DK168217B1 - Fremgangsmåde til fremstilling af 1-dethia-1-oxacepham- og cephalosporinforbindelser - Google Patents
Fremgangsmåde til fremstilling af 1-dethia-1-oxacepham- og cephalosporinforbindelser Download PDFInfo
- Publication number
- DK168217B1 DK168217B1 DK060678A DK60678A DK168217B1 DK 168217 B1 DK168217 B1 DK 168217B1 DK 060678 A DK060678 A DK 060678A DK 60678 A DK60678 A DK 60678A DK 168217 B1 DK168217 B1 DK 168217B1
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- Prior art keywords
- cob
- dethia
- mixture
- oxacepham
- preparation
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- -1 Cephalosporin Compounds Chemical class 0.000 title claims description 21
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 8
- 229940124587 cephalosporin Drugs 0.000 title claims description 6
- 229930186147 Cephalosporin Natural products 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
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- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- CZFNISFYDPIDNM-UHFFFAOYSA-N n,n-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical group C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 101150083668 tfdD gene Proteins 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- LTSUHJWLSNQKIP-UHFFFAOYSA-J tin(iv) bromide Chemical compound Br[Sn](Br)(Br)Br LTSUHJWLSNQKIP-UHFFFAOYSA-J 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
i DK 168217 B1
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af hidtil ukendte 1-dethia-l-oxacepham- og cephalosporin-forbindel ser. Mere specielt angår opfindelsen en fremgangsmåde til fremstilling af de nedenfor viste forbindelser med den almene formel I.
5 Antibakterielle 1-dethia-l-oxacephalosporiner med den følgende formel er beskrevet af Christensen i Journal of American Chemical Society, 96, 7582 (1974), samt i forskellige patentpublikationer:
Acyl-NH^- 10 . o^Y^ch2x'
COB
hvori X' betegner hydrogen, acetoxy eller methyltetrazolylthio.
15 Disse er blevet fremstillet som vist skematisk nedenfor ved adskillige synteseveje. Som følge af den intermediære carboniumion i stilling 4 af azetidinonen resulterer indføringen af en oxygenfunktion imidlertid her i en epimer blanding. Denne blanding er for ca. halvdelens vedkommende ineffektiv 6-epimer af den ønskede 1-dethia-l-oxacephalosporin.
20
Skema 1 (japansk patentskrift 51-149.295) aJJ^0S02CH3 aJ ^ch.coch^
25 05J m -> o^J— NH
H 1) hoc^ckk I *>^ob2 2) Hydratisering ψ iii)rph3 aJjOC1I2C0CH3 30 0JUc=PPh3 COB2 C0B2 * (japansk patentskrift 51-41.385)
H ii π HH
Ki V L 0U A ! I „0.
35 YY ϊη20Η -hci Y-r 3 0Y-nc=cch3 ->0 irø2 COU 2 3 2 DK 168217 B1 (japansk patentskrift 49-133.594) i3 “H2COCH2X" h s ίί + i" , K34-f% „ "H—f ^
C NCHPO(OR') > 0=CCIl2X > I .}!] JL
i. i 2Racemisk0^ ι O«-^ Ύ^.ΟΗ X
S COB -blanding CHP0(0R')2 COB
2 COB2 2 10 hvori A betegner amino eller substitueret amino, COBg betegner carboxy eller beskyttet carboxy, X" betegner hydrogen eller en nukleofil gruppe,
Ph betegner phenyl, og R' betegner aryl eller al kyl.
Den foreliggende opfindelse er i et første aspekt baseret på den 15 opdagelse, at udgangsmaterialet (II) (se nedenfor) ringslutter ved angreb på oxygen fra den modsatte side af ringstrukturen og resulterer i gunstig, stereospecifik dannelse af en carbon-til-oxygen binding. Den dannede α-RCONH-gruppe kan erstattes af /J-RCONH ved indføring af methoxy i stilling 7a eller ved Schiff-base dannelse, epimerisering og hydro-20 lyse, der til sidst giver den ønskede 1-dethia-l-oxacephalosporin med gunstig stereoisomeri.
Den foreliggende opfindelse angår således en fremgangsmåde til fremstilling af hidtil ukendte 1-dethia-l-oxacepham- og cephalosporin-forbindel ser med den almene formel (I): 25 R-CONH^ n
jXV
0 (I) 30 hvori R betegner benzyl, phenoxymethyl eller phenyl eller phenyl substitueret med en substituent valgt blandt chlor, cyano, nitro og C13-alkyl, Y* betegner en divalent gruppe med følgende formel: (1) -ch2 (1)-ch2 (1)-ch2 35 (2) -CHCZCH X (2) -CHC-CH (2) -CHC=CH, I I V 2 I 2
COB COB COB
1 1 1 3 DK 168217 B1 (1) -CH (D -CH2
(2) -CHCCHjX eller (2) -C=CCH2X
5 COB^ hvori (1) og (2) angiver, at bindingerne er knyttet til henholdsvis 0 og N, COBj betegner en carboxygruppe eller en benzyl-, t-butyl- eller 10 diphenylmethylester deraf, X betegner hydrogen, halogen, l-methyltetrazol-5-ylthio, hydroxy eller methyl thi o, og Z betegner hydroxy, acetoxy eller halogen, hvilken fremgangsmåde er ejendommelig ved, at man behandler en forbindelse, der har den almene 15 formel (II):
R
Η P
20 0 (II) hvori R og Y* har de ovenfor anførte betydninger, med en syre i et opløsningsmiddel.
Forbindelserne I kan anvendes som mellemprodukter til fremstilling 25 af kendte antibakterielle forbindelser, f.eks. 1-dethia-l-oxacepha-losporiner (japanske patentpublikationer nr. 49-133594 og 51-149295) i højt udbytte ved indføring eller migrering af en dobbeltbinding til stilling 3, erstatning af R med en antibakterielt foretrukket sidekæde og/eller afbeskyttelse af den beskyttede carboxy i COBj, om ønsket efter 30 indføring af en antibakterielt egnet gruppe X ved det til stilling 3 i 1-dethia-l-oxacephemkernen bundne methylen. Valget af grupperne R, COBj og X i udgangsmaterialerne og mellemprodukterne afhænger hovedsageligt af reaktionslethed, stabilitet under reaktionsbetingelser og faktorer, såsom spild, omkostninger eller andre praktiske og tekniske faktorer.
