tørket og fordampet, hvorved man fikk et residuum som ble kromatografert over silisiuradioksyd med benzen-etylacetat (80:20, volum/volum). Man fikk på denne måten 2,1 g av det for- and 0.62 ml of triethylamine in 10 ml of methylene chloride was added at -15°C with stirring to 0.4 ml of ethyl chloroformate dissolved in 10 ml of anhydrous methylene chloride. The mixture was allowed to stand for 3 minutes under the conditions mentioned. A solution of 1.7 g of 2',2f-21-trichloroethyl-23-thiohydrazodicarboxyethyl-a-isopropenyl-4-oxo-3P-amino-1-azetidine acetate in 30 ml of CHgClg was then added under slow addition and stirring. The mixture was left for 3 hours at -10°C, after which water and CHgClg were added. The organic layer was separated, the aqueous layer was again extracted with CHgClg, and the aqueous layers were dried and evaporated to give a residue which was chromatographed over silica with benzene-ethyl acetate (80:20, v/v). In this way, 2.1 g of the resulting
I ønskede produkt. MR (CDCiy: 1,14 og 1,17 (to t, 6 H, 2 CH^-C(H2) ), 1,40 In desired product. MR (CDCIi: 1.14 and 1.17 (two t, 6 H, 2 CH^-C(H2) ), 1.40
(s, 9 H, -c(CH3)3), 1,94 (s, 3 H, ch3-c«), 4,08 (s, 9 H, -c(CH3)3), 1.94 (s, 3 H, ch3-c«), 4.08
(q, 4 H, 2 CH2-C(H3) ), 4.9° (s, 1 H, -&-CH-C00-), (q, 4 H, 2 CH2-C(H3) ), 4.9° (s, 1 H, -&-CH-C00-),
C«=C«=
4,88 og 5,00 (2 d, 2 H, -C00-CH2-CC13) 5,07 og 0 5,16 (bred s, 2 H, «CHg), 5,28 (s, 1 H, C6(H5)-CH-C-), 4.88 and 5.00 (2d, 2H, -C00-CH2-CC13) 5.07 and 0 5.16 (broad s, 2H, «CHg), 5.28 (s, 1H, C6 (H5)-CH-C-),
f ■ 5,3-5,7 (m, 2 H, H av §-lactam) og 6,5-8,Oa (m, 8 H, aromatisk H og 3 NH). f ■ 5.3-5.7 (m, 2 H, H of §-lactam) and 6.5-8.Oa (m, 8 H, aromatic H and 3 NH).
EKSEMPEL 9 EXAMPLE 9
2f. 2'. 2 T- trikloretyl- 7-/ ft-( ter- butoksykarbonyl)- D- a- fenylglvcin-amid67~ 3- P16tyl- 3- cephem- 4- karboksylat 2 f. 2'. 2 T- trichloroethyl- 7-/ ft-(ter- butoxycarbonyl)- D- a- phenylglucinamide67~ 3- P16tyl- 3- cephem- 4- carboxylate
En oppløsning av 0,4 g 2*,2*,2'-trikloretyl-28-thiohydra2odikarboksyetyl-a-isopropenyl-4-oxo-3P-/N-(ter-butoksy-karbonyl) -D-a-f enylglycinamido/-l-azetidin-acetat i 100 ml benzen ble rørt i nærvær av et overskudd av A1203. Blandingen ble hensatt i 2 timer, så frafiltrert fra nevnte A1203hvorpå residuet ble kromatografert over silisiumdioksydgel idet man eluerte produktet med benzen-etylacetat (90:10, volum/volum), hvorved man fikk 200 mg av cephalosporaninproduktet. Dette produkt hadde samme karakteristika som angitt i litteraturen. (J. Org. Chem. 1971, 36, 1259) Når produktet ble behandlet ved hjelp av kjente fremgangsmåter, ga det 7-(I^-a2iino-o-fenylacetamido)-3-metyl-3-cephem-4-karboksylsyre, med de samme karakteristika som angitt i litteraturen (J. Org. Chem. 1971, 36, 1259). A solution of 0.4 g of 2*,2*,2'-trichloroethyl-28-thiohydra2dicarboxyethyl-α-isopropenyl-4-oxo-3β-/N-(tert-butoxy-carbonyl)-D-α-phenylglycinamido/-1-azetidine -acetate in 100 ml of benzene was stirred in the presence of an excess of Al 2 O 3 . The mixture was allowed to stand for 2 hours, then filtered from said A1203, whereupon the residue was chromatographed over silica gel, eluting the product with benzene-ethyl acetate (90:10, volume/volume), whereby 200 mg of the cephalosporanin product was obtained. This product had the same characteristics as stated in the literature. (J. Org. Chem. 1971, 36, 1259) When the product was treated by known methods, it gave 7-(I^-α2iino-o-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid, with the same characteristics as stated in the literature (J. Org. Chem. 1971, 36, 1259).
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO753955A NO753955L (en) | 1974-06-12 | 1975-11-24 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2388774 | 1974-06-12 | ||
NO752034A NO752034L (en) | 1974-06-12 | 1975-06-09 | |
NO753955A NO753955L (en) | 1974-06-12 | 1975-11-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO753955L true NO753955L (en) | 1975-12-15 |
Family
ID=27273375
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO753955A NO753955L (en) | 1974-06-12 | 1975-11-24 |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO753955L (en) |
-
1975
- 1975-11-24 NO NO753955A patent/NO753955L/no unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4504658A (en) | Epimerization of malonic acid esters | |
EP0023097A1 (en) | De-arylmethylation of N-mono- or N-diarylmethyl-beta-lactams; novel azetizinones having anti-bacterial activity | |
US4122262A (en) | Intermediates and methods for preparing 7-acylamino-8-oxo-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid derivatives | |
SU546282A3 (en) | The method of obtaining 7-α-amino-7 methoxy-cephalosporin esters | |
US4122086A (en) | Isopenicillins | |
US5639877A (en) | Intermediates in the synthesis of cephalosporins | |
IE46611B1 (en) | Thiooxime cephalosporin and penicillin derivatives | |
EP0018546B1 (en) | Process for the production of phenylglycyl chloride hydrochlorides | |
NO752034L (en) | ||
US4252973A (en) | Process for chemically removing the acyl sidechain from cephalosporins and penicillins | |
NO753955L (en) | ||
US3941779A (en) | Method for producing 2-(substituted thio)-3-cephem derivatives | |
US4036835A (en) | Process for preparing cephalosporins | |
US4103086A (en) | 8-Oxo-4-thia-1-azabicyclo (4.2.0)-oct-2-ene derivatives | |
US4284767A (en) | Process for preparing 3-carbamoyloxymethyl cephalosporins | |
US5288860A (en) | Process for preparing thiazolino azetidinone and 2-exo-methylenepenam derivative | |
US4067866A (en) | Process for preparing cephalosporins and certain novel 2β-thiohydrazo-azetidinones as intermediates | |
KR870000528B1 (en) | Process for preparing 3-azidocephalosporins | |
NO753954L (en) | ||
CA1097652A (en) | Eprimerization process | |
US3971776A (en) | Thio-β-lactam penicillins | |
US4143037A (en) | Thiohydrazoazetidinones | |
US4304909A (en) | Process for producing 7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-.DELTA.3 -cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof | |
US3449336A (en) | Process for preparing novel intermediates useful for preparing 7-amino-cephalosporanic acid and derivatives thereof | |
US3988325A (en) | 7-Carboxy or 2,2,2-trichloroethoxy carbonyl- cephalosporins |