DK153483B - PROCEDURE FOR MANUFACTURING GAMMA PYRONS - Google Patents
PROCEDURE FOR MANUFACTURING GAMMA PYRONS Download PDFInfo
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- DK153483B DK153483B DK276177AA DK276177A DK153483B DK 153483 B DK153483 B DK 153483B DK 276177A A DK276177A A DK 276177AA DK 276177 A DK276177 A DK 276177A DK 153483 B DK153483 B DK 153483B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
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Description
DK 153483BDK 153483B
Opfindelsen angår en særlig fremgangsmåde til fremstilling af kendte og hidtil ukendte γ-pyroner med den i krav l's indledning angivne almene formel (I) ved hydrolyse af visse mellemprodukter, hvoraf nogle er hidtil u-5 kendte, hvilke mellemprodukter kan fremstilles ud fra passende furfurylalkoholer ved anvendelse af halogenhol-dige oxidanter.The invention relates to a particular process for the preparation of known and novel γ-pyrones of the general formula (I) of claim 1 by hydrolysis of certain intermediates, some of which are unknown, which intermediates can be prepared from suitable furfuryl alcohols. using halogen-containing oxidants.
Maltol og dets analoge er tidligere blevet fremstillet 10 ud fra en række forskellige forstadier, herunder ved behandling med vandig syre af et epoxid, såsom [>γ> CH3 20 der fremstilles ved enten en 3-trins syntese (dansk patentskrift nr. 148 020) eller en 4-trins syntese (Shono et al., Tetrahedron Letters, side 1363-1364, 1976) ud fra furfurylalkohol. Elektrolysetrinnet, det første trin 25 i denne syntesesekvens, blev tidligere udført af Clau-son-Kaas et al., Acta Chem. Scand., Vol. 7, side 845-848 (1953).Maltol and its analogs have previously been prepared from a variety of precursors, including by treatment with aqueous acid of an epoxide, such as [> γ> CH3 20 prepared by either a 3-step synthesis (Danish Patent No. 148,020). or a 4-step synthesis (Shono et al., Tetrahedron Letters, pages 1363-1364, 1976) from furfuryl alcohol. The electrolysis step, the first step 25 of this synthesis sequence, was previously performed by Clau-son-Kaas et al., Acta Chem. Scand., Vol. 7, pp. 845-848 (1953).
30 35 230 35 2
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Achmatowicz et al., Tetrahedron, vol. 27, side 1973-1996 (1971), fremstillede mellemproduktforbindelser af typen 5 ί^Ύ° 10 der blev anvendt af Shono et al., ved en 2-trins syntese ud fra furfurylalkohol, medens Lefebvre et al., J. Med.Achmatowicz et al., Tetrahedron, vol. 27, pp. 1973-1996 (1971), prepared intermediate compounds of the type 5 δ ^ 10 ° used by Shono et al., In a 2-step synthesis from furfuryl alcohol, while Lefebvre et al., J. Med.
15 Chem., vol. 16, side 1084 (1973), anvendte en 1-trins oxidation til det samme (se også US patentskrift nr.15 Chem., Vol. 16, page 1084 (1973), used a 1-step oxidation to the same (see also U.S. Pat.
3 751 434)t.3 751 434) t.
Paulsen et al., Tetrahedron Letters, side 4377-4380 20 (1974), har beskrevet sukker-afledte optisk aktive vari anter af forbindelserne 3CaPaulsen et al., Tetrahedron Letters, pages 4377-4380 20 (1974), have described sugar-derived optically active variants of the compounds 3Ca
.25 I.25 I
JCXJCX
30 hvori Xa er Cl, Br eller I, og Ra er H eller CH3. Anvendeligheden af disse forbindelser som mellemprodukter ved fremstilling af pyromeconsyre og maltol blev ikke er-35 3Wherein Xa is Cl, Br or I and Ra is H or CH3. The utility of these compounds as intermediates in the preparation of pyromeconic acid and maltol was not realized.
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kendt dér.known there.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anførte.The process according to the invention is characterized by the characterizing part of claim 1.
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Den syre, som kræves til hydrolysen, kan tilsættes reaktionsblandingen, f.eks. ved opløsning af mellemproduktet med formlen (II) eller formlen (V) i en vandig uorganisk eller organisk syre før opvarmningen, eller alternativt 10 kan syren dannes in situ under fremstillingen af mellemprodukterne som beskrevet i det følgende.The acid required for the hydrolysis can be added to the reaction mixture, e.g. by dissolving the intermediate of formula (II) or formula (V) in an aqueous inorganic or organic acid before heating, or alternatively, the acid may be formed in situ during the preparation of the intermediates as described below.
Mellemproduktet med formlen (II) kan fremstilles ved omsætning af en forbindelse med formlen 15 r· <iv) 20 hvori R, R' og R''' har den i krav 1 angivne betydning, 25 i et opløsningsmiddel ved en temperatur på mellem -50 og 50 °C, fortrinsvis ved stuetemperatur, med mindst ét ækvivalent af en halogenholdig oxidant, valgt blandt chlor, brom, bromchlorid, hypochlorsyrling, hypobromsyr-ling og blandinger deraf, indtil reaktionen er i det væ-30 sentlige fuldført.The intermediate of formula (II) can be prepared by reacting a compound of formula 15 wherein R, R 'and R' '' have the meaning given in claim 1, in a solvent at a temperature of between - 50 and 50 ° C, preferably at room temperature, with at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromoric acid and mixtures thereof until the reaction is substantially complete.
Eksempler på egnede opløsningsmidler til denne reaktion er vand, en alkanol eller -diol med 1-4 carbonatomer, fortrinsvis methanol, en ether med 2-10 carbonatomer, 35Examples of suitable solvents for this reaction are water, an alkanol or diol of 1-4 carbon atoms, preferably methanol, an ether of 2-10 carbon atoms, 35
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4 fortrinsvis tetrahydrofuran eller isopropylether, en lavmolekylær keton, fortrinsvis acetone, et lavmolekylært nitril, en lavmolekylær ester eller et lavmolekylært amid.4 preferably tetrahydrofuran or isopropyl ether, a low molecular weight ketone, preferably acetone, a low molecular weight nitrile, a low molecular weight ester or a low molecular weight amide.