35 Forbindelser (1) kan f.eks. underkastes a) HZ-eliminering til dannelse af en 1-dethia-l-oxacephalosporin (4), som også kan fremstilles ved b) dobbeltbi ndingmigrering i forbindelse (2) med en base (f.eks. triethylamin) ved 0°C til 70°C i 5 timer til 3 dage eller ved c) ring- 4 DK 168217 B1 slutning af forbindelse (3) med en Lewis-syre (f.eks. bortri fluorid) ved 0°C til 50°C i 0,1 til 1 time. Nogle illustrerende eksempler er vist nedenfor i udførelseseksemplerne.
5 RCONH RCONH
\—Z a) HZ~eli-mi-neri-ng ^ \- J~N y<ch2x f-ete.(52^0“°™aH) oJ-nY^ch2x (1) COB i (4) COB! s' Λ\ 10 c) ringslutning b) dobbeltbindingmigrering , , ,0,05 eq BF, v £^eKs . i30 vol^ CHJcl2> RCONH Xtéks (1_5ecI N(C2K5)3) (so vol. ci2ei^ \y ch2oh
15 i— 1 J— NC=CCH,X
cr o « 2 I 2 COB , (2) COB-l (3) 1 20 hvori R, COBj, X og Z har de foran anførte betydninger.
Forbindelserne I kan fremstilles ved fremgangsmåden ifølge opfindelsen som vist i følgende reaktionsskema:
Rinqslutninq 25
R
\ J 7 Syre , RCO® . 0^ i—i o -:-i I \i I J—'N—γχ 30 (Π) (I)
Symbolerne i ovenstående reaktionsskema har de tidligere anførte betydninger.
35 Denne metode forklares nærmere i det følgende.
Forbindelserne I kan fremstilles ud fra de tilsvarende oxazolino-azetidiner II ved behandling med en syre. Typiske eksempler på syren 5 DK 168217 B1 omfatter mineralsyrer (f.eks. saltsyre, svovlsyre, phosphorsyre), sulfonsyrer (f.eks. methansulfonsyre, toluensul fonsyre, trifluormethan-sulfonsyre), stærke carboxylsyrer (f.eks. tri fluoreddikesyre), Lewis-syrer, f.eks. bortrifluorid, zinkchlorid, tinchlorid, tinbromid, anti-5 monchlorid, titantrichlorid) og lignende syrer.
Reaktionen er sædvanligvis tilendebragt indenfor 5 minutter til 10 timer, ofte 15 minutter til 3 timer ved -30°C til +50°C, specielt ved 15°C til 30°C til dannelse af forbindelserne I i højt udbytte. Om nødven-digt kan reaktionen udføres med omrøring eller under en inert 10 gasatmos-fære (f.eks. nitrogen, argon, carbondioxid).
Reaktionen udføres i almindelighed i et inert opløsningsmiddel.
Typiske inerte opløsningsmidler omfatter carbonhydrider (f.eks. hexan, cyclohexan, benzen, toluen), halogencarbonhydrider (f.eks. methyl en -chlorid, chloroform, dichlorethan, carbontetrachlorid, chlorbenzen), 15 ethere (f.eks. diethylether, di isobutyl ether, dioxan, tetrahydrofuran), estere (f.eks. ethylacetat, butylacetat, methylbenzoat), ketoner (f.eks. acetone, methyl ethyl keton, cyclohexanon), sul foxider (f.eks. dimethyl -sulfoxid), nitriler (f.eks. acetonitril, benzonitril) og lignende opløsningsmidler og blandinger deraf. Opløsningsmidler med en hydroxyfunktion 20 kan reagere med udgangsmaterialerne II til dannelse af biprodukter, men de kan dog anvendes under kontrollerede reaktionsbetingelser. Typiske eksempler på sådanne hydroxyholdige opløsningsmidler er vand, alkoholer (f.eks. methanol, ethanol, t-butanol, benzyl al koholer), syrer (f.eks. myresyre, eddikesyre, propionsyre) og blandinger deraf.
25 Lejlighedsvis finder dobbeltbindingmigrering, indføring af en nukleofil gruppe, eliminering eller lignende bireaktioner sted under reaktionen, men disse bi reaktioner kan også bevidst anvendes til opnåelse af bedre metoder indenfor opfindelsens rammer.
I et typisk eksempel opløses en oxazolinoazetidin II (en del) i en 30 blanding af 5 - 10 dele halocarbonhydrid (f.eks. chloroform, dichlor-methan) og 0 - 10 dele etheropløsningsmiddel (f.eks. ether, dioxan), blandes med 1 - 0,001 molækvivalent af en syre (f.eks. bortrifluorid-etherat, toluensul fonsyre, kobbersulfat, zinkchlorid, stannichlorid), og opløsningen holdes ved 10 - 60°C i 0,5 - 10 timer til dannelse af den 35 tilsvarende forbindelse I i ca. 50 - 95% udbytte.
Oxazolinoazetidinerne II fremstilles ud fra 6-epi-peni ci 11 i η-1 - . oxider, f.eks. i henhold til følgende reaktionsforløb: 6 DK 168217 B1
0 R R
RCONH. t ij^ko °^a-
0<LJ V 'i-I SH2 ”»^ael j-( CH2OH
5 J 3 osUir3 T*^°' 0 i OsO^+KClO^ COB1 halogene— rings- f .eks.N-bromosuccinimid.
reagens ^ f
R R R
^ nW^sO oxida- N*^^*0
\ / CH OH tions\ orT __ / CH OH
I-[ I 2 reagens I-f jH2 base + H2° \-J | 2 0Jr-^™2X''' f.eks. 0 N^HCCH2rj^s e ' J— NCHC=CH2 L2 COB, CaC6„aq 00ΒΊ C0B1 OsO + KC10 13 1 15 4 3 hvori X"' er halogen, og R og COBj har de foran anførte betydninger. Udnyttelse af bi-reaktioner Når det oprindelige molekyle indeholder reaktionsdygtige grupper, 20 kan det undertiden angribes af reagenset eller opløsningsmidlet under reaktionsforløbet eller oparbejdningen. F.eks. ledsager addition af halogen til 3-exomethylengruppen N-halogenering i 7-amidkæden, iminodan-nelse med en base til 7-methoxyindføring bevirker HZ-eliminering, når Z betyder halogen eller acetoxy, og erstatning af X i betydningen halogen 25 med et nukleofilt reagens resulterer i HZ-eliminering, når Z betegner halogen. Disse kan sædvanligvis betegnes som bi-reaktioner, men når sådanne bireaktioner anvendes i de ønskede retninger, kan der foretages * mere effektiv syntese end ved de konventionelle trinvise reaktionsforløb.
