SE434637B - Ozoniseringsforfarande for framstellning av alfa-(azetidinyl)-alfa-(hydroxietyliden)-ettiksyraforeningar - Google Patents
Ozoniseringsforfarande for framstellning av alfa-(azetidinyl)-alfa-(hydroxietyliden)-ettiksyraforeningarInfo
- Publication number
- SE434637B SE434637B SE7907813A SE7907813A SE434637B SE 434637 B SE434637 B SE 434637B SE 7907813 A SE7907813 A SE 7907813A SE 7907813 A SE7907813 A SE 7907813A SE 434637 B SE434637 B SE 434637B
- Authority
- SE
- Sweden
- Prior art keywords
- alfa
- preparation
- hydroxythylide
- thetic
- azetidinyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 AZETIDINYL Chemical class 0.000 title description 12
- 239000002253 acid Substances 0.000 title description 3
- 238000006385 ozonation reaction Methods 0.000 title 1
- 239000000126 substance Substances 0.000 title 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 13
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 6
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical group OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- NVPCGXUWUBHZBD-UHFFFAOYSA-N 3-hydroxybut-2-enoic acid Chemical compound CC(O)=CC(O)=O NVPCGXUWUBHZBD-UHFFFAOYSA-N 0.000 description 1
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- UELITFHSCLAHKR-UHFFFAOYSA-N acibenzolar-S-methyl Chemical compound CSC(=O)C1=CC=CC2=C1SN=N2 UELITFHSCLAHKR-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical compound C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- TXKMVPPZCYKFAC-UHFFFAOYSA-N disulfur monoxide Inorganic materials O=S=S TXKMVPPZCYKFAC-UHFFFAOYSA-N 0.000 description 1
- 125000001240 enamine group Chemical group 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- OXNSNGFUWQVOKD-UHFFFAOYSA-N iron(2+);dicyanide Chemical compound [Fe+2].N#[C-].N#[C-] OXNSNGFUWQVOKD-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
79ova1s-sg 2 Al ! *lån eller Å:\ šh *N // N ,/ 13/ \ n” \[ - _____L /cngflal ___“_N cH2Ha1 (I, 447 \\?=c\ ¿4* “\çH-co 0 cox °" cox vari A och B vardera betecknar väte eller en substituent, R betecknar väte eller en substituent, Hal betecknar halogen, X betecknar en skyddsgrupp för hydroxi eller en skyddsgrupp för karboxi, den streck- ade linjen visar att då R och B betecknar väte och A betecknar karbo- xylisk acyl, kan substituenterna vara förenade till en azetidinotiazo- linbycyklisk ring, samt enaminderivat därav.
Sedda i ett större sammanhang kan de enligt uppfinningen fram- ställda föreningarna och deras framställningsförfarande anses utgöra värdefulla delmoment i förstadier till exempelvis tillverkning av cefemderivat enligt följande reaktionsschema: f ~ I I \_ f: ~ ~ N SR N SR 1) B, I B/ \ N CH . _ N ca m1 044“""' \c=c( 5 04? \P=c I Y ' cox <1) °°X <2> A" lg ' '“~\ I A\ 2) \N SR /N SR B/ \\ avlägsnande av B. \\.
CH “al skydds rupp CH Hal cox Y I \Y (2) (3) cox A 3)« \N SR ringslutning E A>N S “Lif B \"f _ N 0%? \fl:C<:H2Ha1 67 .\\f¿, OH åox COX (3) _(4) ._.__...___.._. _ ._ _ . .ií___.. v- . .,_._.._,V 7 i, 7907813-5 3 vari A, B, R, Hal, X samt den streckade linjen har angivna betydelser och Y betecknar hydroxi eller en enamingrupp. Då Y betecknar OH kan föreningen föreligga i oxo-form.
Ozonoxidationen vid förfarandet enligt uppfinningen ger få sidoreaktioner, och den är fördelaktig eftersom den endast kräver skonsamma reaktionsbetingelser. Ozonoxidationen kan genomföras genom att man i en lösning av utgångsmaterialen inför en tillräcklig mängd ozon för bildning av en ozonid, varefter blandningen underkastas in- verkan av ett reduktionsmedel, som har förmåga att reduktivt spjälka den bildade ozoniden. Särskilt lämpliga lösningsmedel är alkaner, halogenerade alkaner, etrar, alkanoatestrar, alkansyror, alkoholer, aromatiska kolväten, och särskilt blandningar av kloralkanlösnings- medel och alkoholer, t.ex. metanol, etanol.