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Mellemproduktet med den ovenstående formel (IV), hvori R' er hydrogen, kan fremstilles ved omsætning af en fur-furylalkohol med formlen 10 R* ^ (III) 15 hvori R og R’'' har den i krav 1 angivne betydning, i en vandig opløsning med-mindst ét ækvivalent af en halogen-20 holdig oxidant, valgt blandt chlor, brom, bromchlorid, hypochlorsyrling, hypobromsyrling og blandinger deraf, ved en temperatur på mellem -50 og +50 °C, fortrinsvis ved stuetemperatur, indtil reaktionen er i det væsentlige fuldført. Reaktionen kan gennemføres i nærvær af et 25 hjælpeopløsningsmiddel, som passende kan være et af de opløsningsmidler, som er nævnt ovenfor til fremstilling af mellemproduktet med formlen (II).The intermediate of the above formula (IV) wherein R 'is hydrogen can be prepared by reacting a furfuryl alcohol of formula 10 R * (III) 15 wherein R and R' 'have the meaning given in claim 1, an aqueous solution with at least one equivalent of a halogen-containing oxidant selected from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromoric acid and mixtures thereof, at a temperature of between -50 and +50 ° C, preferably at room temperature until the reaction is essentially complete. The reaction may be carried out in the presence of an auxiliary solvent which may conveniently be one of the solvents mentioned above for the preparation of the intermediate of formula (II).
6-Alkoxy-2H-pyran-3(6H)-oner med den ovenstående formel 30 (IV), hvori R' er alkyl, kan fremstilles ved den metode, som er beskrevet af Shono et al., i Tetrahedron Letters No. 17, 1363-1364 (1976). En furfurylalkohol alkoxyleres anodisk til 2-(1-hydroxyalkyl)-2,5-dialkoxy-dihydrofuranen, og behandling af denne med en stærk organisk syre 356-Alkoxy-2H-pyran-3 (6H) -ones of the above formula 30 (IV) wherein R 1 is alkyl can be prepared by the method described by Shono et al. In Tetrahedron Letters No. 17, 1363-1364 (1976). A furfuryl alcohol is anodically alkoxylated to the 2- (1-hydroxyalkyl) -2,5-dialkoxy dihydrofuran, treating it with a strong organic acid 35
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5 giver den ønskede 6-alkoxyforbindelse. En anden metode går ud på at behandle en passende substitueret furfuryl-alkohol med en i hovedsagen vandfri syre med pKa 4 eller derunder som beskrevet i dansk patentskrift nr. 148 020.5 gives the desired 6-alkoxy compound. Another method is to treat a suitably substituted furfuryl alcohol with a substantially anhydrous acid of pKa 4 or less as described in Danish Patent No. 148,020.
5 En 6-acyloxyforbindelse kan fremstilles ved konventionel behandling af 6-hydroxy-forbindeisen med det passende anhydrid i nærvær af pyridin.A 6-acyloxy compound can be prepared by conventional treatment of the 6-hydroxy compound ice with the appropriate anhydride in the presence of pyridine.
Når R' skal være hydrogen, kan 4-halogendihydropyran-10 mellemproduktet med formlen (II), om ønsket, fremstilles direkte ud fra en passende furfurylalkohol med formlen (III) ved omsætning af den sidstnævnte i et opløsningsmiddel ved en temperatur på mellem -50 og +50 °C med mindst to ækvivalenter af en af de førnævnte halogenhol-15 dige oxidanter, indtil reaktionen er i det væsentlige fuldført.When R 'is to be hydrogen, the 4-halo dihydropyran intermediate of formula (II), if desired, can be prepared directly from a suitable furfuryl alcohol of formula (III) by reacting the latter in a solvent at a temperature of between -50 and + 50 ° C with at least two equivalents of one of the aforementioned halogen-containing oxidants until the reaction is substantially complete.
Ved hver af de ovenfor beskrevne reaktioner er den foretrukne halogenholdige oxidant chlor eller bromchlorid.In each of the reactions described above, the preferred halogen-containing oxidant is chlorine or bromine chloride.
2020
Mellemproduktet med formlen (V) kan fremstilles ved de-hydratisering af en forbindelse med formlenThe intermediate of formula (V) can be prepared by dehydrating a compound of formula
25 X25 X
r>° ,n-, 30 35 6r> °, n-, 30 35 6
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hvori R og X har den ovenstående betydning, idet forbindelsen med formlen (II1') opvarmes til 40 °C i omkring 16 timer.wherein R and X are as defined above, the compound of formula (II1 ') being heated to 40 ° C for about 16 hours.
5 Som beskrevet ovenfor kan mellemproduktet, 6-hydroxy-2H-pyran-3-(6H)-on med formlen (IV), fremstilles ved omsætning af den passende furfurylalkohol med et ækvivalent af en halogenholdig oxidant. Det isolerede mellemprodukt omdannes let til 4-halogen-6-hydroxy-2H-pyran-3(6H)-on 10 med formlen (II) ved omsætning med yderligere et ækvivalent af en halogenholdig oxidant som tidligere beskrevet.As described above, the intermediate, 6-hydroxy-2H-pyran-3- (6H) -one of formula (IV), can be prepared by reacting the appropriate furfuryl alcohol with an equivalent of a halogen-containing oxidant. The isolated intermediate is readily converted to 4-halo-6-hydroxy-2H-pyran-3 (6H) -one 10 of formula (II) by reaction with an additional equivalent of a halogen-containing oxidant as previously described.
Alternativt kan en furfurylalkohol i vandig opløsning 15 med et eventuelt hjælpeopløsningsmiddel omsættes ved mellem -10 og 10 °C med to ækvivalenter af en halogenholdig oxidant. Efter omrøring ved stuetemperatur i 30 minutter indstilles reaktionsblandingens pH-værdi til 2 med en stærk base, og reaktionsblandingen ekstraheres 20 med et opløsningsmiddel, såsom ethylacetat. Fjernelse af opløsningsmidlet giver 4-halogen-6-hydroxy-2H-pyran-3(6H)-onen med formlen (II').Alternatively, a furfuryl alcohol in aqueous solution 15 with an optional auxiliary solvent can be reacted at between -10 and 10 ° C with two equivalents of a halogen-containing oxidant. After stirring at room temperature for 30 minutes, the pH of the reaction mixture is adjusted to 2 with a strong base and the reaction mixture is extracted with a solvent such as ethyl acetate. Removal of the solvent gives the 4-halo-6-hydroxy-2H-pyran-3 (6H) -one of formula (II ').