30
Isolering og rensning af produkterne
De ved ringslutning således fremstillede forbindelser I kan isoleres fra reaktionsblandingen ved fjernelse af det anvendte opløsningsmiddel, uomsatte materialer, bi-produkter og lignende forureninger ved 35 koncentrering, ekstraktion, udvaskning, tørring eller lignende sædvanlige metoder og renses ved genudfældning, kromatografering, udkrystallisation, absorption eller lignende konventionelle rensningsmetoder. Stereoisomere ved stilling 3 kan adskilles ved omhyggelig kromatografe- 7 DK 168217 B1 ring, fraktioneret omkrystallisation eller lignende konventionelle metoder. Om ønsket kan den stereoisomere blanding underkastes næste reaktionstrin i syntesen uden adskillelse.
I det følgende beskrives fremgangsmådens fordele i forhold til den 5 kendte teknik. Ved en kendt fremgangsmåde til fremstilling af 1-dethia- l-oxacephalosporiner går man ud fra en penicillin (japansk patent, publikation nr. 51-149295) ved spaltning af thiazolidinringen, fremstiller den frie azetidinonthiol og genbinder en ny alkoholgruppe til dannelse af en bicyklisk azetidinooxazin. En anden totalsyntese (japansk patent-10 publikation nr. 49-133594) kræver en mere vanskelig intermolekylær ringslutning til dannelse af dihydrooxazinringen. Ved den foreliggende opfindelse tilsigtes intet carbontab i forhold til udgangspenicillinen, hvilket resulterer i glattere intramolekylær ringslutning og færre biprodukter, til dannelse af den ønskede forbindelse I og 1-dethia-l-oxa-15 cephalosporiner i højere udbytte.
Som følge af den intermediære carboniumion ved stilling 4 i ud-gangsazetidinonen resulterer de kendte fremgangsmåder i dannelse af en isomer blanding af 4a- og 4/t-ethere i et forhold på ca. 1:1, hvilket medfører et uønsket tab af ca. halvdelen af etherproduktet. Den fore-20 liggende opfindelse tilvejebringer en stereoselektiv syntese og ledsages af praktisk taget ingen unyttige stereoisomere.
Som følge af de stereospecifikke reaktioner i højt udbytte er produkterne let krystal1 iserbare efter simpel rensning.
Opfindelsen belyses nærmere i de følgende eksempler. De fælles 25 kerner og positionernes nummerering i forbindelserne er i eksemplerne følgende: 3 * ! H 1
Η , I .CL
x ν' o 7 y*2 30 7 Η^Τ"|^Η s
o Y
ΙβΗ',ΒβΗ- eller (lR,5S)-7-oxo-4-oxa- 1-dethia-l-oxacepham 2,6-di azabicyclo[3,2,0]hept-2-en 35
De stereokemiske forhold ved carbonatom 5 i bicyclohept-2-enen er modsat konfigurationen ved carbonatom 5 i 6-epipenicilliner, henholdsvis carbonatom 6 i oxacephamer.
8 DK 168217 B1
Stereokemien omkring carbonatom 6 i 1-dethia-l-oxacephamringsyste-met er identisk med cephalosporinernes ved carbonatom 6 ved stilling 6.
Stereokemien af COBj i formlerne er fortrinsvis den samme som i penicilliner (d.v.s. R-konfiguration) men er ikke nødvendigvis begrænset 5 hertil.
I de følgende eksempler ligger de eksperimentelle fejl i IR-spek-trene indenfor ± 10 cm"1 og for NMR-spektrene indenfor ± 0,2 ppm. Smeltepunkter er ukorrigerede. Vandfri natriumsulfat anvendtes til tørring af alle opløsninger.
10 Fysiske konstanter for produkterne er sammenfattet i tabel II.
I. RINGSLUTNING Eksempel 1-1 - 32
En oxazolinoazetidin (II) opløses i et opløsningsmiddel og blandes 15 med en syre til dannelse af en 1-dethia-l-oxacephamforbindelse (I) under de i tabel I viste betingelser.
Nedenfor er vist detaljerne for reaktion nr. 13 for at belyse den eksperimentelle fremgangsmåde ved ringslutningen.
Ph * Ph 20 \ P CH„ (W Ϊ »T? (2) PhCONH^ 0^ Π I v V Π f20H-* Hf ^Unchc-ch3 0^-nW-°h3 COOCHPh2 C00CIIPh2 C00CHPh2 25 (1) En opløsning af diphenylmethyl-2-[(lR,5S)-3-phenyl-7-oxo-4-oxa- 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-2-isopropenylacetat (12,0 g), osmiumtetroxid (1,0 g) og kaliumchlorat (12,0 g) i en blanding af tetra-hydrofuran (400 ml) og vand (200 ml) omrøres ved 58°C i 3,5 timer. Efter 30 afkøling hældes reaktionsblandingen i is-vand og ekstraheres med ethyl -acetat. Ekstrakten udvaskes med saltvand, vandig 10% natriumthiosul fat og dernæst vandig natriumhydrogencarbonat, tørres og inddampes til dannelse af diphenylmethyl-2-[(lR,5S)-3-phenyl-7-oxo-4-oxa-2,6-diaza-bicycl o[3,2,0]hept-2-en-6-yl ] -3,4-di hydroxy-3-methyl butyrat (12,88 g).
!R: i/C^3 3500br, 1770br, 1742, 1636 cm'1.
35 9 DK 168217 B1 (2) Til en opløsning af produktet (10,88 g) fremstillet under (1) i di ethyl ether (300 ml) sættes bortrifluoridetherat (75 μΐ), og blandingen omrøres i 3,5 timer ved stuetemperatur under nitrogenatmosfære, hældes i kold vandig natriumhydrogencarbonat og ekstraheres med ethyl acetat.
5 Ekstrakten vaskes med saltvand og inddampes. Remanensen vaskes med en blanding af dichlormethan og ether til dannelse af en blanding (10,5 g) af isomere ved stilling 3 af diphenylmethyl-7a-benzamido-3£-methyl-3£-hydroxy-1-dethi a-l-oxacepham-4a-carboxyl at.
10 IR; "ΐχ3 3560’ 3445’ 1774’ 1739, 1670 cm l*
Den isomere blanding kromatograferes på en kolonne af silicagel, der er deaktiveret med 10% vand. Eluatet med en blanding (4:1) af benzen og ethyl acetat omkrystalliseres fra en blanding af acetone og ether og· 15 dernæst fra en blanding af acetone og dichlormethan til dannelse af de to respektive stereoisomere.