Reduktionsmedlen kan utgöras av metall och syra (zink och ättik- syra, järn och saltsyra etc), svaveldioxid eller sulfit (natriumsul~ fit, kaliumvätesulfit, etc), trevärda fosforföreningar (fosfitestrar, fosfitsalter, etc), järn(II)cyanid, sulfid (dialkylsulfid) t.ex. dimetylsulfid, aromatiska sulfider, t.ex. difenylsulfid, dibensyl- sulfid, väte (i närvaro av Raney-nickel, platina, palladium etc), borhydrider eller komplex därav (natriumborhydrid etc), aluminium- hydridkomplex (litiumaluminiumhydrid etc), hydrazin och andra reduk- tionsreagens. Bildningen av ozoniden sker vid en temperatur understi- gande -80°C eller högre än rumstemperatur, men vid lägre temperaturer är ozonet effektivare och sidoreaktioner kan undertryckas. överskott av ozon kan avlägsnas från reaktionsmediet genom att man tillför syre, kväve, luft etc till reaktionsblandningen. Reduktionsreagensen kan sättas till reaktionsblandningen, som innehåller ozoniden i befint- lig form eller efter lämplig koncentrering av blandningen. Reaktionen med reduktionsreagenset kan genomföras under konventionella betingel- ser som är lämpliga för de använda reagensen.
Följande exempel belyser föreliggande uppfinning men exemplen är ej avsedda att begränsa uppfinningens omfattning. ɧÉEEÉl_l- I en lösning av bensyl-(X-[3-fenoximetyl-7-oxo-4-tia-2,6- -diazabicyklo[3,2,Q7hept-2-en-6-yl]-CX-isopropenylacetat (4,22 g) i diklormetan och metanol (5:1) infördes ozoniserat syre tills lösning- ens blåa färg ej bleknade. Därefter blandades lösningen med dimetyl- sulfid, tvättades med vatten, torkades och koncentrerades. Den erhåll- na återstoden renades med kromatografi över silikagel, som innehöll 10% vatten, varvid erhölls bensyl-0(-ÅB-fenoximetyl-7-oxo-4-tia-2,6- -diazabicyklo[3,2,Q7hept-2-en-6-yL7-0(-(1-hydroxietyliden)acetat 7907813-5 (2,98 g: 70,28%).
Exemgel 2.
I en lösning av metyl-°(-[Å-acetyltio-3-ftalimido-2-oxoazetidin- ~1-yl]-0(-isopropenylacetat (200 mg) i metylenklorid (10 ml) infördes ett överskott av ozon vid -5°C. Då gasen vid reaktionskärlets utlopp gjorde ett stärkelsepapper med kaliumjodid färgat, koncentrerades reaktionsblañdningen till 2 ml, blandades med en lösning av natrium- borhydrid (50 mg) i metanol (10 ml) och omrördes i 30 minuter. Reak- tionsblandningen koncentrerades och löstes i metylenklorid, tvättades med vatten, torkades och indunstades. Återstoden omkristalliserades ur en blandning av metylenklorid och eter, varvid erhölls metyl-d- -[Ä-acetyltio-3-ftalimido-2-ozoazetidin-1-yl7-0*-(1-hydroxietyliden) acetat (157 mg). Utbyte 78%, smp 178-1s3°c.
I en lösning av M~lÄ-acetyltio-3-fta1imido-2-oxoazetídin-1-ylZ-äf- -isopropenylättiksyra (100 mg) i metanol (10 ml) infördes vid 0°C överskott av ozon. Då gasen vid reaktionskärlets utlopp gjorde ett stärkelsepapper med kalíumjodid färgat, genombubblades reaktionsbland- ningen med svaveloxidgas. Reaktionsblandningen koncentrerades och den erhållna återstoden löstes i en vattenhaltig lösning av natrium~ vätekarbonat, tvättades med eter, neutraliserades med saltsyra och extraherades med metylenklorid. Extraktlösningen tvättades med vatten, torkades och indunstades, varvid erhölls of-[N~acetyltio-3-ftalimido- -2-oxoa;etidin-l-ylI-af-acetylättiksyra (64 mg). Utbyte: 63 %. skum. Iazv åâílfi 1780, 1730, 1680 cm'1.
Exemgel 4.