4-Halogendihydropyranen kan hydrolyseres direkte til den 25 ønskede γ-pyron, eller den kan dehydratiseres ved opvarmning under vakuum til opnåelse af dimeren, 6,6'-oxy-bis-[4-halogen-2H-pyran-3-(6H)-on], som giver den ønskede γ-pyron ved sur hydrolyse.The 4-halo dihydropyran can be hydrolyzed directly to the desired γ-pyrone or it can be dehydrated by heating under vacuum to give the dimer, 6,6'-oxy-bis- [4-halo-2H-pyran-3- (6H) -on] which gives the desired γ-pyrone by acid hydrolysis.
30 Visse af 4-halogendihydropyran-mellemprodukterne og 6,6'-oxybis-[4-halogen-2H-pyran-3~(6H)-on]-mellemprodukterne er hidtil ukendte forbindelser, nemlig forbindelserne med den almene formel 35 7Some of the 4-halo dihydropyran intermediates and the 6,6'-oxybis [4-halo-2H-pyran-3 ~ (6H) -one] intermediates are novel compounds, namely the compounds of the general formula 35
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XX
Λ/" e R... Γ I di') i 5 K 1 i 10 forbindelserne med den almene formel vAs (vi 20 og forbindelserne med den almene formelΛ / "e R ... Γ I di ') in 5 K 1 in 10 the compounds of the general formula vAs (vi 20 and the compounds of the general formula
yVyV
25 R’ * ’* i (VI) c 2h5 30 hvori R, R1’' og X har den i krav 1 angivne betydning, R''*' har samme betydning som R'1', og R4 betyder alkyl med 1-4 carboantomer eller -C0R", hvor R" betyder methyl, ethyl eller phenyl, idet R'’'' ikke kan være hydrogen, når X er chlor, og R1^ er ethyl.R '*' * in (VI) c 2h5 wherein R, R1 '' and X are as defined in claim 1, R '' * 'has the same meaning as R'1', and R4 is alkyl of 1- 4 is carbon, atoms or -COR ", where R" is methyl, ethyl or phenyl, where R "'" cannot be hydrogen when X is chlorine and R1 is ethyl.
3535
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sp
Om ønsket kan 4-halogendihydropyranen med formlen (II) fremstilles og isoleres ved udførelse af halogeneringen af mellemproduktet med formlen (IV) ved en temperatur på fra -20 til 20 °C, fortrinsvis 5-10 °C, i nærvær af en 5 organisk base, såsom triethylamin. Efter omkring 30 minutter får reaktionsblandingen lov at opvarmes til stuetemperatur, filtreres for at fjerne triethylamin-hydro-chlorid, og opløsningsmidlet fjernes under vakuum til opnåelse af 4-halogendihydropyranen. Denne forbindelse 10 hydrolyseres let til γ-pyronen med formlen (I) ved opvarmning i omkring 1 time i sur vandig opløsning, fortrinsvis ved en temperatur i området 70-160 °C, mest fo-retrukkent 100-110 °C.If desired, the 4-halo dihydropyran of formula (II) can be prepared and isolated by carrying out the halogenation of the intermediate of formula (IV) at a temperature of from -20 to 20 ° C, preferably 5 to 10 ° C, in the presence of an organic base, such as triethylamine. After about 30 minutes, the reaction mixture is allowed to warm to room temperature, filtered to remove triethylamine hydrochloride and the solvent removed in vacuo to give the 4-halo dihydropyran. This compound 10 is readily hydrolyzed to the γ-pyrone of formula (I) by heating for about 1 hour in acidic aqueous solution, preferably at a temperature in the range of 70-160 ° C, most preferably 100-110 ° C.
15 Fremgangsmåden, hvorved 6-acyl- eller 6-alkoxy-2H-pyran- 3-(6H)-onen med formlen (IV) omsættes i et organisk opløsningsmiddel med et ækvivalent af en halogenholdig oxidant, og 4jhalogen-dihydropyran-mellemproduktet med formlen (II) opvarmes, indtil omdannelse til den ønskede 20 γ-pyron er i det væsentlige fuldført, adskiller sig fra den flertrinsproces, som er beskrevet af Shono and Mat-sumura i Tetrahydron Letters Γ7, 1363 (1976), ved hvilken 6-alkoxy-2H-pyran-3(6H)-onen behandles med en metha-nolisk opløsning af hydrogenperoxid i natriumhydroxidop-25 løsning til opnåelse af en epoxy-keton, og den isolerede epoxy-keton derpå opvarmes under tilbagesvaling i vand med "Dowex®50"-ionbytterharpiks til opnåelse af den ønskede γ-pyron. Det bemærkes også, at denne kendte fremgangsmåde ikke er anvendelig på de mere lettilgængelige 30 forbindelser med formlen (IV), hvori R' er hydrogen.The process wherein the 6-acyl or 6-alkoxy-2H-pyran-3- (6H) -one of formula (IV) is reacted in an organic solvent with an equivalent of a halogen-containing oxidant and the 4-halo-dihydropyran intermediate of formula (II) is heated until conversion to the desired 20 γ-pyrone is substantially complete, different from the multistage process described by Shono and Mat-sumura in Tetrahydron Letters Γ7, 1363 (1976), in which 6-alkoxy The -2H-pyran-3 (6H) -one is treated with a methanolic solution of hydrogen peroxide in sodium hydroxide solution to give an epoxy ketone and the isolated epoxy ketone is then heated under reflux in water with "Dowex®50 "ion exchange resin to obtain the desired γ-pyrone. It is also noted that this known process is not applicable to the more readily available compounds of formula (IV) wherein R 1 is hydrogen.
Den foreliggende fremgangsmåde tilvejebringer således en overraskende simpel ét-trins fremgangsmåde til fremstilling af γ-pyroner med formlen (I) ud fra mellemprodukter 35Thus, the present process provides a surprisingly simple one-step process for producing γ-pyrones of formula (I) from intermediates 35
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9 med formlen (II)/ som på deres side kan fremstilles meget simpelt ud fra lettilgængelige udgangsmaterialer.9 of formula (II) / which in turn can be prepared very simply from readily available starting materials.
Efter at opfindelsen var gjort, har det været muligt at 5 forklare reaktionsmekanismen ved fremgangsmåden ifølge opfindelsen, nemlig omdannelsen af forbindelsen (II) til den ønskede γ-pyron (I), f.eks. som hydrolyse, ketonise-ring, eliminering af vand eller alkohol og enolisering som følger: 10 fH o ,11, —► *\Lf° —► _► 15After the invention was done, it has been possible to explain the reaction mechanism of the process of the invention, namely the conversion of the compound (II) to the desired γ-pyrone (I), e.g. such as hydrolysis, ketoneization, elimination of water or alcohol, and enolization as follows: 10 fH o, 11, --► * \ Lf ° --► _► 15
Juf' — jffVJuf '- jffV
20 om ikke nødvendigvis i nøjagtigt denne rækkefølge. Det er klart, at denne forklarende mekanisme ikke kunne forudsiges før den foreliggende opfindelse.20, if not necessarily in exactly this order. It is clear that this explanatory mechanism could not be predicted prior to the present invention.
2525
De følgende eksempler belyser fremstillingen af γ-pyro-nerne med formlen (I) ved fremgangsmåden ifølge opfindelsen, mens præparationerne belyser fremstillingen af mellemprodukterne med formlerne (II) og (V).The following examples illustrate the preparation of the γ-pyrones of formula (I) by the process of the invention, while the preparations illustrate the preparation of the intermediates of formulas (II) and (V).
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Hvor der i eksemplerne er anført spektraldata, angives NMR-data for kemiske skifter ved konventionelle litteratursymboler, og alle skift udtrykkes som δ-enheder fra tetramethylsilan: 35Where the examples are given spectral data, NMR data for chemical shifts are indicated by conventional literature symbols and all shifts are expressed as δ units from tetramethylsilane: 35
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ίο s = singlet d = dublet t = triplet 5 q = kvartet m = multiplet br = bred PRÆPARATION 1 10 4-brom-6-hydroxy-2-methyl-2H-pyran-3(6H)-onίο s = singlet d = doublet t = triplet 5 q = quartet m = multiple br = broad PREPARATION 1 10 4-bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one
Til en opløsning af 25 g l-(2-furyl)-l-ethanol i 125 ml tetrahydrofuran og 125 ml vand ved 0-5 °C sattes dråbe-15 vis 2f2 ækvivalenter brom. Under hele tilsætningen holdtes temperaturen ved 5-10 °C. Efter bromtilsætningen blev opløsningen omrørt ved stuetemperatur i 30 minutter , og pH-værdien indstillet til 2,1 med 2N natriumhydroxidopløsning·;· Reakbionsblandingen blev ekstraheret 20 med ethylacetat (3 x 100 ml). Ethylacetatekstrakterne blev kombineret, tørret over magnesiumsulfat, filtreret og inddampet til tørhed. Remanensen blev kromatograferet på silicagel og elueret med chloroform/ethylacetat (95:5). Produktet var en orange olie, som blev genkroma-25 tograferet på silicagel og elueret med chloroform/ethyl-^ acetat (95:5).To a solution of 25 g of 1- (2-furyl) -1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 0-5 ° C was added dropwise 2f2 equivalents of bromine. Throughout the addition, the temperature was maintained at 5-10 ° C. After the bromine addition, the solution was stirred at room temperature for 30 minutes and the pH was adjusted to 2.1 with 2N sodium hydroxide solution · The reaction mixture was extracted with ethyl acetate (3 x 100 ml). The ethyl acetate extracts were combined, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel and eluted with chloroform / ethyl acetate (95: 5). The product was an orange oil which was chromatographed on silica gel and eluted with chloroform / ethyl acetate (95: 5).
NMR (CDC13, δ) 7,3 (IH, d) 5,6 (IH, d) 30 4,7 - 5,0 (IH, q) 1,1 - 1,5 (3H, m).NMR (CDCl 3, δ) 7.3 (1H, d) 5.6 (1H, d) 4.7 - 5.0 (1H, q) 1.1 - 1.5 (3H, m).
35 1135 11
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PRÆPARATION 2PREPARATION 2
Proceduren fra præparation 1 blev gentaget med furfuryl-alkohol og l-(2-furyl)-l-propanol til dannelse af de 5 følgende forbindelser med formlen (II): R =The procedure of Preparation 1 was repeated with furfuryl alcohol and 1- (2-furyl) -1-propanol to give the following 5 compounds of formula (II): R =
Hydrogen: 4-brom-6-hydroxy-2H-pyran-3(6H)-on 10 NMR (CDCI3, δ) 7,4 (IH, d) 5.5 (IH, d) 4.6 (2H, d af d) 15 Ethyl; 4-brom-6-hydroxy-2-ethyl-2H-pyran-3(6H)-on NMR (CDCI3, δ) 7,4 (IH, d) 4.6 - 4,9 (IH, m) 1,8 - 2,2 (2H, m) 20 1,0 - 1,3 (3H, t) PRÆPARATION 3Hydrogen: 4-bromo-6-hydroxy-2H-pyran-3 (6H) -one NMR (CDCl 3, δ) 7.4 (1H, d) 5.5 (1H, d) 4.6 (2H, d of d) ethyl; 4-bromo-6-hydroxy-2-ethyl-2H-pyran-3 (6H) -one NMR (CDCl 3, δ) 7.4 (1H, d) 4.6 - 4.9 (1H, m) 1.8 - 2.2 (2H, m) 1.0 - 1.3 (3H, t) PREPARATION 3
Fremgangsmåden fra præparation 1 blev gentaget under an-25 vendelse af chlor i stedet for brom og de passende fur-furylalkoholer til fremstilling af de følgende forbindelser med formlen (II): 30 35The procedure of Preparation 1 was repeated using chlorine instead of bromine and the appropriate furfuryl alcohols to prepare the following compounds of formula (II):
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12 R =12 R =
Methyl: 4-chlor-6-hydroxy-2-methyl-2H-pyran-3(6H)-on 5 NMR (CDCI3, δ) 7,1 (IH, d) 5,8 (IH, d) 4.6 - 5,0 (IH, m) 4.4 (IH, br.s.) 1,2 - 1,5 (3H, m) 10Methyl: 4-chloro-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one NMR (CDCl 3, δ) 7.1 (1H, d) 5.8 (1H, d) 4.6-5 , 0 (1H, m) 4.4 (1H, m.p.) 1.2 - 1.5 (3H, m) 10
Ethyl: 4-chlor-6-hydroxy-2-ethyl-2H-pyran-3(6H)-on NMR (CDCI3, δ) 7,0 - 7,1 (IH, d) 5.6 - 6,0 (2H, m) 15 4,4 - 5,0 (IH, m) 1.6 - 2,1 (2H, m) 0,9 - 1,1 (3H, t)Ethyl: 4-chloro-6-hydroxy-2-ethyl-2H-pyran-3 (6H) -one NMR (CDCl 3, δ) 7.0 - 7.1 (1H, d) 5.6 - 6.0 (2H, m) 4.4 - 5.0 (1H, m) 1.6 - 2.1 (2H, m) 0.9 - 1.1 (3H, t)
Hydrogen: 4-chlor-6-hydroxy-2H-pyran-3(6H)-on 20 NMR (CDCI3, δ) 7,1 - 7,2 (IH, d) 5.6 (IH, d) 4.4 - 4,9 (2H, d af d) (D20 tilsat) 25 PRÆPARATION 4 4-brom-6-hydroxy-2-methyl-2H-pyran-3(6H)-on blev opvarmet under vakuum i 16 timer ved 40 °C. Det resulterende olieagtige faste stof blev krystalliseret fra isopropyl-30 alkohol til opnåelse af 6,6'-oxybis[4-brom-2-methyl-2H-pyran-3(6H)-on], smp.: 125 °C.Hydrogen: 4-Chloro-6-hydroxy-2H-pyran-3 (6H) -one NMR (CDCl 3, δ) 7.1 - 7.2 (1H, d) 5.6 (1H, d) 4.4 - 4.9 (2H, d of d) (D20 added) PREPARATION 4 4-Bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one was heated under vacuum for 16 hours at 40 ° C. The resulting oily solid was crystallized from isopropyl alcohol to give 6,6'-oxybis [4-bromo-2-methyl-2H-pyran-3 (6H) -one], mp: 125 ° C.
35 1335 13
DK 153483BDK 153483B
PRÆPARATION 5PREPARATION 5
Fremgangsmåden fra præparation 4 blev gentaget ud fra forbindelserne med formlen (II), hvori X er chlor, og R 5 er henholdsvis methyl og ethyl, til dannelse af de følgende forbindelser med formlen (V): R_X_Snip. ( °C) 10 CH3 Cl 177-179 CH2CH3 Cl 132-135 PRÆPARATION 6 15 4-chlor-6-methoxy-2-methyl-2H-pyran-3(6H)-onThe procedure of Preparation 4 was repeated from the compounds of formula (II) wherein X is chloro and R 5 is methyl and ethyl, respectively, to give the following compounds of formula (V): R_X_Snip. (° C) 10 CH3 Cl 177-179 CH2 CH3 Cl 132-135 PREPARATION 6 4-Chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one
Til en opløsning af 6-methoxy-2-methyl-2H-pyran-3(6H)-on (0,05 mol) i 70 ml dichlormethan ved -10 °C sattes chlor (0,05 mol) via et gasindførselsrør. Efter denne tilsæt-20 ning tilsattes langsomt triethylamin (0,05 mol), medens temperaturen holdtes ved -10 °C. Efter 30 minutters omrøring fik reaktionsblandingen lov at opvarmes til stuetemperatur, hvorpå den blev filtreret for at fjerne tri-ethylamin-hydrochlorid, og opløsningsmidlet blev fjernet 25 under vakuum. Genopløsning af det rå produkt i ether/-benzen og filtrering fjernede de sidste spor af tri-ethylamin-hydrochlorid. Fjernelse af opløsningsmidlet gav 4-chlor-6-methoxy-2-methyl-2H-3(6H)-on (udbytte 99%). NMR-analyse af signalerne ved 5,05-5,25 viste 30 klart to dubletter i et forhold på 3:1 svarende til protonen ved C-6 af de to mulige isomere af forbindelsen. Begge optiske former af trans-isomeren var blevet syntetiseret fra et carbonhydrat-forstadium af Paulsen, Eberstein and Koebernick, Tetrahedron Letters 35To a solution of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one (0.05 mol) in 70 ml of dichloromethane at -10 ° C was added chlorine (0.05 mol) via a gas feed tube. After this addition, triethylamine (0.05 mole) was slowly added while maintaining the temperature at -10 ° C. After 30 minutes of stirring, the reaction mixture was allowed to warm to room temperature, then filtered to remove triethylamine hydrochloride and the solvent removed in vacuo. Redissolving the crude product in ether / benzene and filtration removed the last traces of triethylamine hydrochloride. Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2H-3 (6H) -one (yield 99%). NMR analysis of the signals at 5.05-5.25 showed clearly two doublets in a ratio of 3: 1 corresponding to the proton at C-6 of the two possible isomers of the compound. Both optical forms of the trans isomer had been synthesized from a carbohydrate precursor by Paulsen, Eberstein and Koebernick, Tetrahedron Letters 35
DK 153483BDK 153483B
14 4377 (1974).14 4377 (1974).
PRÆPARATION 7 5 4-brom-6-methoxy-2-methyl-2H-pyran-3(6H)-onPREPARATION 7 5 4-Bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one
Proceduren fra præparation 6 blev gentaget under erstatning af chlor med brom til opnåelse af 4-brom-6-methoxy- 2-methyl-2H-pyran-3(6H)-on i 93% udbytte. De to optiske 10 former af trans-isomeren var blevet syntetiseret af Paulsen og medarbejdere, Tetrahedron Letters 4377 (1974).The procedure of Preparation 6 was repeated replacing chlorine with bromine to give 4-bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one in 93% yield. The two optical forms of the trans isomer had been synthesized by Paulsen and co-workers, Tetrahedron Letters 4377 (1974).
PRÆPARATION 8 15 4-brom-6-acetoxy-2H-pyran-3(6H)-onPREPARATION 8 4-Bromo-6-acetoxy-2H-pyran-3 (6H) -one
En opløsning i dichlormethan af 6-acetoxy-2H-pyran-3(6H)-on, fremstillet ved den metode, som er beskrevet i 20 Tetrahedron 27, 1973 (1971), blev bromeret ved proceduren fra præparation 7 til opnåelse af 4-brom-6-acetoxy-2H-pyran-3(6H)-on, smp.: 78-80 °C. Forbindelsens massespektrum viste de forventede stam-maksima ved 234 og 236 masseenheder.A solution in dichloromethane of 6-acetoxy-2H-pyran-3 (6H) -one, prepared by the method described in Tetrahedron 27, 1973 (1971), was brominated by the procedure of Preparation 7 to give 4 bromo-6-acetoxy-2H-pyran-3 (6H) -one, mp: 78-80 ° C. The mass spectrum of the compound showed the expected strain maxima at 234 and 236 mass units.
25 PRÆPARATION 9 4-brom-6-acetoxy-2-methyl-2H-pyran-3(6H)-on 30 Proceduren fra præparation 8 blev gentaget med 6-aceto-xy-2-methyl-2H-pyran-3(6H)-on til opnåelse af 4-brom-6-acetoxy-2-methyl-2H-pyran-3(6H)-on, som viste stam-mas-ser på 249,96 og 247,96 ved massespektroskopi og det følgende NMR-spektrum: 35PREPARATION 9 4-Bromo-6-acetoxy-2-methyl-2H-pyran-3 (6H) -one 30 The procedure of Preparation 8 was repeated with 6-aceto-xy-2-methyl-2H-pyran-3 (6H). ) -one to give 4-bromo-6-acetoxy-2-methyl-2H-pyran-3 (6H) -one, which showed strain masses of 249.96 and 247.96 by mass spectroscopy and the following NMR spectrum: 35
DK 153483BDK 153483B
15 δ, CDC13): 7,3 (IH, d) 6,4 (IH, d af d) 4,7 (IH, q) 2,2 (3H, s) 5 1,4 (3H, S) EKSEMPEL 1Δ, CDCl 3): 7.3 (1H, d) 6.4 (1H, d of d) 4.7 (1H, q) 2.2 (3H, s) 1.4 (3H, S) EXAMPLE 1
En opløsning af 4-brom-6-hydroxy-2-methyl-2H-pyran-10 3(6H)-on blev fremstillet ved opløsning af forbindelsen i en vandig uorganisk eller vandig organisk syre. Opløsningen blev derpå opvarmet til tilbagesvaling, afkølet til stuetemperatur, pH-værdien indstillet til 2,1 med 6N natriumhydroxidopløsning, og reaktionsblandingen ekstra-15 heret med chloroform. Koncentrering gav maltol. Syrerne, reaktionstiden og udbytterne af maltol var som følger:A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-10 3 (6H) -one was prepared by dissolving the compound in an aqueous inorganic or aqueous organic acid. The solution was then heated to reflux, cooled to room temperature, the pH adjusted to 2.1 with 6N sodium hydroxide solution, and the reaction mixture extracted with chloroform. Concentration gave maltol. The acids, reaction time and yields of maltol were as follows:
Koncentra- Reaktions- UdbytteConcentration- Reaction- Yield
Syre_tion (¾)_tid (h)_(%) 20 HC1 32 2 68 HC1 32 5 52 HC1 18 5 35 HCl 25 3 49 HBr 18 5 24 25 H2SO4 35 2 26 H3PO4 35 2 29 CH3COOH 35 2 69 CF3COOH ren 3 36 HNO3 35 3 0,4 30 CF3COOH ren 3 70 CH3COOH ren 3 77 HCOOH ren 3 24 H2S04 35 5 48 35 EKSEMPEL 2 16Acid_tion (¾) _time (h) _ (%) 20 HC1 32 2 68 HC1 32 5 52 HC1 18 5 35 HCl 25 3 49 HBr 18 5 24 25 H2SO4 35 2 26 H3PO4 35 2 29 CH3COOH 35 2 69 CF3COOH pure 3 36 HNO3 35 3 0.4 30 CF3COOH pure 3 70 CH3COOH pure 3 77 HCOOH pure 3 24 H2SO4 35 5 48 35 EXAMPLE 2 16
DK 153483BDK 153483B
En opløsning af 4-brom-6-hydroxy-2-methyl-2H-pyran-3(6H)-on (0/0025 mol) i 20 ml 35% phosphorsyre blev op-5 varmet under tilbagesvaling i 5 timer. Maltol (34%) blev isoleret ved proceduren fra eksempel 1.A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one (0/0025 mol) in 20 ml of 35% phosphoric acid was heated at reflux for 5 hours. Maltol (34%) was isolated by the procedure of Example 1.
EKSEMPEL 3 10 Forbindelserne med formlen (V), hvori X er brom eller chlor, og R er henholdsvis hydrogen, methyl og ethyl, behandles ved fremgangsmåden ifølge eksempel 2 til opnåelse af de følgende forbindelser med formlen (I):EXAMPLE 3 The compounds of formula (V) wherein X is bromine or chlorine and R are hydrogen, methyl and ethyl, respectively, are treated by the procedure of Example 2 to give the following compounds of formula (I):
15 R_Smp., °CR-m.p., ° C
H 117-118 CH3 (maltol) 160 CH2CH3 (ethylmaltol) 90 20 EKSEMPEL 4 I en rundbundet kolbe forsynet med omrøringsstav og tilbagesvaler fyldtes 1 g 4-chlor-6-methoxy-2H-pyran-3(6H)-25 on og 10 ml eddikesyre, og reaktionsblandingen blev opvarmet til tilbagesvaling i 1 time. Maltol (65%) blev opnået ved afkøling.H 117-118 CH3 (maltol) 160 CH2CH3 (ethyl maltol) 90 EXAMPLE 4 In a round bottom flask equipped with stirring bar and reflux 1 g of 4-chloro-6-methoxy-2H-pyran-3 (6H) -25 one and 10 g ml of acetic acid and the reaction mixture was heated to reflux for 1 hour. Maltol (65%) was obtained by cooling.
EKSEMPEL 5 30EXAMPLE 5 30
Proceduren fra eksempel 4 blev gentaget med tilsvarende resultater under anvendelse af myresyre i stedet for eddikesyre.The procedure of Example 4 was repeated with similar results using formic acid instead of acetic acid.
3535
DK 153483 BDK 153483 B
17 EKSEMPEL 6EXAMPLE 6
Proceduren fra eksempel 4 blev gentaget ud fra forbindelserne med formlen (II), hvori X er brom eller chlor, 5 R' er hydrogen, methyl eller acetyl, og R er henholdsvis hydrogen, methyl og ethyl, til dannelse af de følgende forbindelser med formlen (I):The procedure of Example 4 was repeated from the compounds of formula (II) wherein X is bromine or chloro, R 5 'is hydrogen, methyl or acetyl and R is hydrogen, methyl and ethyl respectively to give the following compounds of formula (IN):
R_Smp., °CR-mp, ° C
10 H 117-118 CH3 (maltol) 160 CH2CH3 (ethylmaltol) 90 15 20 25 30 3510 H 117-118 CH3 (maltol) 160 CH2CH3 (ethylmaltol) 90 15 20 25 30 35
Claims (5)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK326086A DK153401C (en) | 1976-08-02 | 1986-07-09 | 4-HALOGEN-6-HYDROXY-2H-PYRANE-3 (6H) -ON COMPOUNDS FOR USE AS INTERMEDIATES IN THE PRODUCTION OF GAMMA PYRONS AND PROCEDURES FOR THE PRODUCTION OF INTERMEDIATE PRODUCTS |
| DK325986A DK153484C (en) | 1976-08-02 | 1986-07-09 | PROCEDURE FOR MANUFACTURING GAMMA PYRONS |
| DK326186A DK154079C (en) | 1976-08-02 | 1986-07-09 | METHOD OF PREPARING 4-HALOGEN-2H-PYRANE-3 (6H) -ON COMPOUNDS |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71090176A | 1976-08-02 | 1976-08-02 | |
| US71090176 | 1976-08-02 | ||
| US05/721,885 US4082717A (en) | 1976-08-02 | 1976-09-09 | Preparation of gamma-pyrones |
| US72188576 | 1976-09-09 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK276177A DK276177A (en) | 1978-02-03 |
| DK153483B true DK153483B (en) | 1988-07-18 |
| DK153483C DK153483C (en) | 1988-11-28 |
Family
ID=27108548
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK276177A DK153483C (en) | 1976-08-02 | 1977-06-22 | PROCEDURE FOR MANUFACTURING GAMMA PYRONS |
| DK326186A DK154079C (en) | 1976-08-02 | 1986-07-09 | METHOD OF PREPARING 4-HALOGEN-2H-PYRANE-3 (6H) -ON COMPOUNDS |
| DK326086A DK153401C (en) | 1976-08-02 | 1986-07-09 | 4-HALOGEN-6-HYDROXY-2H-PYRANE-3 (6H) -ON COMPOUNDS FOR USE AS INTERMEDIATES IN THE PRODUCTION OF GAMMA PYRONS AND PROCEDURES FOR THE PRODUCTION OF INTERMEDIATE PRODUCTS |
| DK325986A DK153484C (en) | 1976-08-02 | 1986-07-09 | PROCEDURE FOR MANUFACTURING GAMMA PYRONS |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK326186A DK154079C (en) | 1976-08-02 | 1986-07-09 | METHOD OF PREPARING 4-HALOGEN-2H-PYRANE-3 (6H) -ON COMPOUNDS |
| DK326086A DK153401C (en) | 1976-08-02 | 1986-07-09 | 4-HALOGEN-6-HYDROXY-2H-PYRANE-3 (6H) -ON COMPOUNDS FOR USE AS INTERMEDIATES IN THE PRODUCTION OF GAMMA PYRONS AND PROCEDURES FOR THE PRODUCTION OF INTERMEDIATE PRODUCTS |
| DK325986A DK153484C (en) | 1976-08-02 | 1986-07-09 | PROCEDURE FOR MANUFACTURING GAMMA PYRONS |
Country Status (36)
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| JP (7) | JPS5318578A (en) |
| AR (1) | AR216080A1 (en) |
| AT (3) | AT362790B (en) |
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| CA (3) | CA1095921A (en) |
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| CS (3) | CS203921B2 (en) |
| DD (1) | DD132494A5 (en) |
| DE (3) | DE2760220C2 (en) |
| DK (4) | DK153483C (en) |
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| ES (5) | ES459994A1 (en) |
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| HK (5) | HK30381A (en) |
| HU (4) | HU185686B (en) |
| IE (5) | IE45642B1 (en) |
| IT (1) | IT1106258B (en) |
| LU (1) | LU77600A1 (en) |
| MX (1) | MX4597E (en) |
| MY (3) | MY8100267A (en) |
| NL (5) | NL170955C (en) |
| NO (7) | NO150561C (en) |
| NZ (1) | NZ184342A (en) |
| PH (5) | PH13557A (en) |
| PL (4) | PL215008A1 (en) |
| PT (1) | PT66694B (en) |
| RO (4) | RO78952A (en) |
| SE (6) | SE433079B (en) |
| SU (2) | SU955859A3 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1095921A (en) * | 1976-08-02 | 1981-02-17 | Thomas M. Brennan | Preparation of gamma-pyrones |
| FR2402654A1 (en) * | 1977-09-12 | 1979-04-06 | Shinetsu Chemical Co | Tetra:hydro-pyranone derivs. - useful as intermediates for cpds. used as food flavours |
| JPS5444675A (en) * | 1977-09-12 | 1979-04-09 | Shin Etsu Chem Co Ltd | Production of 3-hydroxy-4-pyrone analog |
| JPS5741226U (en) * | 1980-08-20 | 1982-03-05 | ||
| JPS59135008U (en) * | 1983-02-28 | 1984-09-10 | 松下電工株式会社 | Distribution board device |
| JPS6050245A (en) * | 1983-08-29 | 1985-03-19 | Nissan Motor Co Ltd | Fuel injection device in internal-combustion engine |
| JPH0226945Y2 (en) * | 1985-09-11 | 1990-07-20 | ||
| JP2586607B2 (en) * | 1987-10-30 | 1997-03-05 | 日産化学工業株式会社 | Production method of optically active alcohol |
| AU2008232262B2 (en) * | 2007-03-28 | 2013-02-14 | Apotex Inc. | Fluorinated derivatives of deferiprone |
| WO2009129592A1 (en) | 2008-04-25 | 2009-10-29 | Apotex Technologies Inc. | Liquid formulation for deferiprone with palatable taste |
| SG177462A1 (en) | 2009-07-03 | 2012-02-28 | Apotex Technologies Inc | Fluorinated derivatives of 3-hydroxypyridin-4-ones |
| WO2017168309A1 (en) * | 2016-03-29 | 2017-10-05 | Dr. Reddy’S Laboratories Limited | Process for preparation of eribulin and intermediates thereof |
| CN108609456B (en) * | 2016-12-13 | 2021-03-12 | 奥的斯电梯公司 | Openable expansion panel and elevator suspended ceiling, elevator car and elevator system with same |
| CN111606879A (en) * | 2020-05-25 | 2020-09-01 | 安徽金禾实业股份有限公司 | Method for preparing 2-hydroxymethyl-3-alkoxy-4H-pyran-4-ketone by one-pot method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3751434A (en) * | 1968-07-29 | 1973-08-07 | American Home Prod | Derivatives of 2h-pyran-3(6h)-ones |
| DK148020B (en) * | 1975-08-28 | 1985-02-04 | Pfizer | METHOD FOR PREPARING 6-ALCOXY-2H-PYRANE-3 (6H) -ON COMPOUNDS |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3491122A (en) * | 1966-09-14 | 1970-01-20 | Monsanto Co | Synthesis of 4-pyrones |
| JPS5145565B1 (en) * | 1968-10-12 | 1976-12-04 | ||
| US3621063A (en) * | 1968-12-24 | 1971-11-16 | Monsanto Co | Unsaturated acyclic ketones |
| US3832357A (en) * | 1971-05-26 | 1974-08-27 | Daicel Ltd | Process for preparation of 3-hydroxy-2-alkyl-4-pyrone |
| JPS5212166A (en) * | 1975-07-17 | 1977-01-29 | Tatsuya Shono | Process for preparation of 4-pyron derivatives |
| CA1095921A (en) | 1976-08-02 | 1981-02-17 | Thomas M. Brennan | Preparation of gamma-pyrones |
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1977
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1978
- 1978-02-03 PH PH20745A patent/PH15185A/en unknown
- 1978-02-03 PH PH20746A patent/PH13926A/en unknown
- 1978-05-25 JP JP53062820A patent/JPS5814433B2/en not_active Expired
- 1978-05-25 JP JP6282178A patent/JPS5436270A/en active Granted
- 1978-05-25 JP JP6281778A patent/JPS5436266A/en active Pending
- 1978-05-25 JP JP6282278A patent/JPS5436271A/en active Granted
- 1978-05-25 JP JP6281878A patent/JPS5436267A/en active Granted
- 1978-05-25 JP JP6281978A patent/JPS5436268A/en active Pending
- 1978-06-07 CS CS783706A patent/CS203923B2/en unknown
- 1978-06-07 CS CS783705A patent/CS203922B2/en unknown
- 1978-06-13 ES ES470746A patent/ES470746A1/en not_active Expired
- 1978-06-13 ES ES470744A patent/ES470744A1/en not_active Expired
- 1978-06-13 ES ES470745A patent/ES470745A1/en not_active Expired
- 1978-06-13 ES ES470743A patent/ES470743A1/en not_active Expired
- 1978-07-05 SU SU782631651A patent/SU1015826A3/en active
-
1979
- 1979-02-01 PH PH22150A patent/PH13874A/en unknown
- 1979-02-01 PH PH22149A patent/PH14625A/en unknown
-
1980
- 1980-03-06 AT AT0124380A patent/AT364356B/en not_active IP Right Cessation
- 1980-03-06 AT AT0124480A patent/AT363470B/en not_active IP Right Cessation
- 1980-10-24 CA CA000363274A patent/CA1117541A/en not_active Expired
- 1980-10-24 CA CA363,273A patent/CA1110254A/en not_active Expired
- 1980-10-30 CH CH808580A patent/CH625235A5/en not_active IP Right Cessation
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1981
- 1981-02-20 CH CH116081A patent/CH626357A5/en not_active IP Right Cessation
- 1981-02-20 CH CH116181A patent/CH626358A5/en not_active IP Right Cessation
- 1981-07-02 HK HK303/81A patent/HK30381A/en unknown
- 1981-07-02 HK HK306/81A patent/HK30681A/en unknown
- 1981-07-02 HK HK305/81A patent/HK30581A/en unknown
- 1981-07-02 HK HK307/81A patent/HK30781A/en unknown
- 1981-07-02 HK HK304/81A patent/HK30481A/en unknown
- 1981-12-09 NL NLAANVRAGE8105537,A patent/NL182476C/en not_active IP Right Cessation
- 1981-12-09 NL NLAANVRAGE8105540,A patent/NL182805C/en not_active IP Right Cessation
- 1981-12-09 NL NLAANVRAGE8105539,A patent/NL182478C/en not_active IP Right Cessation
- 1981-12-09 NL NLAANVRAGE8105538,A patent/NL182477C/en not_active IP Right Cessation
- 1981-12-30 MY MY267/81A patent/MY8100267A/en unknown
- 1981-12-30 MY MY262/81A patent/MY8100262A/en unknown
- 1981-12-30 MY MY287/81A patent/MY8100287A/en unknown
-
1982
- 1982-01-29 SE SE8200521A patent/SE452616B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200520A patent/SE444564B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200522A patent/SE444565B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200518A patent/SE445041B/en not_active IP Right Cessation
- 1982-01-29 SE SE8200519A patent/SE445042B/en not_active IP Right Cessation
- 1982-06-03 NO NO821849A patent/NO150559C/en unknown
- 1982-06-03 NO NO821847A patent/NO150042C/en unknown
- 1982-06-03 NO NO821851A patent/NO150560C/en unknown
- 1982-06-03 NO NO821848A patent/NO150043C/en unknown
- 1982-06-03 NO NO821850A patent/NO821850L/en unknown
- 1982-12-07 YU YU02703/82A patent/YU270382A/en unknown
- 1982-12-13 YU YU2747/82A patent/YU42613B/en unknown
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1983
- 1983-05-16 FI FI831703A patent/FI73424C/en not_active IP Right Cessation
- 1983-05-16 FI FI831700A patent/FI72119C/en not_active IP Right Cessation
- 1983-05-16 FI FI831704A patent/FI72721C/en not_active IP Right Cessation
- 1983-05-16 FI FI831702A patent/FI72720C/en not_active IP Right Cessation
- 1983-05-16 FI FI831701A patent/FI72723C/en not_active IP Right Cessation
- 1983-08-08 YU YU1663/83A patent/YU43190B/en unknown
- 1983-11-18 NO NO834236A patent/NO151365C/en unknown
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1986
- 1986-07-09 DK DK326186A patent/DK154079C/en active
- 1986-07-09 DK DK326086A patent/DK153401C/en not_active IP Right Cessation
- 1986-07-09 DK DK325986A patent/DK153484C/en active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3751434A (en) * | 1968-07-29 | 1973-08-07 | American Home Prod | Derivatives of 2h-pyran-3(6h)-ones |
| DK148020B (en) * | 1975-08-28 | 1985-02-04 | Pfizer | METHOD FOR PREPARING 6-ALCOXY-2H-PYRANE-3 (6H) -ON COMPOUNDS |
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