Eksempel 1-33
Ph 20 O OCHO PhCONH., ^ ' I cil2 -> J Γ ] o/-NC=kll3 0^Ny^CH3 COOCH2Ph C00CH2Ph 25 (a) Til en opløsning af benzyl-2-[(lR,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)]-3-formyloxymethyl-2-butenoat (54 mg) i methanol (2 ml) sættes bortrifluoridetherat (19 μΐ) under afkøling ved -20°C, og blandingen omrøres ved -20°C - 0°C i 40 minutter, ved 0°C i 2 30 timer og dernæst ved stuetemperatur i 1 time, blandes med vandig 5% natri umhydrogencarbonat og ekstraheres med dichlormethan. Ekstrakten vaskes med vand, tørres og inddampes. Remanensen udkrystalliseres fra methanol til frembringelse af benzyl-7o!-benzamido-3-methyl-1-dethia-l-oxa-3-cephem-4-carboxylat (10 mg = 20% udbytte). Smeltepunkt 208-212°C.
35 (b) Analogt med det foregående, men under anvendelse af trifluor- methansulfonsyre (5 μΐ) i 130 minutter under isafkøling eller 0,38 N hydrogenchlorid i methanol (0,5 ml) i 3 timer i stedet for bortrifluorid opnås samme produkt (14 mg eller 5 mg) (27,5% eller 7% udbytte).
10 DK 168217 B1
Smeltepunkt 208-212°C.
REFERENCEEKSEHPLER
Fremstilling af udgangsmaterialet (1) 5 Ph p?i ' Νΐ^ο ir^o W. i ? P\ i- 0 XCII/ XCII Jpu 0 ch2oh 10 C00CHP1i2 C00CHPh2
Til en opløsning af forbindelse (a) (512 mg) i en blanding af benzen (10 ml) og methanol (1 ml) sættes tri phenylphosphin (0,4 g), og blandingen omrøres ved 65°C i 1,5 time. Remanensen kromatograferes på en 15 kolonne af silicagel (30 g), der er deaktiveret med 10% vand. Eluering med benzen indeholdende 20 - 30% eddikesyre giver 202 mg af forbindelse (b).
IR: Æl3 3370, 1782, 1755, 1635 cm max ’ ’ ’ 20 NMR: $CDC13 2,50-335m!H, 4,18s2H, 5,08slH, 5,22slH, 5,28d(3Hz)lH, 5,50slH, 6,08d(3Hz)lH, 6,93slH, 7,20 - 8,00ml5H.
Fremstilling af udgangsmaterialet (2) CH0Ph CHpPh 25 Jvf Jk
ψ ο Ψ P
\-f CH 1) Cl2_ \-1'' CHoOH
^—>NCHi=CH2 2) Nal ^ ^ NCH(LcH2 C00CHPh2 3) H20 C00CIiPlx2 30 (Trin 1) Til en opløsning af diphenylmethyl-2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3,2,0]hept-2-en-6-yl)-3-methyl-3-butenoat (4,6 g) i ethylacetat (70 ml) sættes 2,74 M opløsning saltsyre i ethylacetat (3,8 ml) og 1,47 M opløsning chlor i carbontetrachlorid (12 ml), og blandin-35 gen omrøres ved stuetemperatur i 15 minutter. Dernæst sættes vandig 5% natriumthiosul fat (80 ml), natriumhydrogencarbonat (3,4 g) og acetone (240 g) til reaktion.sblandingen, og den forenede opløsning holdes ved stuetemperatur i 2,5 timer. Produktet isoleres ved ekstraktion med DK 168217 B1 π ethylacetat, tørring over natriumsulfat og inddampning til dannelse af diphenylmethyl-l-2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo-[3,2.0]hept-2-en-6-yl)-3-chlormethyl-3-butenoat (3,33 g), smeltepunkt 82 - 83°C.
(Trin 2) Ovennævnte butenoat opløses i acetone (25 ml),bl andes med 5 natriumiodid (3,3 g) og holdes ved stuetemperatur i 2 timer. Reaktionsblandingen koncentreres til fjernelse af acetone og ekstraheres med ethylacetat. Ekstrakten vaskes med vandig 5% natriumthiosulfat og vand, tørres over natriumsulfat og inddampes efterladende det tilsvarende i odid (3,0 g).
10 (Trin 3) Til en opløsning af ovennævnte iodid (1,59 g) i en blan ding af dimethyl sul foxid (13 ml) og vand (3 ml) sættes cuprioxid (0,77 g), og blandingen omrøres ved 39°C i 1 time. Reaktionsblandingen filtreres til fjernelse af faste stoffer og ekstraheres med ethylacetat. Ekstrakten vaskes med vand, tørres over natriumsulfat og inddampes til 15 dannelse af diphenylmethyl-2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo-[3,2,0]hept-2-en-6-yl)-3-hydroxymethyl-3-butenoat (0,35 g), smeltepunkt 40 - 55°C.
12 DK 168217 B1
Forklaring af forkortelser i tabeller -Ph = phenyl -STetr = l-methyl-l,2,3,4-tetrazol-5-ylthio -CgH^NOg-p = p-nitrophenyl 5 -CgH4CH3-p = p-tolyl -CgH^CN-p = p-cyanophenyl -CgH^Cl-p = p-chlorphenyl -Bu-t = tertiær butyl -OAc = acetoxy 10 = mellem Xj og Zj = CH2Xj og betegner tilsammen methyl en -0- mellem Xj og Zj = Xj og Zj betegner epoxy Wt = vægt af udgangsmaterialet =CH2 = vægt af 3-exomethylenudgangsforbindel sen EtOAc = ethyl acetat THF = tetrahydrofuran 15 DMF = Ν,Ν-dimethylformamid c-H2S04 = koncentreret H2S04 Et20 = diethyl ether t-BuOCl = tertiær butylhypochlorit eq = ækvivalent 20 DBN = l,5-diazabicyclo[3,4,0]nonen-5 (CH2)5NH = piperidin Temp = reaktionstemperatur reflux = tilbagesvalingstemperatur hr = time 25 hv = lysbestråling Δ2 eller Δ3 for Zj = en dobbeltbinding ved 2(3) eller 3(4) i stedet for en fraspaltelig gruppe ved stilling 3.