I en omrörd lösning av 2,2,2-trikloretyl-af~[U~(2-bensotíazoly1)- ditio-3~fenoxiacetamido-2-oxoazetidin-l-ylf-Q'-isopropenylacetat (l,76 g) i en blandning av metylenklorid (70 ml) och metanol (18 ml) infördes ozon under kylning med torrís/aceton tills lösningen fick en svagt blå färg. Då kvävgas införts behandlades reaktionsblandningen med svaveldioxídgas tills lösningen fick en svagt gul fäg (ca 30 sekun- der) och lösningen koncentrerades. Den bildade återstoden extraherades med metylenkloríd, tvättades med saltvatten, torkades och koncentre- rades, varvid erhölls en pulverartad återstod (1,35 g). Rening av åter- stoden med kromatografi över silikagel (30 g) gav 2,2,2-trik1orety1- -K~[3-(2-bensotiazolyl)ditio-3-fenoxiacetamido-2~oxoazetidin-l~ylZ~ -ç(~(l~hydroxietyliden)~acetat (1,09 g; utbyte: 62,0 %, smp. 130-13100) och 2,2,2-trík1oretyl-ät-[Ü-(2~bensotiazolyl)ditio~5~fenoxiacetamído- -2~oxoafetidín~l-yl]-6(-(1,l-dimetoxietyl)-acetat (0,30 g; utbyte: 7907813-5 ExemEe1_§.
I en lösning av Q-[Ä-substituerad (H2) tio-3-substituerad amino- (Rl)-2-oxoaZetidin-l-ylI-äf-isopropenylacetatester (R3) i ett lösníngs~ medel infördes ozon under kylning. Då gasen vid reaktionskärlets utlopp gjorde ett stärkelsepapper med kaliumjodid blått avbröts tillsatsen av ozon och överskott av ozon avlägsnades genom tillförsel av kväve» gas. Reduktionsmedel tillsattes till reaktionsblandníngen och blandning- en fick reagera i l0~30 minuter. Efter reduktionen förångades lösnings- medlet och återstoden kristalliserades eller också iiltrerades reak- tionsblandningen genom ett silikagelskikt och filtratet indunstades till G-[Ä-substituerad tio-3-substituerad amino-2-oxoazetidin-1-yl]- -0(-(1-hydroxietyliden)ättiksyraester.
Reaktionsbetingelserna visas i nedanstående tabell I och pro- dukternas fysikaliska konstanter visas i tabell II.
Exemgel 6.
Pâ liknande sätt som i exempel 5 framställes följande 4-substi- tuerade tio-3-substituerade amino-2-oxo-o(-(1~hydroxietyliden- eller acetyl)a1etidin~l~ättiksyraestrar från motsvarande qFisopropenyl~ ázesiainaerivat. l (l) p-metoxibensyl-6{-[H-(2-metyl~l,3,H-tíadiazol-5~yl)ditio-3-(2- tienylacetamido)-2-oxoa2etidin-l-yLZ-äf-(l~hydroxietyliden)acetat; (2) 2,2,2~trikloretyl~Af-[U-(o-nitrofeny1)ditio-3-(2,2,2-tríklor- etoxikarbonamid)-2-oxoazetidin-l-yl7-aí-(1-hydroxietyliden)acetat; (3) difenylmetyl-o(~[¶-cyklopropylmetoxikarbonyltio-3-tert.butoxi- karbonamido-2-oxoazetidin-l~y1]-¿x-(l-hydroxietyliden)acetat3 (U) 2,2,2-trikloretyl-o(-Lfi-acetyltío~3-(N-tert.butoxikarbonanido~ -¿X-fenylglycinamido)-2-oxoazetidin-l~ylï-6(-(l~hydroxietyliden)acetaä; (5) p-bromfenacyl~a(-[U-(bensotiazol-2-yl)ditio-3~(?,2wdimetyl-3~ nitroso~4-feny1-5-oxoinídazolidin~l-yl)-2-oxoaZetidin-l~yl]-¿ï~(l- hydroxietyliden)acetat; (6) p~nitrobensyl-a(-ÅÄ-(1,3,H-tiadiazol-5-yl)ditio~3~(o-nitrobensy1 idenamino)-2~oxoa2etidin~l~yl]-6%-(1-hydroxíetyliden)acetat; (7) metyl-¿(-Lfl~bensyliditio-3-(2,6-dimetoxibensoylamino)-2~oxo- awwtidin~l-yl]~¿(~(l~hydroxietyliden)acetat; _ (8) etyl-6(~[U-acetyltio-3-cyanoacetamido-2-oxoazetidin-l-yl]~q(~(l~ hydroxietyliden)acetat; (9) acetoximetyl{fl-acetyltio~3~(q{~indanyloxikarbonyl-of~fenyl~ acetamido)-2~oxoazetidin-l-yl]~ß(-(l~hydroxíetyliden)acetat; och (10) dinatrium-OK-Lä-pyriditio~3-(øX-sulfo-c¿-feny1acetamido)~2- oxoafictidin~l-yl]-a(~(l-hydroxietyliden)acetat. 7907813-5 6 gbell 1 1 2 nl ' s-RZ s-n rf 0112 1) 05 0113 f - ~< o “fån -_-~> kf en 5 . medel _ 2 ' (ID Lösningš-Temp.Reduk-_ 1 (12) || :n _ -,===-_~.........-...- ä ä _ 1 2 3 medel t1onmed.Pro-¶ Ut- ë R R . R .(10%) . (oc) 00 ' 1 1 @( xïr- -coczn _0115 15100 °"2°.12 _30 cnfiscffö 10900 71.5 00» _ J 1 300 - . 6 - få; v , ~ , en 01 +0.=:_0H cmscfi. 1 e - _0001- -cxr 0 111.0 5100 _ 2 2 g -70 n a 40,0 95.0 2 rnocrraczr- *p 2 6 4 2 - zcofio 5 , 0 " ~ ' h I 1 _ I-'ÉÉ _00cfl_ -cxleh 4200 Clfzclfcåøfi aflnclfäscljs 3100 74.0 'j Phüvzízßll-ï j __ 2' 5060 . Elf Å00c1f- -ca 001 0000 °H2°l2*°"5°H aencñä-SCH; , 7000 97.0 4 PhÛCkIZCIW J ~ 2 3 0240M50 . 15 0' _ _ _, Il" -cooczf . »ca 0,21 wo 106 °H2°l2+°“3°*[ _30 CHYSWL' 103 97 5 1110011200- _ 2 2 0 4* 2 51,1 ”ma” _ . ' . ' l 0 - - 0 H . .- ß yhocílzgàn -0112000 _CHZCGH4I_.OZ 272 0H¿012+01r.¿0s1 _78 0030005 am BO 1-0409 _ 10+§ _ 1 0 n _- ~ uu _. , _ . ., ,.o 011201 ___cn._.s0.»r._ .I _. 7 Phocilzcrk s- 83:? cxzcêfiæloz 9, H50 2 <1 a 10-8; 5:0 56 f ' 0 ' N - _- _ __ 'FCH Gil . .cll- f .8 Phocuzcuï 0112112 1000. 2 Saw; <1 a js 5 960 90 0 1: . _ _ . ~ fi.. _ "H _°_ / _CH cCl_ 2 oo CH2Cl2TßH30h _6 CH Son" 16,0 6, .9 2110011200- *' <5 - . 2 a 5 250,50 _ .5 i; 3- 1 ° 0 4 n e . , ._. _ _; HÉI' -s-< -cH 001 0200 cflzclz <1.a.°“3°°^*5 7100 06.3 1.0 PnCnZCnK- . s 2 3 _ 500 8 - - _' O _ _ (133005 51.7 ~ ufl @;g1.3 gg Ia '_ ~(l l4dimetOXi- ll yhggnzçnl ..S_¿'_ -CHZCCLS IÉGQ 12 Bal* G_ ein-LI HSO) 'tylïderivat ~ . _ f' 5"” “nå 250 17.9 e En , ' _ ' 011 01 11-1201: so (ny/yo 59.1 _, -g / 0:1 001 1300 2 2 11.1. 2 12 Fhøcflzclv- S 2 3 r__(l,_ï_=a-imet0X-ï._ . - kwggfåëlgäât Tíllförseln av ozon fortsabtes tills lösningen visar beständig blå färg. I tabellen innebär "d.a." att reaktionen genomföres' under kylning med torrís och aceton.