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m n B n a cn røtnnsmin— incnan— — ^ ^ ™ rr .5 in n - w - m r- -- a i - n - - - o Ό t3 2 a t3 ωΝ o t- .— r-nr-SnNaoBBBr-a -cso ^ i o toa u m N-oi-'-BSotacoa+inmnc* cn m o « ® w - aa 'O Nuir-cn - — — — Ό E - *· * ' ^ JT ' _, > «i h a in - B - — - ^ντονγ-οΒγ-·^* ^rt-^r 1 .. η μ - r- cn W rør- -BnBainn-- „i ~ n a — r- a - a a w i a oo r- co - - tnaa aaa am B n røcTiCMta—tniiCncN--'-—' r-inOri't 9λ“" — in a - inn —r- — - tn Or- Ό— i mtn tn i o.rfio t-π -do Ό r- oc-'C--o -om omio'io- n na^--oSO-t--cNtTiBaiacr\,3'oin momama g a «2S5 οί"1 'Ϊ1'1- "-S »3 -ίS » oV »o ^'3 ns 8 S il-5 o'V +S to o o® »i o 3« i* oa o® o”.
tø cn >* + K? CNJ ro Γ0 CN · 04 *» <N MH OJvO OJ r-j ^ ^ ϋ}Γ**0·» y) «. O N3 O*· W co O« tor"* t/3 XiW ίΛ H tøtø ^ ^ tn t «· [S I Λ m co h fO Cd HvO VO ro I co I CO Γ0Γ-- CO H OJCO CO I r-i <o B Pdi®"1. “ - -æ - - η ηΛ nn cn ^ r- nn ^ r- ^ro ^r-i - r\j Hr* - *t-J (V) -—* «rH W *»·· ** *· *“** *·* 2 ro p·- p-j ro r-ι ^ -— i—i cn ^ o o- ^ lo ^J1 O' ^lo i-Hiri V ino om o t— com mmcrim m n m nj gna mt— -¾1 n a-^r r—- i—i t ^ cn ^ cn n or-t- røar- r- ar- r— aat^ f" ^ ^ ^
f—( r—i Γ0 rH «Η «Η HH HHHH Η Η H
noooinco o nrøiriinmrøo a t- a ϋΧσι mt-^^a o r- ^ n r- a o r- o tcSr-røa^rørø r- ncr-mnar-r- rø r- ^ ^ f) g c-1 nr-inHr-l H rHinHCNrørørø rø 1-1 1-1 ^ *> ·.!«.«>«»«·» ·> *- ** *· ** OOOO OO O ro o CO LO O cn to LO CN LO in O to OH o LO cn o ·· inao^)< ma mt-· oa rø nr- n-^· t— >-)σ> cno ho B ^raar- mr- ^ra røa r- ^j<a r- ^<a ^10 n2 η η η η h nrø nrH n r-ι rø n^t η-Η h nn nn nr-ι cnh om aner, ^ 'J S' o o ai?,^ a — cn Hrørø <-*
ti i i i I II
ani i i I r-nco 11 a i cnco Soi i i i aq^r il a i32 W CN I I I * r-tr-ti—I II rø I r-lr-l
a M
r_| o an a N = i = id = = = = < < u -μ <u , .
i ^ Μ o n ’ 1-1 w w 9 t
Xll = = = r = --l I
Λ a K a 3 η a a a a i
h o u V
a = = = = = = = = = = i i 1 ft a a a a i i cn ^ ΒΗΖΟΛΛ n ooozaa £ _ -^r N* rø "d* O O a , a a a a cn cn i_i a a a a a a * ΰ^ι υυυουυ _9 H o;:=;r = II I II 1 = = 1
rH
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— B
N CM
r-, B B Λ
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Xj cr> co nh - -h t n m ro b 0 - · o BQtnHæ - p h Λ! ro B - co O »-in tNBotn ^in m —'UB-g-noin
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φ BOB ro ro - O N co -tn cm ro i-h co p n r- u M Q in •w -obo co co o
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Oft Bo BCO BB B Γ» id BO U S3
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tn-ra'dtntntn'd tn co λ m ·. 0*3* o r- m -h --to ·· r» 1 cm r— B in-ociM'ninM'oinot'co S ·Β ------ J - - - -
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rH o u £0=1=1== = -r- 0 <3· C · -r -H >
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h e r- in r- >· B B ^ S
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m ΓΟ i—t H LO tjt — tO H CO CO H
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m Zj CN in — · Ti · CN H tntflrH
t. 2 m tn > ^.ecoEcO m t^roto s O o B o o co to ‘ ts in σι m m rrj o lOCOCOH-HCOH *.*.0] -H ro - - I CO g ro S - , ' ro lo » >03 LO N* t-' -O-^HE LO *»-Ln v ·. · cn ro « - ' ro «-BE«· l,coB B ..+Ο0Ε0ΟιηΕ<Ν,-ιΕ m + CO CNinOlCOICOCN.--»tnC3i
Hib m tn + ro οι en o in tn N ro en Ό co ^ tn c- r- tn * o - - m S ti* in sj in ro m en h ^ lo lo c— ro cn cn-uo S ro o ro ^ rr in — E ro E E nt -p - ^ 1 — — — - H » Η H - t7* B -
nboB” B B b tn B tn tn E B h E
Brororo-q« ro CN ro Li ro O Vi ro fiCtOCN
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ti ^ o Ti o CN o vi ommroor-oo 2 S 2 * 2 m .. cobcocncdcq CNCN CNCO ro^r roen roco offl om
M É ro 2 CN Γ- Γ- 2 O't-'^LO'cfr^'ti'LD ^ LO Ν' LO Ν' LO
tu H ro ^ ro Η H w ΓΟΗ ΙΟ H rOH rOH ro ,-ι ro H ro Η
+J
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tn ο ο η η σ'
C *— H CN Η H
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X I = s III | = ;= I =
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iH a.HCNro-LjttnLor-cocriHHH-H
ar 20 DK 168217 B1 i—i · in co aa m - oo - .-i - *· φ aa aa - aa m aa aa 4-> - r-1 H VOrH M CM ·“) c aa m in in aa in in 3 CM CO vO -CM Γ- IX) o •u ~ cn η ai cn -a- m o in N - - .-1--- - - *· - ta aa vo m m vo 33 vo -a- m aa aa 0 CM - - -10 - H - - - - - H CM · .y^aiaaaar-iaamaaaaaaaaaa m m aa in — h cm η - ηγ-hhcmimcm m Min tu m in in in m in h in in in m in aa aa -π ca i—i * co .—i co in -r-vnor^mocog •h — aa cm <o σι - h m ο o co cm m -vt- in o
Htfio - - - aa - - - - - - - - -m
Xjm^iin -a· <o cm m aa in in -¾1 in mi· id -¾1 -
Of£g - - - cn - cm - - - - - - r~ ϋ co o k aj a: io a: in as aa a: a: aa aa aa aa< O - CM CM · ,-1 IO CM M ^ -3« ro .—I CM O H CM Γ- M -coin in 33 in - in aa in in in in in ,-ι in in .-i qjmpio vo -vr .-1 mc cn r~ o io cn cm cm E r- r- - tn - cm m cm ri cn io r~i m ^ σι o cmcoo .Mr- •ej 53 ^ s ^ g ^ s ^ % ^ ^ «, ^ «, «, >mr-Mt· -s- o m aa mi< in -a- -¾1 cn in -3- - m ^-33 01- - - <JI - cm - - - - - · - · - r- -,-1
Mmaaaa aa-aa in a: aa a! aa aaaaaaaaaaiaa aatn
Φ in ri w mr-cM in cm cm m cm CMinM-ocoin-a-'cnr-•m -tncn mim cm in in m in mtnin,-imcMtn33mcD
-d cnom voom - in m · r- vo voocMEo-comr-- s-i -en·5? r- r-i m «a< cm cm 33 oo vo vocn^rmcor'-'-a-r-iiovo RJ aa- - --- - - <d- - - -- -m -- -E -- > cm io mi* mr-MT - μ- ,-ι m cn mr-n,-cnoa'^,Om33 1 /—. — — — — — 33 — — g - — ·— --Γ— — ^-1- VO— r—1 n n aa aa as aa a3 cn a: aamaa aaaaaaaamiaamaa-aam aa 03 H co · m h cm · m<m cn-cM enm m h cMr- cm m cm r- cm m cMmtnaammmaaoaam ωωω mmmcnmcMinaami in o rHC-OMfOvoinn*oo^i,r~ cnim cnom,-io-Oinmmor-cn --ΓΟνοι-ΊνΩοι -3-.-1 — c c— r- cm vo io1' iom idn ioc· ,-1 σι - — g - - - g mg - - - - · - — - - - - - — - - — — BS Hui ciii rtiu MMfl coco mr-coaacnr-cococoaacoiorot'-mio ft —- - -σι - - -cn -cn - · - - -in - - - - -h - - - - - - u ft w aa aa-aaaa aa-aa-aaa; aa a: aim aaaa aa 33 aim aaaa aaaa aaaa ΜΗ m r- cn h mco cooo cn^j* m ,-ι com <n .-i σι,-ι com cocm co .-i eo .-i co «cm tni mm mi mi hi h mm in aa mm mm in aa mm mm mm ·· or- ooco oo H ftvo m m og cocm enen o id in h coo or- cn cm cmcm 1¾ m o cno m σι voo ιο m ioco vo σι m* cn m m mo cor- μ1 μ -ί οι ίι- o 2 - - - - - - - - - - -i - - - - - - - - - - - - - - - - 2 com cMr- cmvo cor- cn r- cn r- mvo enr- .-i vo h in envo com envo com m .—i — σι — — o —
i o m o co o vo ocNin om O
E -a- co co co σι h ornen γ-γμ o u r- in vo vo vo r-vor- ,-ι r- r- i—I ι-H i—I i—! i—I — i—1 ,—1 i—1 — 1 I 1—1 m - - - - - in --- cn- - .-lUimr-ococM ocnmvo ooco cm OXcoocMcMCMr- m cn co cn r-co cn aaidr-cor-r-r-r-i cmvocmvo i-ir- r~
¢) g i—! i—1 i—I i—l i—I CM '—I i—i >—I i—1 i—I
ft O CO 00 CO CO O in r-Ι Ο Γ- ο ο 00 o ·· cn co co ω co σι cmcm^cm 0.-101 .-1 (¾ vf id r r r r ^ r vf r μ· μ* h -a- h cn ,-ι i-m h .m rM coHcnrH cnmvo cn U oo 0 r-
—. i—I
• I
ft VO
S Γιο ,-1
M
-I 31 co m N l<3=<= = = = = = = = = =
MM Μ M *M
+J 4J +J 4-1 -M
<D dl O) d) Φ , Μ *-Ι ΕΊ ,—I ΪΗ rM Em »-I Ε-* *—I Eh
1-1 33 υ ω ο w Ο conmcjM
X I III | = = T= |T| I I
CM JZ CM
aa -P ft aa O, ml cm Pi S aa P a: aa ή α u ffl u u CQ= = = 1 = = = 1 1= 1= | = a: i " VO ^ I 1 VO (_) 33 —' m vo aa aa cm aa o vo vo aa η CJ cm o o o H --i, i Q --i o aa
Pi= ft = 2 = O§0i = = = = = =
rH
(13 "S M-n-mvor-oocnor-icMm'd-mior-
Em Sir-I-—IrMr-l^-I^MCMCMCMCMCMCMCMCM
21 DK 168217 B1 •»—n * hi (UB * JJ CM » ^ G tn B to (0 o r-ι - jn .μ m en B 00 tn » oo -i ' C in co tn * m 0 - - t"- ·* B - ** *.
λ; B CO η b cm a β B
(Λ ,-| - - r-l U1 CM r-l ft tntnffi in tn Η m w tn c cm ^ - to to · co h m •hcoS B i—i *· B m tH · t Η - m oi n «q* ». tnm * <-H n* m m
0-m « *· B S " " .Τι*! Β 1 B-QBcmoBBB
(S) CM r» CM tø - CM CN CM
Mtn - tn η oimr-in oi tn m cm m tn - m cm i m · o o mm - m m m »ri ot si ίο · io h » a - ^ ^ o * B * > oi a -31 - 0) · · CM *. «·«·*· S ' 6 '
H a ^ Β B tø ffi Β Β Β O Β Ο B
0) tN jo cn^m cm en r-ι m s cm - cm -ht tn η oir-ixi tn t n en tn co in co tn Ό en en mgin^m-cDcocoimim· (M - (MtD IMS MK M5l cool NH N®
JH ·. | -'tf «.«.»CM
> <3· a - -ih <ί Η Ί1 Η en io n io h
1 « CM B »»»g »g »"*·""" "S
CO atnen aBBtnB'tfBBBBBBBm å co u oi corHm-m»mr-imcMm,-im» m n in cntntnootncotntnuitntntntnoo o m o* · r~ cm m i oi o to oo m m o i <n co cm » a r-σι ["-cm co h m σ> mcM co σι cd cm r-ι . « » co O > ·> ** - ~ - ' ' - * *·*·
Hg . n cn «. h mm <nr- m r- mm mm mm mr-
Qj s s dj £ ·>··. *· *· **·» *» ·** ·*** ** ** *·
u ft a K CMC- BK Β B HIB BB BB BB BB
mm M" mr-tm^mrHm^-imi-tmtMmrH
<-o tnsjor" tnui tnoi oitn tnoi 0101 tntn tn tn ·· m cm co i ommcMincocomfocomincoco B <g>m m η ιο H men to æ m ri m r-ι mcM men 2 «.Ih *, «I ·> H. ** S ·*·* »i ». *·· ** »· *· "* ** 2 m C"- m r-· mm mm mm cnlo cn in mm mm J ] «. w ·. ·* i o o cm m m æ en co c r» en m en co h cm cm y Γ" t"· m to to t"- Γ" r~
I-1 I—I I—I I—1 1—I I—I <—I 1 I
en '» - - - - - - " h oo ommooHo πχ oo co cn cm cm co cn cn a ed mm οίογ-'Γ-'Γ'Γ-Γ'· CJ g CO H CM r-l r—II—I Η I—I r-4 p oo m h o co oomooco .. m cm cm m co cm co <n cn ro æ B mc^ nt r- r~- r~ m1 io m< io m1 iu
h con m η H i-ι ro r-ι co r-ι m rH
U H
0 m ft ό i i i i i i !