Reakbíonen mellan reaktíonsmedlet och ozoniden forbsattes tills färgreaktionen av ett stärkelsepapper med kalíumjodíd ej längre kan iakttagas. vsovs1z-5 »mïwnoufinæumflxovmëflvlflÄvnvo _ .mfimïïmNA.šäåë.NzmwmwflwwwwwwwflwwwwwmßmwwwHw .Nmšhzæšflfimwww “WWW fooNšl Qwïvnw- rmmNmwoonm d.. dÉïNFNHmmWM .Sïwza . nfiuvNä.. QWKVH? fiußuwNmonm 3 R.U$. .omwffåmfiüoqä omwmm. näuNän QMVVJT -mwwßonm .m z .o . ä.wàåššumïm.Eâfiíåfim.NNMWWWMWMMWMW .oådïfifiofin .EÃÉ NÉS- Qmvåï wwwmmuofifl w . z .o .v . nßtmafiâ.ïUNTm.mfleåßèwHmwmwwwmflmmwwwwuw .Jmßóïaflmmww N30 wowwmwvNmv| Qwxvnm.. vwwNmoonm w . z .Q ßmv.mdm~.m_mNmmm.m_m~@oWHNNMMMMMNWNWMMMMHWNWNWWWNN _m~>HUN»WMHWWMM OMWM Nozwmmowmo- ^,wæ@¶°w~mUN .wwwmuogm w . o o . flßoflHMNWWMWMNWNWMMMWWWMNWMWNMMWNWNWWMWMWMNMHN. _nH>HUwWWMH%WWM MWWHW Nozqmwowmu- wymmvooo- .mmmmuofim m .omfismfiñøfià .HP/Ham maouNmol nšo? .WMMMNNNQQQN .N .vÅmZïJRA:Aåšmäf _ .mNmmNHNwLHN.fifiïønfim . .owâ _ N m hzoNmoonm n .. 2. - n .. i m mNUmm N ämfiN N mmåñN .omfi.otu...oNvm E33 âš- m8? å. n. .mimínmæfiNmNñm.wfiNß.NNNMMWWEMMWMMUMMWWWWHW aâäfimåumwwm.. .Ešw NouflNmwoNmï Que? -mwmmoagm N .MSASUNNÅNIHN .Éfiuwwwwumwwfln uwwfifi nä- mmuou- »zmooš .n , 8 mwgwnmwkïownwwvßflonumuflzz . Tfiaøvßfiwmufmfi _ .men nu Nm .mm .å »mono SC n%vLNNw -EÉMNNMMMNN HH Éwnma NNTW Nm ,
Claims (1)
1. ?9fi7e1z-5 8 P a t e n t k r a v Förfarande för framställning av en förening med formeln: - nl- a snz f ° 5 COOR OH ' ~ - a co vari Rl betecknar en grupp \š_ I OBH ä NH co/ _ 2 _ _ eller -CHageNlí-fch H2 betecknar en grupp -COCHy -COOCHQ-q , N . _gH2C00-b.cuH9 eller -S-ii :I:::1 , eller också nl och$R2 tillsammans S qH20C6H5 betecknar en grupp -N=C-S- , och R3 betecknar väte eller en grupp -CH3, -CH2C6H5, _ H CH2C6H4N°2f 1,/'C535 eller -CH CCl , -C\\ f 2 3 C6H5 k ä n n e t e c k n a t a v att man medelst ozon oxiderar en före- ning med formeln: 1 2 R SR \ _: CH o;ç.____N /T 2 3 COOR CH3 vari de olika symbolerna har ovan angivna betydelser, och att den sålunda bildade ozoniden reduceras med ett reduktionsmedel. företrädesvis en dialkylsulfid, borhydrid eller svaveldioxid.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50019612A JPS5198265A (sv) | 1975-02-17 | 1975-02-17 | |
| JP50022229A JPS51105051A (sv) | 1975-02-21 | 1975-02-21 | |
| JP50028452A JPS609516B2 (ja) | 1975-03-07 | 1975-03-07 | セフエム骨格の環化製法 |
| JP50033808A JPS5817460B2 (ja) | 1975-03-20 | 1975-03-20 | チアゾリンカンノ カイカンホウホウ |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE7907813L SE7907813L (sv) | 1979-09-20 |
| SE434637B true SE434637B (sv) | 1984-08-06 |
Family
ID=27457226
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7601715A SE421691B (sv) | 1975-02-17 | 1976-02-16 | Nya azetidinforening till anvendning som mellanprodukter for framstellning av 3-cefemforeningar |
| SE7907812A SE434950B (sv) | 1975-02-17 | 1979-09-20 | Forfarande for framstellning av 3-hydroxi-cefalosporinforeningar |
| SE7907813A SE434637B (sv) | 1975-02-17 | 1979-09-20 | Ozoniseringsforfarande for framstellning av alfa-(azetidinyl)-alfa-(hydroxietyliden)-ettiksyraforeningar |
| SE7907811A SE444811B (sv) | 1975-02-17 | 1979-09-20 | Azetidinylforening for framstellning av 3-hydroxi-cefemforeningar och forfarande for dess framstellning |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7601715A SE421691B (sv) | 1975-02-17 | 1976-02-16 | Nya azetidinforening till anvendning som mellanprodukter for framstellning av 3-cefemforeningar |
| SE7907812A SE434950B (sv) | 1975-02-17 | 1979-09-20 | Forfarande for framstellning av 3-hydroxi-cefalosporinforeningar |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7907811A SE444811B (sv) | 1975-02-17 | 1979-09-20 | Azetidinylforening for framstellning av 3-hydroxi-cefemforeningar och forfarande for dess framstellning |
Country Status (24)
| Country | Link |
|---|---|
| US (4) | US4079181A (sv) |
| AR (1) | AR225878A1 (sv) |
| AU (1) | AU508160B2 (sv) |
| BE (1) | BE838656A (sv) |
| BG (5) | BG25216A3 (sv) |
| CA (5) | CA1136132A (sv) |
| CH (5) | CH627160A5 (sv) |
| DD (5) | DD124986A5 (sv) |
| DE (1) | DE2606278A1 (sv) |
| DK (1) | DK156575C (sv) |
| ES (1) | ES445250A1 (sv) |
| FR (1) | FR2334669A1 (sv) |
| GB (3) | GB1548642A (sv) |
| GR (1) | GR60437B (sv) |
| IE (1) | IE42479B1 (sv) |
| IL (5) | IL49048A (sv) |
| MX (1) | MX3818E (sv) |
| NL (1) | NL190721C (sv) |
| NZ (1) | NZ180037A (sv) |
| PH (1) | PH18022A (sv) |
| PT (1) | PT64806B (sv) |
| RO (4) | RO74958A (sv) |
| SE (4) | SE421691B (sv) |
| YU (5) | YU40272B (sv) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1136132A (en) * | 1975-02-17 | 1982-11-23 | Teruji Tsuji | Cyclization to form cephem ring and intermediates therefor |
| US4579684A (en) * | 1975-02-20 | 1986-04-01 | Ciba-Geigy Corporation | Process for the manufacture of enol derivatives |
| US4550162A (en) * | 1975-02-20 | 1985-10-29 | Ciba-Geigy Corporation | Process for the manufacture of enol derivatives |
| AT342197B (de) * | 1975-02-20 | 1978-03-28 | Ciba Geigy Ag | Neues verfahren zur herstellung von 3-cephemverbindungen |
| GB1543048A (en) * | 1976-02-04 | 1979-03-28 | Beecham Group Ltd | 4-mercapto-3-phenoxyacetamido-2-azetidinone |
| US4271305A (en) * | 1979-02-01 | 1981-06-02 | Eli Lilly And Company | Thiazolinoazetidinones and process therefor |
| JPS55133355A (en) * | 1979-04-03 | 1980-10-17 | Shionogi & Co Ltd | Inversion of 3-amino group of beta-lactam ring |
| US4430268A (en) | 1979-04-30 | 1984-02-07 | Eli Lilly And Company | Allylic chlorination process |
| US4518531A (en) * | 1979-04-30 | 1985-05-21 | Eli Lilly And Company | Allylic chlorination process and compounds prepared thereby |
| CA1145339A (en) * | 1979-04-30 | 1983-04-26 | Eli Lilly And Company | Allylic chlorination process and compounds prepared thereby |
| CA1148938A (en) * | 1979-05-08 | 1983-06-28 | John R. Corfield | Preparation of cephalosporins and intermediates employed therein |
| US4237279A (en) * | 1979-07-27 | 1980-12-02 | Eli Lilly And Company | Crystalline 3-hydroxycephalosporin solvates |
| EP0065488B1 (de) * | 1981-05-19 | 1985-08-14 | Ciba-Geigy Ag | Verfahren zur Herstellung von 4-Thio-azetidinon-Verbindungen |
| FR2511376A1 (fr) * | 1981-08-17 | 1983-02-18 | Rhone Poulenc Sante | Nouveaux derives de la cephalosporine et leur prepration |
| JPS5832884A (ja) * | 1981-08-20 | 1983-02-25 | Otsuka Chem Co Ltd | ３−エキソメチレンセフアム誘導体の製造方法 |
| JPS59101485A (ja) * | 1982-11-29 | 1984-06-12 | Otsuka Chem Co Ltd | アセチジノン誘導体 |
| US4533497A (en) * | 1982-12-27 | 1985-08-06 | Eli Lilly And Company | N-ethylidene azetidinones |
| KR850000291B1 (ko) * | 1983-02-07 | 1985-03-16 | 한국과학기술원 | 3-메틸렌 세팜 화합물의 제조방법 |
| JPS59164771A (ja) * | 1983-03-10 | 1984-09-17 | Otsuka Chem Co Ltd | 塩素化アゼチジノン誘導体の製造方法 |
| EP0133670A3 (de) * | 1983-08-09 | 1985-12-18 | Bayer Ag | Verfahren zur Herstellung von 7-Acylamino-3-hydrocy-cephem-4-carbonsäuren und 7-Acylamino-3-hydroxy-1-de-thia-1-oxacephem-4-carbonsäuren |
| DE3725375A1 (de) * | 1987-07-31 | 1989-02-09 | Bayer Ag | Stabile oxapenem-3-carbonsaeuren |
| JP3007986B2 (ja) * | 1990-03-02 | 2000-02-14 | 大塚化学株式会社 | β―ラクタム誘導体の製法 |
| US5206361A (en) * | 1990-03-08 | 1993-04-27 | Otsuka Kagaku Kabushiki Kaisha | Thiazolinoazetidinone derivative |
| US5604222A (en) * | 1993-12-27 | 1997-02-18 | Lupin Laboratories, Ltd. | Method for the preparation of 2-chloro sulfinyl azetidinones |
| US5578721A (en) * | 1994-07-11 | 1996-11-26 | Lupin Laboratories Limited | Process for preparation of 3-exomethylene cepham sulfoxide esters |
| IT1277048B1 (it) * | 1995-12-06 | 1997-11-04 | 3 Exo S R L | Procedimento per la preparazione di cefalosporine attraverso ciclizzazione riduttiva dicarbonilica per trattamento con |
| US5986091A (en) * | 1996-03-13 | 1999-11-16 | Otsuka Kagaku Kabushiki Kaisha | Process for preparation of β-lactam compounds |
| US8883772B2 (en) | 2007-10-09 | 2014-11-11 | Sopharmia, Inc. | Broad spectrum beta-lactamase inhibitors |
| CN101525341B (zh) * | 2009-04-01 | 2012-07-04 | 浙江东邦药业有限公司 | 一种3-羟基头孢化合物的制备方法 |
| ES2700575T3 (es) | 2013-03-12 | 2019-02-18 | Gladius Pharmaceuticals Corp | 3-Estiril-cefalosporinas derivadas |
| CN108727409A (zh) * | 2017-04-24 | 2018-11-02 | 浙江省化工研究院有限公司 | 一种3-羟基头孢菌素的制备方法 |
| CN111647638A (zh) * | 2020-04-17 | 2020-09-11 | 江苏正泰药业有限公司 | 一种7-anca的制备工艺 |
| CN115397807B (zh) * | 2020-04-17 | 2024-08-13 | 帝斯曼知识产权资产管理有限公司 | 用于制备取代的烯胺化合物的方法 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3862164A (en) * | 1971-02-03 | 1975-01-21 | Lilly Co Eli | Thiazolidine azetidinones |
| GB1457421A (en) * | 1973-01-04 | 1976-12-01 | Glaxo Lab Ltd | Cepham derivatives |
| AU498131B2 (en) * | 1974-02-26 | 1979-02-15 | Ciba-Geigy Ag | Production of cephems by cyclization |
| JPS5188955A (sv) * | 1975-01-30 | 1976-08-04 | ||
| CA1136132A (en) * | 1975-02-17 | 1982-11-23 | Teruji Tsuji | Cyclization to form cephem ring and intermediates therefor |
| US4147864A (en) * | 1975-02-20 | 1979-04-03 | Ciba-Geigy Corporation | Process for the manufacture of 7β-amino-3-cephem-3-ol-4 carboxylic acid compounds |
| AT342197B (de) * | 1975-02-20 | 1978-03-28 | Ciba Geigy Ag | Neues verfahren zur herstellung von 3-cephemverbindungen |
| JPS5214789A (en) * | 1975-07-22 | 1977-02-03 | Shionogi & Co Ltd | Process for preparing 3-substiuted cephem compounds by ring closure |
| US4008230A (en) * | 1975-10-29 | 1977-02-15 | Eli Lilly And Company | Process for preparing 3-hydroxy cephalosporins |
| JPS6019315B2 (ja) * | 1976-01-23 | 1985-05-15 | 塩野義製薬株式会社 | アゼチジノン化合物 |
| GB1529913A (en) * | 1976-02-04 | 1978-10-25 | Beecham Group Ltd | Beta-lactam compounds |
| US4264597A (en) * | 1978-06-06 | 1981-04-28 | Masashi Hashimoto | Cephalosporin analogues and processes for the preparation thereof |
-
1976
- 1976-02-09 CA CA000245317A patent/CA1136132A/en not_active Expired
- 1976-02-16 IL IL49048A patent/IL49048A/xx unknown
- 1976-02-16 PT PT64806A patent/PT64806B/pt unknown
- 1976-02-16 DK DK061976A patent/DK156575C/da active
- 1976-02-16 SE SE7601715A patent/SE421691B/sv not_active IP Right Cessation
- 1976-02-17 NL NL7601613A patent/NL190721C/xx not_active IP Right Cessation
- 1976-02-17 US US05/658,665 patent/US4079181A/en not_active Expired - Lifetime
- 1976-02-17 GB GB41073/78A patent/GB1548642A/en not_active Expired
- 1976-02-17 FR FR7604318A patent/FR2334669A1/fr active Granted
- 1976-02-17 DD DD191283A patent/DD124986A5/xx unknown
- 1976-02-17 RO RO7694587A patent/RO74958A/ro unknown
- 1976-02-17 MX MX76898U patent/MX3818E/es unknown
- 1976-02-17 RO RO7684836A patent/RO68460A/ro unknown
- 1976-02-17 RO RO7694586A patent/RO75006A/ro unknown
- 1976-02-17 ES ES445250A patent/ES445250A1/es not_active Expired
- 1976-02-17 BG BG034106A patent/BG25216A3/xx unknown
- 1976-02-17 BG BG032385A patent/BG24948A3/xx unknown
- 1976-02-17 DD DD7600195998A patent/DD127902A5/xx unknown
- 1976-02-17 BG BG034105A patent/BG24949A3/xx unknown
- 1976-02-17 BE BE164401A patent/BE838656A/xx not_active IP Right Cessation
- 1976-02-17 DE DE19762606278 patent/DE2606278A1/de active Granted
- 1976-02-17 AR AR262283A patent/AR225878A1/es active
- 1976-02-17 YU YU384/76A patent/YU40272B/xx unknown
- 1976-02-17 DD DD7600195993A patent/DD127899A5/xx unknown
- 1976-02-17 DD DD7600195997A patent/DD127901A5/xx unknown
- 1976-02-17 GR GR50078A patent/GR60437B/el unknown
- 1976-02-17 BG BG034107A patent/BG27557A4/xx unknown
- 1976-02-17 AU AU11181/76A patent/AU508160B2/en not_active Expired
- 1976-02-17 DD DD7600195995A patent/DD127900A5/xx unknown
- 1976-02-17 GB GB6187/76A patent/GB1548641A/en not_active Expired
- 1976-02-17 CH CH191876A patent/CH627160A5/de not_active IP Right Cessation
- 1976-02-17 NZ NZ180037A patent/NZ180037A/xx unknown
- 1976-02-17 BG BG034108A patent/BG25076A3/xx unknown
- 1976-02-17 IE IE313/76A patent/IE42479B1/en unknown
- 1976-02-17 GB GB41074/78A patent/GB1548643A/en not_active Expired
- 1976-03-03 PH PH18164A patent/PH18022A/en unknown
- 1976-07-17 RO RO197694535A patent/RO74936A/ro unknown
-
1977
- 1977-12-01 US US05/856,806 patent/US4160085A/en not_active Expired - Lifetime
-
1978
- 1978-11-26 IL IL56050A patent/IL56050A0/xx not_active IP Right Cessation
- 1978-11-26 IL IL56049A patent/IL56049A0/xx not_active IP Right Cessation
-
1979
- 1979-05-28 IL IL57418A patent/IL57418A0/xx not_active IP Right Cessation
- 1979-06-11 IL IL57541A patent/IL57541A0/xx unknown
- 1979-09-20 SE SE7907812A patent/SE434950B/sv not_active IP Right Cessation
- 1979-09-20 SE SE7907813A patent/SE434637B/sv not_active IP Right Cessation
- 1979-09-20 SE SE7907811A patent/SE444811B/sv not_active IP Right Cessation
- 1979-10-19 CA CA000337975A patent/CA1095026A/en not_active Expired
- 1979-10-19 CA CA000337973A patent/CA1144924A/en not_active Expired
- 1979-10-19 CA CA000337974A patent/CA1077936A/en not_active Expired
- 1979-10-22 CA CA000338132A patent/CA1132547A/en not_active Expired
-
1980
- 1980-01-30 CH CH75080A patent/CH628030A5/de not_active IP Right Cessation
- 1980-01-30 CH CH74880A patent/CH630074A5/de not_active IP Right Cessation
- 1980-01-30 CH CH75180A patent/CH628031A5/de not_active IP Right Cessation
- 1980-01-30 CH CH74980A patent/CH634579A5/de not_active IP Right Cessation
- 1980-02-27 US US06/125,233 patent/US4346218A/en not_active Expired - Lifetime
-
1982
- 1982-01-11 US US06/338,651 patent/US4440683A/en not_active Expired - Lifetime
- 1982-08-10 YU YU1738/82A patent/YU40411B/xx unknown
- 1982-08-10 YU YU1742/82A patent/YU40414B/xx unknown
- 1982-08-10 YU YU1741/82A patent/YU40413B/xx unknown
- 1982-08-10 YU YU1739/82A patent/YU40412B/xx unknown
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