g ^ 1 I I I I I I
tn h i i i i i i i rI en
Nr <= = = = = = = ΰ = = i (U ft ft >1 E-ι m i a
W B r-t 4J
5^*= i = “ - - OUB
«ϋ· o1 ft B B et)
cl CM m CO C
B A U U —
CM S «Ί ni CM
B B a B B
Η o o O υ o
Β I i r = = = : I I I
il η· sr
^ 0 «3« ^ B B
t" c B B m to —· -rt > m to u o w S -Η υ o B rn
□ ed U >-t O CM Β I I I
hhi<u οζοολββ;
Bn-'0= = Oi ft ft ft ft ft ft I—l 01 'ei]^cDcnOr-icMcnn<mmt''· acMcMmmmmmmmm
Claims (2)
- DK 168217 B1 Fremgangsmåde til fremstilling af hidtil ukendte 1-dethia-l-oxacepham- og cephalosporinforbindelser med den almene formel (I): R-CONH% q π) hvori R betegner benzyl, phenoxymethyl eller phenyl eller phenyl substitueret med en substituent valgt blandt chlor, cyano, nitro og Cj^-al-10 kyl, Y1 betegner en di valent gruppe med følgende formel: (1) -CH2 (1)-CH2 <1)—φΗ2 (2) -CHCZCH2X (2) -CHC-CH- (2) -CHC=CH~ I I 0 j
- 2 COB COB COB 1 1 1 15 (1) “CH (1) -CH2 (2) -CHCCH X eller (2) -C=CCH0X I I 2 C0^ COB^ 20 hvori (1) og (2) angiver, at bindingerne er knyttet til henholdsvis 0 og N, COBj betegner en carboxygruppe eller en benzyl-, t-butyl- eller di phenylmethyl ester deraf, X betegner hydrogen, halogen, 1-methyltetrazol-5-ylthio, hydroxy eller methyl thi o, og 25. betegner hydroxy, acetoxy eller halogen, k e n d e t e g n e t ved, at man behandler en forbindelse, der har den almene formel (II): r M O s / ( 1 /0H 30 (II) O hvori R og har de ovenfor anførte betydninger, med en syre i et opløsningsmiddel.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1581377A JPS53101391A (en) | 1977-02-15 | 1977-02-15 | 1-oxadithiacephem compounds |
| JP1581377 | 1977-02-15 | ||
| JP52067025A JPS6040438B2 (ja) | 1977-06-06 | 1977-06-06 | １−オキサデチアセフアロスポリンの製法 |
| JP6702577 | 1977-06-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK60678A DK60678A (da) | 1978-08-16 |
| DK168217B1 true DK168217B1 (da) | 1994-02-28 |
Family
ID=26352032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK060678A DK168217B1 (da) | 1977-02-15 | 1978-02-10 | Fremgangsmåde til fremstilling af 1-dethia-1-oxacepham- og cephalosporinforbindelser |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4366316A (da) |
| AR (1) | AR227867A1 (da) |
| AU (1) | AU514377B2 (da) |
| BG (4) | BG32855A3 (da) |
| CA (1) | CA1099715A (da) |
| CH (1) | CH636618A5 (da) |
| DE (1) | DE2806457A1 (da) |
| DK (1) | DK168217B1 (da) |
| ES (4) | ES466949A1 (da) |
| FI (1) | FI68401C (da) |
| FR (1) | FR2380284A1 (da) |
| GB (1) | GB1557552A (da) |
| GR (1) | GR69965B (da) |
| HU (1) | HU177897B (da) |
| IE (1) | IE47711B1 (da) |
| IL (1) | IL54044A (da) |
| MX (1) | MX5479E (da) |
| NL (1) | NL191891C (da) |
| NO (1) | NO162343C (da) |
| NZ (1) | NZ186437A (da) |
| PH (4) | PH15515A (da) |
| PL (1) | PL114451B1 (da) |
| PT (1) | PT67648B (da) |
| RO (3) | RO79886A (da) |
| SE (1) | SE443144B (da) |
| YU (2) | YU41307B (da) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4259485A (en) * | 1979-04-24 | 1981-03-31 | Eli Lilly And Company | Crystallization process |
| US4304774A (en) | 1980-09-17 | 1981-12-08 | Eli Lilly And Company | Bis-tetrazolmethyl substituted β-lactam antibiotics |
| JPS58185588A (ja) * | 1982-04-23 | 1983-10-29 | Shionogi & Co Ltd | 空気酸化によるハロメチル化合物の酸化方法および酸化生成物 |
| DE3231060A1 (de) * | 1982-08-20 | 1984-02-23 | Bayer Ag, 5090 Leverkusen | In 6-stellung unsubstituierte 7-oxo-4-oxa-diazabicyclo-(3.2.0)-hept-2-en derivate, verfahren zu ihrer herstellung und ihre verwendung als zwischenprodukte zur synthese von ss-lactamantibiotika |
| US4458071A (en) * | 1982-11-16 | 1984-07-03 | Eli Lilly And Company | Process for 1-oxa-β-lactams |
| US4652651A (en) * | 1983-05-31 | 1987-03-24 | Hoffmann-La Roche Inc. | Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage |
| DE3404906A1 (de) * | 1984-02-11 | 1985-08-14 | Bayer Ag, 5090 Leverkusen | 1-oxadethiacephalosporinderivate sowie verfahren zu ihrer herstellung |
| US4645769A (en) * | 1985-03-01 | 1987-02-24 | Merck & Co., Inc. | 1-oxa-1-dethia-cephalosporin compounds and antibacterial agent comprising the same |
| CN102286004A (zh) * | 2011-09-21 | 2011-12-21 | 河北九派制药有限公司 | 拉氧头孢钠中间体的制备方法 |
| CN103254215B (zh) * | 2013-05-24 | 2015-06-03 | 浙江东邦药业有限公司 | 一种烯丙基氯代氧头孢化合物的制备方法 |
| CN106749335B (zh) * | 2016-11-29 | 2019-02-12 | 浙江新和成股份有限公司 | 一种卤代氧头孢类中间体的制备方法和应用 |
| CN107118224B (zh) * | 2017-06-15 | 2019-09-17 | 浙江新和成股份有限公司 | 一种氧头孢母核中间体的制备方法、其溶剂化合物及其制备方法 |
| CN114315858B (zh) * | 2022-01-11 | 2023-05-09 | 深圳市立国药物研究有限公司 | 一种氟氧头孢中间体的合成方法 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL178005C (nl) * | 1972-11-06 | 1986-01-02 | Merck & Co Inc | Werkwijze voor het bereiden van een farmaceutisch preparaat met antibacteriele werking, alsmede werkwijze ter bereiding van een cefalosporine-antibioticum. |
| GB1510794A (en) * | 1974-08-06 | 1978-05-17 | Univ Kingston | 1-oxacephems and intermediates therefor |
| FR2361114A1 (fr) * | 1975-11-12 | 1978-03-10 | Shionogi & Co | Procede de preparation d'analogues de cephalosporine a propriete antibacterienne et nouveaux produits ainsi obtenus |
| US4150156A (en) * | 1975-11-21 | 1979-04-17 | Merck & Co., Inc. | 7-(Substituted methyl)-3-(substituted thio)-cephalosporins, derivatives and pharmaceutical compositions containing them |
| CY1158A (en) * | 1976-03-25 | 1983-01-28 | Shionogi & Co | Arylmalonamido-1-oxadethiacephalosporins |
| CA1085392A (en) * | 1976-03-25 | 1980-09-09 | Masayuki Narisada | Arylmalonamido-1-oxadethiacephalosporins |
| US4079179A (en) * | 1976-03-30 | 1978-03-14 | Merck & Co., Inc. | 6-Loweralkoxy or loweralkylthio-3-cephem-4-carboxylic acids |
| JPS607635B2 (ja) * | 1976-04-27 | 1985-02-26 | 塩野義製薬株式会社 | オキサゾリジン化合物 |
| US4044002A (en) * | 1976-06-09 | 1977-08-23 | Eli Lilly And Company | Reduction process for cephalosporin sulfoxides |
| JPS609514B2 (ja) * | 1976-08-05 | 1985-03-11 | 塩野義製薬株式会社 | ７−アミノ−３′−ノルセファロスポラン酸類 |
| CA1090806A (en) * | 1977-01-10 | 1980-12-02 | Mitsuru Yoshioka | Oxazolines |
| JPS5398951A (en) * | 1977-02-08 | 1978-08-29 | Shionogi & Co Ltd | Azetidinone derivatives and process for their preparation |
| US4207782A (en) * | 1978-07-31 | 1980-06-17 | Brunswick Corporation | Multi-conductor insulation stripping apparatus |
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1978
- 1978-02-09 AU AU33164/78A patent/AU514377B2/en not_active Expired
- 1978-02-09 GB GB5339/78A patent/GB1557552A/en not_active Expired
- 1978-02-10 NZ NZ186437A patent/NZ186437A/xx unknown
- 1978-02-10 IE IE298/78A patent/IE47711B1/en not_active IP Right Cessation
- 1978-02-10 CA CA296,776A patent/CA1099715A/en not_active Expired
- 1978-02-10 DK DK060678A patent/DK168217B1/da not_active IP Right Cessation
- 1978-02-13 PT PT67648A patent/PT67648B/pt unknown
- 1978-02-13 IL IL54044A patent/IL54044A/xx unknown
- 1978-02-14 YU YU335/78A patent/YU41307B/xx unknown
- 1978-02-14 BG BG040119A patent/BG32855A3/bg unknown
- 1978-02-14 NO NO780508A patent/NO162343C/no unknown
- 1978-02-14 GR GR55452A patent/GR69965B/el unknown
- 1978-02-14 SE SE7801697A patent/SE443144B/sv not_active IP Right Cessation
- 1978-02-14 RO RO78100614A patent/RO79886A/ro unknown
- 1978-02-14 RO RO78100613A patent/RO79398A/ro unknown
- 1978-02-14 ES ES466949A patent/ES466949A1/es not_active Expired
- 1978-02-14 FR FR7804162A patent/FR2380284A1/fr active Granted
- 1978-02-14 RO RO78100612A patent/RO78545A/ro unknown
- 1978-02-14 BG BG038671A patent/BG32853A3/xx unknown
- 1978-02-14 MX MX786846U patent/MX5479E/es unknown
- 1978-02-14 BG BG040118A patent/BG32854A3/xx unknown
- 1978-02-14 PL PL1978204616A patent/PL114451B1/pl unknown
- 1978-02-14 HU HU78SI1619A patent/HU177897B/hu unknown
- 1978-02-14 FI FI780474A patent/FI68401C/fi not_active IP Right Cessation
- 1978-02-15 CH CH167278A patent/CH636618A5/de not_active IP Right Cessation
- 1978-02-15 DE DE19782806457 patent/DE2806457A1/de active Granted
- 1978-02-15 PH PH20789A patent/PH15515A/en unknown
- 1978-02-15 NL NL7801708A patent/NL191891C/xx not_active IP Right Cessation
- 1978-06-16 BG BG040120A patent/BG32856A3/bg unknown
- 1978-11-16 ES ES78475142A patent/ES475142A1/es not_active Expired
- 1978-11-16 ES ES475141A patent/ES475141A1/es not_active Expired
- 1978-11-16 ES ES78475140A patent/ES475140A1/es not_active Expired
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1979
- 1979-12-20 PH PH23440A patent/PH15291A/en unknown
- 1979-12-20 PH PH23438A patent/PH15294A/en unknown
- 1979-12-20 PH PH23439A patent/PH15513A/en unknown
-
1981
- 1981-11-18 US US06/322,662 patent/US4366316A/en not_active Expired - Lifetime
-
1982
- 1982-01-01 AR AR22786782D patent/AR227867A1/es active
-
1983
- 1983-03-07 YU YU548/83A patent/YU42073B/xx unknown
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| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |