PROCEDURE FOR PREPARING 4-HYDROXY-5-ALKYL- AND 4-HYDROXY-2,5-DIALKYL-3-OXO-2H-FU RANI.

Description

Description of the invention entitled w Process for preparing 4-hydroxy-5-alkylated 4-hydroxy-2,5-dialkyl-3-oxd-2H-furans in the name of PFWBV, AMERSFOORT (Netherlands) + 29 MAR. 1978 _ 2171«* / 7« filed on with No. -=oOo=The present invention relates to a new process for the preparation of 4-hydroxy5-alkyl-3-osad-2H-furans and 4-hydroxy-2,5-dialkyl-3-osad-2H-furans of general formula or its tautomeric forms, where R^ represents an alkyl radical with 1-6 carbon atoms, and R 2 represents hydrogen or an alkyl radical with 1-4 carbon atoms. The invention also relates to the novel intermediates used in the process. In recent years, Bml-type furan derivatives have received considerable attention in flavor research. A review of the literature reveals that these compounds are useful in a wide variety of food and beverage applications. For example, U.S. Patent No. 3,647,825 reports that 4-hydroxy-5-methyl-3-oxal-2H-furan • ft ·· · -2' BffEVET7ì Ε ™Γ WWO - Viale Bianca Maria, 33 has been added, with beneficial results, to bread, biscuits, sweets, chocolate, natural and processed meat, dairy products, processed foods obtained from eggs, fresh and smoked fish, and vegetables / „ as well as to concentrated soap powders, dried fruit and nuts, canned fruit, soft drinks, liqueurs, wine, whisky, instant coffee and even cigars and cigarettes, chewing gum and oral hygiene preparations such as toothpaste, mouthwashes and liquids. U.S. Patent No. 3,887,589 teaches the uses of 2,5-diethyl-4-hydroxy-3-Oxymethyl-2H-furan in bakery products for the purpose of imparting a more pleasant taste and the impression of greater freshness. U.S. Patent No. 3,576,014 teaches the use of 4-hydroxide. Si-2-methyl-5-ethyl-3-ox.-2H-furan and 4-hydroxy-2ethyl-5-methyl-3-oxo-2H-furan as raspberry or gooseberry flavoring. U.S. Patent No. 3,709,697 teaches the use of 4-hydroxy-2-methyl-5-ethyl-3-ox.-2H-furan and 4-hydroxy-2,5-diethyl-3-ox.-2H-furan as additives to impart or enhance a bread flavor. Many syntheses have been suggested to prepare furans of the type mentioned. But these are always e... Hifi multi-stage, non-economical laboratory methods, ·· ·· -3NOTARGABìCLO δ GHPVASI STUDIO EfitVcTTI E MARCHI 20122 MILANO · Viale Bianca Maria, 33 which cannot be usefully applied to the production of the compounds on a commercial scale, or use very expensive natural products, such as yrhamnose (see Proc.Am.Soc.Brewing Chemists, 84(1963) obtainable only in small insufficient quantities, of unpredictable quality and therefore unsuitable as raw materials for the production, on a commercial scale, of furans. For the techniques proposed so far for the purpose of preparing those compounds, reference can be made to J.Org.Chem., 31«2391-4(1966) and J.Org.Chem., 38, 123-5(1973), to American patents 3,709,697; 3,647,825; 3,887,589; 3,576,014; 3,694,466; 3,651,097 3,853,918; 3,629,292 and 3,629,293, to British patent No. 1,440,270 and to Swiss patent No. 565,168. According to the present invention, it has been found that furan derivatives of the indicated class can be prepared in a technically very simple and commercially feasible manner. The new process of the present invention comprises the following steps: a) condensation of a dialkyl ester of an alpha-alkylglycolic acid with a diester of oxalic acid, in the presence of an alkaline condenser, to prepare the disodium salt of 2-carbalkoxy-3,4-dihydroxy-5-alkylur an; ·· ·· • « ···· ··· · ftft • · · ftft !· ·« ·· *· ·· ft • ftft • ftft • · · • · • · · • · • ftft • ftft ··· • · -4NOTARBARTCLQ & GERVASI PATENT AND TRADEMARK STUDIO 20122 MILAN - Viale Bianca Maria, 33 b) hydrolysis of the carbalkoxy group of this disodium disulfide; c) decarboxylation of the hydrolyzed product; and fl) recovery of 4-hydroxy-5-aleyl-3-ox<-2HfUranus. If desired, the disodium salt of 2-carbalkoxy3,4-dihydroxy-5-alkylfuran can be alkylated to its 2,5-dialkyl homologue by treating it with a lower alkyl halide before hydrolysis. The process of the invention is represented schematically by the reaction schemes described below, where B 1 has the meaning specified above and is an alkyl radical with 1-4 carbon atoms, E. is an alkyl radical suitable for description 4 of the alkyl radical denoted by Rg, M is an alkali metal ion X is a halogen. Raw materials I and II are easily prepared compounds. Compound I is a dialkyl ester of alpha-alkylglycolic acid. It can be obtained by reacting an alkyl haloacetate (bromide and chloride) with an alkyl ester of an alpha-hydroxycarboxylic acid. The synthesis is described in by A.Soladie-Cavallo and P.Vieles in Bull.Soc.Chim. ···· • · • •ft· • · * · · .·«· '· ·· • · · «e • · · ee • · · · '··· ·· · · • ft ·«· · ft ftft ft ft ft » ft ft ft • · · ft · · « ft V ft * ftft· ft ft · · ··· • · • ftft Γ:· : hI'Ì lN,r· ili ί ! NOTARBAFÌTGLO & GERVASJ PATENT AND TRADEMARK FIRM 20122 MILAN - Viale Bianca Maria, 33 - 5France, 1967, pages 517 et seq. The preferred compounds are diethyl and dimethyl esters. Diayloxyl esters (compound II) are inexpensive and commercially available. Diethyl and dimethyl esters are very common, and are therefore preferred for the reaction. Other lower alkyl esters can also be used with equally good results. The reaction between alpha-alkylglycolic acid diester and dialkyl oxalate produces the disodium salt of 2-carbalkoxy-3,4-dialkylfuran (compound III). The reaction is carried out in an inert diluent or solvent, in the presence of an alkali condenser, preferably an alkali metal alkoxide of a 1- to 4-carbon alcohol, or an alkali metal hydride. Condensers based on one of the alkali metals, such as lithium, potassium, and sodium, may be used. Preferred alkali condensers are sodium methoxide, sodium ethoxide, and sodium hydride. Some of the intermediate compounds in the reaction will often be referred to, from now on, as sodium salts. It is clear that these compounds can, and may also, be salts of other alkali metals. By diluent or inert solvent we mean a · »··· >··· • · · · · • · ftft··· ••ftft O ftft · e · · · * • · · • · .* • · · ·*· ♦ * ··· -6NOTABMBTCLO & diluent: An organic liquid that does not enter into the reaction itself or cannot otherwise react with the other reagents. The diluent can be polar or nonpolar. Organic liquids such as aliphatic and aromatic hydrocarbons, alcohols, dimethylformamide, dimethyl sulfoxide, ethers, and nitriles can be used. The choice of diluent can affect the temperature at which the reaction occurs, but the necessary conditions for a particular diluent can easily be determined experimentally. In carrying out reaction scheme A, equimolar amounts of the alpha-alkylglycolic acid dialkyl ester and the dialkyloxalate, I and II, are added to a solution or suspension of 2 equivalents of the alkaline condensing agent in the inert diluent at low temperature. The reaction begins virtually immediately upon contact of reagents I and II. It is convenient to remove the alcohol formed in the condensation reaction as the reaction proceeds, as this drives the reaction to completion, providing better yields. This is not critical for the formation of the intermediate disodium salt of 2-carbalkoxy-3,4-dihydroxy-5-alkylfuran. When the reaction is completed, the disodium salt can be recovered as such, »··· •oo· • ​​OO 0 · ··· • · · oo ► o · · · · · ·** •Z · *··· • · ♦ 0 ···< 4« ·· · • O ' 4 O • 0404 OR 04 0 . Reaction scheme NOTARBARTCLO δ GERVASf STLìDiO E,OVETTI e tòlìCHl 20122 MILAN - Viale Bianca Maria, 33 on: ibi·acidified in its 3,4-dihydroxy form and recovered or immediately subjected to hydrolysis and decarboxylation, in order to transform it into 4-hydroxy-5-alkyl-3-oxA_2H-furan or it can be used in reaction scheme B (see above) without intermediate recovery operations. Carrying out scheme B, in which intermediate compound III is alkylated to form a product 2,5-dialkyl-substituted, the solvents or diluents shown in Scheme A may be used, but a bipolar, aprotic diluent or solvent is preferred. The reaction proceeds more rapidly in the presence of such a solvent. Dimethyl sulfoxide, dimethylformamide, or a mixture of at least 10% or more by weight of one of them in toluene or another polar or nonpolar organic liquid are preferred. Before performing the alkylation, it is advisable to convert the disodium salt into the monosodium salt by adding the calculated amount of an anhydrous organic acid or a mineral acid to the reaction mixture. It has been found that the monosodium salt is more soluble in the organic reaction medium, and that the alkylation proceeds more rapidly and more selectively when performed with this salt. .··· than with disodium salt. Tji— NOTARbXrTGLO & GERVASf PATENT AND TRADEMARK STUDIO 20122 MILAN - Viale Bianca Maria. 31 The alkylation reaction is done with an equinecular amount, related to compound III, of an alkyl halide with 1-4 carbon atoms. Any alkyl halide that satisfies this description may be used, e.g. alkyl chlorides, -bromides and -iodides. The reaction can take place at 2O-8O®C, in 1-20 hours, depending on the temperature. The completion of the alkylation reaction is indicated by a constant pH reading between 6.5 and 7.5. the As mentioned in the case of compound III, the initial alkylation product VII can be recovered as such or immediately subjected to hydrolysis and decarboxylation, without intermediate recovery. THE The conversion of intermediate compounds into their desired final products is done in the same way, for both reaction schemes A and B. In each case, the ester is hydrolyzed to its alkali salt form and then decarboxylated. The hydrolysis of the ester can be done with an alkali metal hydroxide, in a manner known to those skilled in the art for hydrolyzing an ester. The resulting carboxylic acid de-ester group is not stable and decarboxylation occurs spontaneously, for neutralization of acids. r £ L t THE. NOTARBARTOLO & GERVASI PATENT AND TRADEMARK STUDIO 20122 MILAN - Viale Bianca Maria, 33 fication, As mentioned previously, intermediate products IV and VII of the reaction can be isolated and, if desired, recovered. They can be treated as previously mentioned, at a later stage, by hydrolysis and decarboxylation. In particular, it is useful to recover product IV in the intermediate state, because it can then be used to prepare the final alkylated product required. These intermediates, 2-carbalkoxy-3,4-dihydroxy-Si-5-alkylfuran (IV), which may exist in small amounts in its tautomeric pheto-enol forms, and 2-carbalkoxy-4-hydroxy-2,5dialkyl-3-oxo-2H-furan (VII), are novel compounds. In addition to their usefulness as intermediates in the present process, they are useful additives to some types of flavors, given their properties of enhancing the fragrance, generating a richer and better balanced flavor, and improving the background characteristics. In this respect, they are useful in a variety of applications, such as confectionery, soft drinks, confectionery, and as components of artificial sweeteners. ···· ?Λ·Λ ·· * · · · » .;·;· ···· • · · · · « · • · · · · • · · ♦· · ·»··· · ····· · · · » « « · » 99449 ** .··· ·····: :. : • · · · • . • · · · * ··.· · .· · a · · *···· ​​.,·· ·· ' « * • · · · · · • ·· · , • · ··· The following examples illustrate the invention -11t..... l· f: I' r t. ' ir The______ I fri# NOTARBARTOLO & GERVASf Patent and Trademark Firm 20122 MILAN - Viale Bianca Maria, 33 Example 1 2-carbethoxy-5-methyl-3,4-dihydroxyphorane In a 6-liter, three-necked flask, equipped with a mechanical stirrer, a drip funnel, a thermometer, a 30-cm Vigreux column connected to a dephlegmator, and a gas inlet tube, a suspension of 408 g of sodium ethoxide in 3 liters of anhydrous toluene is placed. To the stirred suspension, under nitrogen at 0°C, are added: 438 g of diethyl oxalate in 75 minutes. To the yellow reaction mixture, add at 0-2°C, 612 g of diethyl-alpha-methyldiglycolate in 90 minutes (A. Solladie-Cavallo and P. Vieles, Bull, Soc. Chim. Trance 1967, 517). The reaction mixture is stirred at room temperature for another 2 hours. The reaction mixture is then gradually heated and an ethanol-toluene mixture is distilled until the vapor temperature is 107°C. The reaction mixture is cooled to room temperature and stirred for 30 minutes with two liters of water. The reaction mixture is transferred to a separate funnel. Afterwards, the toluene layer is removed and the aqueous layer is washed successively with diisopropyl ether and pentane. The aqueous solution is acidified with concentrated hydrochloric acid.Du · · · · » · * Λ · · · * · · · _ · · · · • » · e · « · ♦ · t · · · · · · ♦ ♦ · 9 · · * • « · « · · NOTARRARTOÌO & GERVASJ PATENT AND TRADEMARK STUDY 20122 MILAN - Viale Biacca Maria, 33 ii ll,r V f 1' l· impeller acidification, the temperature is maintained at 0*C. The solid product is filtered and dried, giving 425 g (T6?é) of 2-carbethoxy-5-methyl-3,5-dihydroxyphorane; recrystallizing from alcohol: p. melting 120-121®C. mSH(CDCl 3) $1.40(3H,t) ;2.28(3H,s);4.40(2H,q); 6,O(2H, broad). Example 2 2-carbethoxy-5-methyl-3,4-dihydroxy-forane In a 2-liter, three-necked flask, with a mechanical stirrer, a thermometer, a nitrogen inlet tube and a reflux condenser, protected by a calcium chloride tube, a solution of 102 g diethyl-alpha-methyldiglycolate is placed. 1 g of ethyl-oxalate in 1 liter of anhydrous dimethylformamide. 24 g of sodium hydride and 0.5 ml of ethanol are added to the stirred reaction mixture at room temperature. The reaction mixture is then heated under nitrogen to 90°C, when an exothermic reaction with the evolution of hydrogen is observed. The temperature is maintained at 110°C for another 15 minutes. The reaction mixture is then cooled to room temperature and the solvent is removed under vacuum. The residue is dissolved in water and the aqueous solution is acidified with acid. ft · · · · ··· ·♦ ·· ftftftft ) · » · · I · « « · * ft · » · « ft ju..,. j;-, r t..... k— fl'll 1 ' r 1 -13NOTARBARTQLG & GERVASI STUDIO PATENTS AND MARKS 20122 MILAN - Viale Giacca Maria, 33 concentrated hydrochloric acid. During acidification, the temperature is maintained at 0°C*. The solid product is filtered and dried. Yield: 39.5 g (42.5%) of 2-carbethoxy-5-methyl-3,4-dihydroxypropyl phosphate, melting point 119-120°C. Example 3 4-Hydroxy-5-methyl-3,4-dihydroxyfuran A solution of 37.2 g of 2-carbethoxy-5methyl-3,4-dihydroxyfuran and 32 g of sodium hydroxide in 450 ml of water is kept at room temperature, under nitrogen, for 20 hours. The reaction mixture is acidified (pH = 3) with concentrated hydrochloric acid, then stirred at 50°C for 4 hours and extracted continuously for 6 hours with ether. The ether extract is dried and concentrated under vacuum until the total volume of the solution is reduced to approximately 50 ml. The ether solution is cooled to -70°C and filtered. The solid product is washed with pentane and dried, giving 13 g (57%) of 4-hydroxy-5-methyl-3-oxo2H-furan, recrystallized from alcohol-ether, melting point 128.2-129.6°C. RMR(CDCl^) £2.26(3H,t); 4.52(2H,q); 6.9(1H,wide) Example 4 4-hydro xy-5-methyl-3-os so— 2H-furan • · · · ft ··· • ·· · ft ····. ftft·· 4 • ftft • ftft • ♦ • · ♦ • · ft · · ft · ft ··· ft · • · · NOTARBARTgLo & GERVASJ BEVETTI AND MARCHI STUDIO 20122 MILAN · Viale Bfaca Maria, 33 t jì. ii· r pull -14In a 4-liter, three-necked flask, with a mechanical stirrer, a dripping funnel, a thermometer, a 30-cm Vigreuz column connected to a dephlegmator, and a gas inlet tube, a suspension of 408 g of sodium ethoxide in 3 liters of anhydrous toluene is placed. To the stirred suspension, 438 g of diethyl-0.5 salt is added over 75 minutes under nitrogen at 0-5°C. To the yellow reaction mixture, at 4-6°C, over 90 minutes, is then added: 612 g of diethyl-alpha-methyldiglycolate. The reaction mixture is stirred at room temperature for another 2 hours. The reaction mixture is then gradually heated, and the ethanol-toluene mixture is distilled until the vapor temperature is 107°C. The reaction mixture is then cooled to room temperature and stirred for 30 minutes with 2 liters of water. The reaction mixture is transferred to a separating funnel, the toluene layer is separated, and the aqueous layer is washed with ether. After adding 240 g of sodium hydroxide, the aqueous layer is kept at room temperature, under nitrogen, for 20 hours. The reaction is acidified (pH = 3) with concentrated hydrochloric acid, stirred at 30°C for 2 hours, and extracted continuously for 10 hours with ether. The ethereal extract is dried and the sun is removed. « 9 9 · · • *·· ·· ·· *·· · ♦ · # • ···· • · · ··· ft · ft ft » NOTARBARTOLO & GERYASI PATENT AND TRADEMARK STUDY 20122 MILAN - Viale Elenca Maria, 33 -15vented under vacuum. The solid residue is recrystallized from ethane; yield 243 g (71%) of 4-hydroxy5-methyl-3-oxo-2H-furan (melting point 130-130.5°C). the Example 5 4-hydroxy-5-methyl-3-oxo-2H-furan Example 4 may be repeated, replacing diethyloxalate with dimethyloxalate and diethyl-alpha-methyldiglycolate with dimethyl-alpha-methyldiglycolate. 253 g (74%) of 4-hydroxy-5-methyl-3-oxo 2H-furan were obtained, melting point 129.5-130°C. Example 6 4-hydroxy-5-methyl-3-oxo-2H - furan In a 2-liter, three-necked flask equipped with a mechanical stirrer, a dripping funnel, a thermometer, and a reflux condenser, a solution of 108 g of sodium methoxide in 500 ml of methylene chloride is stirred. 146 g of diethyl oxalate is added to the stirred solution within minutes at 0-10°C. 204 g of diethyl alpha-methyl diglycolate is added to the reaction mixture within 120 minutes at 0-10°C. The reaction mixture is then stirred at reflux temperature for another 13 hours. The solvent is distilled off, and the residue is dried at 100°C under vacuum. The dry residue is dissolved in 600 ml of 15% sodium hydroxide solution. The solution is 4 4 ·. _ · • ••44 !* 4· ·· φ *··· • · · 4* 4 4 4 · • 4 '· · 4 4 4 NOTARBARTOm δ GERVASI studio fiirevàrn E marchi 20122 MILAN - Vide Bùnca Maria, 33 16k. ìli. The alkaline reaction mixture is kept at room temperature for 20 hours. The reaction mixture is acidified and continuously extracted with ether. The ether extract is dried and the solvent is removed under vacuum. The solid residue is recrystallized from alcohol! Yield 69 g (60%) of 4-hydroxy-5-methyl-3oxo-2H-furanohypto. Melting point 130-130.5°C. Example 7 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2Hfuran In a 0.5 litre, three-necked flask, equipped as described in Example 1, a suspension of 27.2 g of sodium ethoxide in 180 ml of anhydrous toluene and 20 ml of anhydrous dimethylformamide is placed. 0°C, 29.2 g of diethyl oxalate was added to the stirred suspension over 15 minutes. 40.8 g of diethyl alpha-methyl diglycolate was then added to the yellow reaction mixture at 0-5°C over 15 minutes. The reaction mixture was stirred at room temperature for another 30 minutes. Then, the reaction mixture was gradually heated and the ethanol-toluene mixture was distilled until the vapor temperature reached 107°C. The reaction mixture was then cooled to 0°C and 40.8 g of diethyl alpha-methyl diglycolate were added. 9.2 g of formic acid, followed by a solution ·· ·· ···· •J*i* ···· ••ftft · ft · • ftft ftft • · ···· · · · « · · · · ···· · · ft • · ftftftft ..... . .;· .·· ···· : . : . .· ···· • · ft» · • ftft · · ft· * ftftftft ···· ···· ftft · · · * • · ftftftft ft ftftftft* • · · ft· -17NOTARBARTCLO & GERVASf STUDIO ΒΠΞνΕΤΠ E MARCHI 20122 MILAN - Viale Bianca Maria. 33 of 9.2 g of ethanol and 0.5 g of sodium iodide in 60 cc of dimethylformamide, Through the reaction mixture: The reaction mixture, vigorously stirred, was bubbled through a wall of methyl gas at 40-50°C until the pH of the reaction mixture reached 7.0-7.5. The solvents were removed under vacuum (the complete elimination of dimethylformamide is essential for optimal treatment of the solid product), and the residue was dissolved in ether. The sodium bromide was filtered off and the ether solution was concentrated. under vacuum and pentane is added to the concentrated ether solution. The ether-pentane solution is cooled and filtered. The solid product is washed with pentane and dried: yield 24 g (70%) of 2-carboxy-2,5-dimethyl-3-oswo-4-hydroxy-2H-furan, recrystallized from cyclohexane; melting point 89.2-89.5*0. HMRtCDClj) £ 1.27(3H,t)> 1.65(3H,s); 2.32(3H,s)i 4.22(2H,q)j 6,OO(1H, wide). Example 8 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan Example 7 was repeated, substituting methyl iodide for methyl bromide. 22 g (64%) of 2-carbethoxy-2,5-dimethyl-3-O3SO-4-hydroxy-2H-furan were obtained; melting point 89.8-90.2°C. ···· • · · · · >··· :· ·· «· · ···· •i · ···· · ····. • ···· * · ·· · ΝΟΤΑΒΒΑΠΤΗΟ S CSE'”3I PATENT AND TRADEMARK STUDY 20122 MILAN - Viale Giunca Maria, 33 -18il·, 11·,. Example 9 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan Example 7 may be repeated, substituting methyl chloride for methyl bromide. 23 g (67%) of 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy2H-furan were obtained; melting point 89.7-90*0. Example 10 2-carboxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furanium In a 250 cc three-necked flask, with a mechanical stirrer and a gas inlet tube, a solution of 3.4 g sodium ethoxide is placed in 100 ml of ethanol. 9.3 g of 2-carbethoxy-5-methyl-3,4-dihydroxyfuran and 0.5 g of sodium iodide are added to the stirred solution at room temperature under nitrogen. Gaseous methyl bromide is bubbled through the vigorously stirred reaction mixture at 50-60°C until the pH of the reaction mixture reaches 6.5-7.0°C. The solvent is removed under vacuum and the residue is dissolved in ether. The sodium bromide is filtered, the ether solution is concentrated under vacuum and the residue is distilled with a low Vigreux-Il column. 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan is collected at 102-105*0 / 0.2 mm. Yield: 8.1 g (81%) recrystallized from cyclohexane; melting point 89.8 · ... 444 .··* • · «44 '··! ··>· 4 4 *·· 4 4· 1 NQTARBAR7GLQ & GERVASI STUDI® PATENTS AND TRADEMARKS 20122 MILAN - Viale Bianca Maria, 33 -1990,1<»C. Example 11 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan A solution of 9 g of 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan and 5.4 g of sodium hydroxide in 50 ml of water is maintained at room temperature under nitrogen for 20 hours. The reaction mixture is acidified with hydrochloric acid, then stirred at 30°C for one hour and extracted continuously for 6 hours with ether. The ether extract is dried and the solvent is removed under vacuum; the residue is dissolved in a mixture of 5 ml of anhydrous ether and 5 ml of anhydrous pentane. The solution is cooled to -10°C and filtered. The solid product is dried: yield 4.1 g (70%) of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan. The isolated product is identical (NMR and IE) to a sample of 4-hydroxy-2, 5-dimatil-3-oxo-2H-furan prepared from rhamnose (see citation) at 82-84°C. Example 12 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan In a 20-liter, three-necked flask, equipped with a mechanical stirrer, a dripping funnel, a thermometer, a nitrogen inlet tube and a 30 cm Vigreux column connected to a dephlegmator, ftft is emitted »♦ * · ♦ · ·· ♦ ·· « ft ft ft ft·'· •ft · • · ftft ft · · ft · · >· · ft ► ftft •ftft · ft · • * ftftftft ftftftft ft ft· ft • · • · • ftft -20— PATENTED STUDIES AND enwi.w.taX, a suspension of 1512 g of sodium methoxide in 10.5 liters of dimethylformamide. To the stirred suspension, 2044 g of diethyl oxalate are added under nitrogen at 50°C over 90 minutes. To the yellow reaction mixture, 2856 g of diethyl2-methyldiglycolate are added over 3 hours at 2-5°C. The reaction mixture is stirred at room temperature for another 3 hours. The reaction mixture is then gradually heated to 90-100°C and held at that temperature until the distillation of the alcohol ceases. Then the reaction mixture is cooled to room temperature and 649 g of formic acid is added. Methyl bromide at 40-50°C is bubbled through the reaction mixture until the pH of the reaction mixture reaches 7.0-7.5. The solvents are removed under vacuum and the residue is dissolved in a solution of 2472 g of sodium hydroxide in 9 liters of water. The reaction mixture is kept at room temperature, under nitrogen, for 20 hours, then acidified with hydrochloric acid and continuously extracted with ether. The ether extract is dried and the solvent is extracted under vacuum, the residue is recrystallized from ether: yield 916 g (51%) of 4-hydroxy-2,5-dimethyl-3-oxo-2H-pharane; melting point 80-82*0. • · · · · ··· e · a » v ·· ·· • · · · :· ·· «· « • · * « · .· • ♦ · ··· » ♦ • · · ····. • « * · · N0TARBART0L9 & GERVASI PATENT AND TRADEMARK STUDY 20122 MILAN - Viale Birnia Mera. ?3 -21i The isolated product is identical (HMR and IR) with a sample of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan prepared from rhamnose (see citation). Example 13 4-hydroxy-2,5-dimethyl-3-οxo-2H-furan Example 12 is repeated, replacing formic acid with hydrochloric acid. 4-hydroxy,si-2,5-dimethyl-3-oxo-2H-furan is obtained in a yield of 48%; melting point 80-82°C. Example 14 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan A suspension of 34 g of 30-dioethoxide in a mixture of 100 ml of dimethylformamide and 300 ml of toluene was placed in a 1-liter three-neck flask equipped with a mechanical stirrer and a gas inlet tube. To the stirred suspension, 93 g of 2-carboxy-5-methyl-3,4-dihydroxyfuran were added at room temperature under nitrogen. Gaseous methyl bromide was bubbled through the stirred reaction mixture at 30-40°C until the pH of the reaction mixture reached 6.5-7.0. The solvents were removed under vacuum, and the residue was dissolved in a solution of 80 g of sodium hydroxide in 350 cc of water. The reaction mixture was kept at room temperature, under • ·· · * ·· ♦· • · «ftft :· • · ·· ♦ • « ·* ···· ··· « · • · « · ··· ····« • φ·· 4 -22NGTARBARìCIO δ GERVASf patent and trademark studio! 20122 MILAN Vij| and Bianca Maria. 33 nitrogen, for 20 hours; then it is acidified with hydrochloric acid and continuously extracted with ether. The ether extract is dried and the solvent is removed. toned under vacuum, the residue is recrystallized from ether, yield 41.5 g (65%) of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan; melting point 81.5-83.1*0. Example 15 4-hydroxy-2-methyl-5-ethyl-3-oxo-2H-furan and 4-hydroxy-2-ethyl-5-methyl-3-oxo-2H-furan In a 1-liter, three-necked flask equipped with a mechanical stirrer, a drip funnel, a thermometer, a nitrogen inlet tube and a reflux condenser. protected by a calcium chloride tube, a suspension of 20.4 g sodium ethoxide is placed in 180 cc toluene and 120 cc dimethylformamide. Ϊ 3chla stirred reaction is added 55.8 g! of 2-carboxy-5-methyl-3,4-dihydroxypropyl phosphate. During the addition, the temperature is kept below 20°C. To the clear red solution, 120 g of ethyl bromide is added over 15 minutes. Then the reaction mixture is stirred at 40°C for another 20 hours. The sodium bromide is removed under vacuum and the residue is dissolved in ether. The sodium bromide is filtered and the ether solution is extracted with 5% sodium bromide solution. ···· • ···· »·· • 9 -2320122 ΖΖ,η £ MAfiCHI U'° * Viaie Bianca Maria. ?? k..' l· K' f-... The· js. F'l· I 1' ir jl··cold sodium hydroxide. The aqueous solution is acidified with hydrochloric acid. While acidifying, a temperature of 0°C is maintained. The acidified aqueous solution is extracted, continuously, for 6 hours with ether. The ether extract is dried, the solvent is removed under vacuum, and the residue is distilled with a short column. Vigreux. The product is collected as an isomeric mixture of 4-hydroxy-2-methyl-5-ethyl-3-oxo-2H-furan (40#) and 4-hydroxy-2-ethyl-5-methyl-3-ί pxo-2H-furan (60#) at 74-76°C / O.3 mm. Sample: 15 g (35#); n^° 1.5096. NMR(CC1, )£0.99(t); 1.37(t); 1.85(m); 2.25(s); 2.65(q)ϊ 4»38(m); 7.2 (wide s) Example 16 4-hydroxy-2-methyl-5-hexyl~3-oxo-2H-furan and 4-hydroxy-2-hexyl-5-methyl-3-oxo-2H-furan In a 1-liter, three-necked flask, equipped with: Using a mechanical stirrer, a dripping funnel, a thermometer, a nitrogen inlet tube, and a reflux condenser protected by a calcium chloride tube, a suspension of 19.8 g of sodium ethoxide in 130 cc of anhydrous toluene and 15 ml of anhydrous dimethylformamide is placed. After stirring for 1 hour, j ···· • 4 ··*· 44 · · · 4* · 4 4 · ·;·:* ·· 4· • 4 · 4 «· 4 4 4 4 4 ····· ;·:· '· 44 4 444 4 4 * ··.·, 4 4 ··' 4 .· 4 4 4 4 4· ι: -24WOTARBARTGLO fi GERVASI STUDIO t?,Wm E MARCHI 20122 MILAN - Viale Bianca Maria, 33 1' jr ? Hey... 21.3 g of diethyloxalate are added at 10°C under nitrogen. To the yellow reaction mixture, 40 g of diethyl-alpha-hexyl diglycolate (prepared according to A. Solladie-Cavallo and P. Vieles, Bull. Soc. Cbim. France, 1967, 517; pto eb. 112°C / 0.3 mm; n 1.4345) are added dropwise at 10–15°C. The reaction mixture is stirred at room temperature for another 15 minutes, and then gradually heated. The ethanol-toluene mixture is distilled until the vapor temperature reaches 110°C. Then, the reaction mixture is cooled to 0°C, and another 6.9 g of formic acid are added, followed by 6.9 g of ethanol and 100 ml of dimethylformamide. Gaseous methyl bromide is bubbled through the vigorously stirred reaction mixture at 25-45°C until the pH of the reaction mixture reaches 7.0-7.5. The solvents are completely removed under vacuum, and the residue is dissolved in 200 ml of ether and 24.5 g of sodium hydroxide in 100 ml of water.The resulting slurry is stirred at room temperature, under «Boto», for 20 hours. The mixture is acidified with hydrochloric acid (pH = 3.4). During the acidification, the temperature is maintained at 20°C. The acidified aqueous solution is neutralized with a 10 N aqueous solution of sodium hydroxide, « « « « « ft · · ftft ftft · « * · · ' ftft · · · · ftftftft • ftft • · · • * ftft·. -25ha / e B, 3nca Marfa C-. fr4' if ϋιr..... |! |rtl to pH = 6.8, then extracted continuously for 6 hours with ether. The ether extract is dried and the solvent is eliminated under vacuum. The residue is astilled in a short Vigreux column. The product is collected at 102°C / 0.1 mm, in the form of an isomeric mixture of 4-hydroxy-2-methyl-5-hexyl-3-oxo-2H-1 furan (55%) and 4-hydroxy-2-hexyl-5-methyl-3-oxo-2H-1 furan (45%) at 1O2°C / 0.1 mm. BgSa: 12.5 g (42%); n £1,4935. HME(CDC1 3 ) 5 0.9; 1.45(d); 2.28(d); 2.6(t);4.5(m) ; 7.3 (wide) Example 17 ί 4-hydroxy-2-methyl-5-pentyl-3-oxo-2H-furan and 4-hydroxy-2-pentyl-5-methyl-3-ο s so-2H-phorane Example 16 was repeated, substituting diethylalpha-pentyldiglycolate (prepared according to A.Solladije Cavallo and P.Vieles.Bull.Soo.Chim.France,1967.517; pto eb.1O6-1O8°C / O,2 mm) to diethyl-alpha-hexyl diglycolate, in equivalent stoichiometric quantities. A mixture of 4-hydro^ si-2-methyl-5-pentyl-3-oxo-2H-furan (55%) and 4-hydro^ si-2-pentyl-5-methyl-3-oxo-2H-furan (45%) was obtained, with a yield of 52%. eb. 102°C / 0.4 mm; n 1.4956. D HME(CDC1 3) ί 0.84;2.20(d);2.56(t);4.40(m);6.9(ampib) • ft ·· «ftft ftft • · ft · · -··· • · · · « • · · · · ftftftft· « -··· ' ·· ftftftft· ft • ftft · _ « · • ftft ··· • • ftft -26NOTARBARTCLO & GERVASI PATENT AND TRADEMARK STUDIO 20122 MILAN - Viale Bianca Maria, 33 THE......_ Jl· ί ììl 4' li ih Example 18 4-hydroxy-2-methyl-5-isobutyl->-oxo-2H-furan and 4-hydroxy-2-γ3butyl-5-methyl-3-oxo-2H-furan Example 16 can be repeated, substituting diethyl-alpha-isobutyldiglycolate (prepared according to A. Solladie-Cavallo and P. Vieles. Bull. Soc. Chim. Trance, 1967 517; pto eb. 106-110°C / 0.9 mm) for diethyl-alpha-hexyldiglycolate in an equivalent stoichiometric quantity. A mixture of 4-hydroxy-2-methyl-5-isobutyl-3-oxo-2H-furan (67%) and 4-hydroxy-2-isobutyl-5-methyl-3-oxo-2H-furan (33%) was obtained in a yield of 57% at pto eb. 97°C / 0.9 mm; n 2^ 1.4998. HMR(CLC1 3)SO,98;1.44(d);2.14(d);2.5l(d);4.5(m) 7.7(wide). Example 19 4-hydro s si-2-methyl-5-butyl-3-o sso-2H-furan and 4-hydroxy-2-butyl-5-methyl-3-oxo-2H-furan Example 16 can be repeated, replacing diethylalpha-butyldiglycolate (prepared according to A. Bolladie— Cavallo and P. Vieles. Bali. Soc. Chim. Trance. 1967«517; pto eb. 90-91°C / 0.2 mm) with diethylalpha-hexyldiglycolate, in equivalent stoichiometric quantities. An isomeric mixture of diethylalpha-hexyldiglycolate was obtained, with a yield of 40%, 4« · B « · · * *··· B ··· ^ « ·♦·· *« · • * · • * »· · • · · **· -27NOTARBAR'it'.Q & GERVASI PATENT AND TRADEMARK STUDIO 20122 MILAN - Viale Bianca Maria. ?? 4-hydroxy-2-methyl-5-butyl-3-oxo-2H-furan(5®$) and 4-hydroxy-2-butyl-5-methyl-3-oxo-2H-furan(50$), pto eb.104ￂﾰC / 0.7 mmjUjj 1.4998 ￂﾷ flMR(CDCl 3 )£ O.95C3H); 1.44(d);2.25(d);2.60(t) 4»43(m); 6.9 (wide). Example 20 4-hydroxy-2-methyl-5-ethyl-3-oxo-2H-phorane and 4-i dro s si-2-e til-5-me t i1-3-oxo-2H-furan Example 16 was repeated, substituting diethyl-; alpha-ethyldigliodate (prepared according to A.SolladieCavallo and P.Yieles.Bull.Soc.Chim.France, 1967»517: 20 pto eb.80-81°C / 0.2 mm; n ^»1.4255) to diethyl-alphahexyldiglycolate, in equivalent stoichiometric quantities. An isomeric mixture of 4-hydroxy-2-methyl-5-ethyl-3-oxo-2H-furan (438%) and 4-hydroxy-2-ethyl-5-methyl-3-oxo-2H-furan (62$) was obtained in a yield of 46%. θ = 1.5111; pto eb.80-82°C / 0.6 mm. Example 21 4-hydroxy-5-ethyl-3-oxo-2H-furan In a 1-liter, three-necked flask, equipped with a mechanical stirrer, a dripping funnel, a thermometer, a nitrogen inlet tube and a reflux condenser protected by a calcium chloride tube, a suspension of 25.2 g sodium is placed. ♦ ··· • · ·· ·* **'·** • ft* ~ * · e · ·· • · · · » • · · · :· • · · · · · · · * · • · · ft · · « · · · ft ... -28N0TARBARTCL9 & GERVASI STUDIO ΒΟΕΠΙ E MARCHI 20122 MILAN-Viale Bianca Maria, 31 k ili fi! lf'.· ethoxide in 185 cc of anhydrous toluene. After 15 minutes of stirring, 27.1 g of diethyl oxalate are added dropwise at 10°C under nitrogen. To the yellow reaction mixture, 40.5 g of diethyl alpha-ethyl diglycolate (prepared according to A. Solladie-Cavallo and P. Vieles, Bull. Soc. Chin. Prence, 1967, 517; pto eb. 80-81®C / 0.2 mm; n 1.4255) are added dropwise at 10-15°C. The reaction mixture is stirred at room temperature for another 12 hours. The reaction mixture is then gradually heated and the ethanol-toluene mixture is distilled until the vapor temperature is 104°C. The reaction is then cooled to room temperature and stirred for 30 minutes with 200 ml of water. The reaction mixture is transferred to a separatory funnel and the toluene layer is separated. A solution of 15.2 g of sodium hydroxide in 200 ml of water and 100 ml of ether is then added to the aqueous layer. This mixture is stirred at room temperature under nitrogen for 20 hours.The reaction mixture is acidified (pH ~ 3) with concentrated hydrochloric acid, then stirred at room temperature for 2 hours. The resulting solution is neutralized with 10 K aqueous sodium hydroxide solution to a pH of ≤ 6.8, then continuously extracted for 10 hours. ··· • ·· ft · ···* ·· · *··· ·: · • · ft, ··· · ♦ ♦ftft· • ftft • ft • ftft • ftft • · .· • ftft ·· ♦ · • ftft. -29 '-<» MOTAfiRAiTTC; π & BEVETTI AND MARCHI STUDIO 20122 MILAN Viale Cianca Maria. 3? THE I with ether, the ether extract is dried and the sol- i 1 V * i vent eliminated under vacuum, giving 13.3 g of solid material. Crystallizing from ether, we obtain; 1 'ì *' 8.3 g of 4-hydroxy-5-ethyl-3-oxo-2H-furan (yield / 35%); melting point 52-54°C. / HME(CDC1 3) ί1,24(t,3H);2,64(q,2H);4,52(d,2H); ' i 6.5(s,1H). ; 5 I ; · * Example 22 ! 4-hydroxy-5-hexyl-3-oxo-2Ii-furan ' « Example 21 was repeated, substituting diethylalpha-hexyldiglycolate (prepared according to A.SolladieCavallo and P.Viàles.Bull.Soc.Chim.France,1967,517 ; ' pto eb.112°C / 0.3 ma; n 1.4345) to diethyl-alpha-ethyl diglycolate in equivalent stoichiometric quantity. 61 g of solid material were obtained. Crystallizing from ether, 20 g (30%) of i ! ι ί were obtained 4-hydroxy-5-hexyl-3-oxo-2H-furan; pto fusion 51-52°C. ! ! |flME(CDCl 3 ) i O,9(3H); 1.3-1.8(m,8H); 2.60(t,2H) • 4.49(d,2H); 7.1 (wide, 1H). Example 23 ; 4-hydroxy-2,5-diethyl-3-oxo-2H-furan > j In a 1-liter, three-necked flask, equipped with a mechanical stirrer and a dripping funnel; ; thermometer, nitrogen inlet tube and a condenser -30'- ·<* 't, In a reflux flask protected by a calcium chloride tube, a suspension of 68 g of diethyl-ethyl-diglycolate is placed in 375 ml of dimethylformamide. 73 g of diethyl oxalate are added dropwise to the stirred reaction mixture at 5°C under nitrogen. After stirring for 15 minutes, 109 g of diethyl-alpha-ethyldiglycolate are added dropwise at 5-10°C. The reaction mixture is stirred for 12 hours at room temperature and then the temperature is gradually increased. The reaction mixture is stirred off. The ethanol is distilled off, while the reaction mixture is held at 100°C for 6 hours. After vigorous stirring, the reaction mixture becomes a thick slurry. A total of 37 g of ethanol is collected. The reaction mixture is then cooled to 20°C, and 46 g of formic acid, 89.5 g of ethyl bromide, and 9 g of sodium iodide are added in 3.0 minutes. The reaction mixture is stirred at 40°C for another 16 hours. The solvent is completely removed in vacuo, and the residue is dissolved in a solution of 88.3 g of ethyl iodide. of sodium hydroxide in 500 cc of water. The resulting slurry is stirred at room temperature, under nitrogen, for 3 days. The mixture is then acidified with hydrochloric acid (pH = 3). During acidification, the temperature is maintained at 20°C. The solution the -31•· -«4 ΝΟΤΑΠΒΛΠϊγίΟ ίί GERVASf STUDIO BiTEVETTI AND MARCII! 20122 MILAN - Viale Bianca Maria. The acidified aqueous solution is neutralized with a solution aqueous solution containing 10 N sodium hydroxide, until pH = 6.8 and then continuously extracted with ether. After 6 hours, The ethereal extract is dried and the solvent is eli-; mined under vacuum, giving 43.5 g of residue. Another 12-hour extraction period gives 18.5; gl of material. The combined residues are distilled; f * · ' * with a short Vigreux column, giving 27 g (35%? of .;*·· |-hydroxy-2,5-diethyl-3-oxo-2H-furan, pto eb.89°C / j ..... L2' 3.9 mm; n D= SMRtCDCap ί j Example 24 ' Mixing the following ingredients, they were I prepared two aromatic pastes: AB 1.5090 . O,98(t,3H); 1.27(t,3H)}1.85(m,2H); 2.7l(q,2H); 4.40(m,1H); 7,4(wide s,1B). acetoin 3.0 3.0 diacetyl 2.0 2.0 vanillin 2.0 2.0 ethyl butyrate 1.0 1.0 datol 0.5 0.5 £ -decalactone 1.0 1.0 ethyl lactate 5.0 5.0 butyric acid 5.0 5.0 caproic acid 0.5 0.5 -32'· NOTAREARTCLQ & GERVASI STUDIO CAVETTI E MASCHI 20122 MILAN / Viale Bianca Maria. 33 THE 2-carbethoxy-5-methyl3,4-dihydroxyfuran - 50 propylene glycol 980 930 r 1000.0 1000.0 Mixtures A and B were added, separated- ; 4. specifically, to an 8% sugar solution, at a concentration of 0.2 g / liter. The solutions were tasted and compared. The commission preferred the solution containing mixture B over the solution containing mixture A, because the solution And the mixture with B had more j characteristics. The richest, sweetest and creamiest of the coq solution, the A. blend. ' Example 25 By mixing the following ingredients two strawberry flavours were prepared; ethyl acetate 2.0 2.0 ethyl butyrate 5.0 5.0 ethyl formate 1.5 1.5 ethyl isovalerianate 1.0 1.0 ethyl caproate 0.5 0.5 y -undeealactone 0.8 0.8 ethyl phenylglycidate 10.0 10.0 benzoate of ethyl 2.5 2.5 A. -33NOTARBARTìJìQ & GERV.3SI PATENT AND TRADEMARK STUDIO 20122 MILAN - Viale Bianca Maria. 3a L ί; tt iimethylanthranilate 2.0 2.0 solution 10$ methylisopropylphenylpropionic aldehyde(x) 0.5 0.5 solution 10$ methyl octyl carbonate(x) 0.5 0.5 naltclo 3.5 3.5 I i aéetoino 10.0 10.0 j 2-carbethoxy-2,5-dimethyl3-oxo-4“hydroxy-2H-furan - 12,5 ί propylene glycol 960.2 947.7 j 1000.0 1000.0 (x) propylene glycol. ί THE Mixtures A and B were added, separately, to a drink containing 8$ sugar and 0.05$ acid. citric. The drinks were tasted and compared-J The commission preferred the drink with blend B to the drink with blend A because it had fuller, sweeter and more: ! strawberry balance that the drink containing the · t : ^mixture A.

Claims

1. Claims 1) A process for the preparation of 4-hydroxy-5-alkyl-3-oxo-2H-furans (VI) comprising: a) the condensation of a dialkyl ester of ι-34NOTAABBAPTAO of GERVASI STUDIO Cx'£VETTi E MARJHJ ^2 MILANO Vieie Bianca Maria. 33 alpha-alkylglycolic acid (I) with a diester of oxalic acid (II), in the presence of an alkaline condensation agent; b) hydrolysis of the carboxylic group of the product resulting from the reaction; c) decarboxylation of the hydrolyzed product; d) recovery of the 4-hydroxy-5-alkyl-3-oxo-2H-furan (VI). 1 2) The process of claim 1, which comprises the further step of alkylation I of the condensation product of step a), prior to hydrolysis. J ì 3) The process of claim 1, wherein the alkaline condensing agent is selected from the class consisting of alkali metal alkoxides and alkali metal hydrides. 4) The process of claim 2, wherein the alkaline condensing agent is selected from the class consisting of alkoxides and hydrides of alkali metals. 5) The process of claim 4, wherein the akylation step is carried out in the presence of an inert organic liquid selected from the class consisting of a) dimethylformamide, b) dimethylsulfide, c) a mixture of inert organic liquids containing at least 10% of a) or b), and d) an alcohol. 6) The process of claim 5, wherein half of the alkaline condensing agent is acidified by the alkylation. 7) The process of claim 3, wherein the dialkyl ester of alpha-alkylglycolic acid (I) has 1-6 carbon atoms in the alpha-alkyl group. ; 8) The process of claim 7, wherein the alpha-alkyl group is selected from class I consisting of the methyl, ethyl and n-hexyl groups. | 9) A process for the preparation of 4-i- i ! ' i hydroxy-2,5-dialkyl-3-oxo-2H-furan (IX) comprising a) condensation of an alpha-alkylglycolic acid dialkylester (I) having 1-6 carbon atoms in the alpha-alkyl group with an oxalic acid ester (II) in the presence of an alkaline condensing agent selected from the class consisting of alkali metal alkoxides and alkali metal hydrides; b) alkylation of the product of step a) with a 1-4 carbon alkyl halide; c) hydrolysis of the alkylated product; -36NOTARBARTOLO SG pRV^Sf study Ει^ Επ, e ώ 20122 MILANO - Viale Bianca Maria. 33 d) decarboxylation of the product of phase c); ·, and ϊ ί e) recovery of 4—hydroxy-2,5-dialkyl-3-oxo-2H- ( i furan (IX). ii 10) 2-carbalkoxy-3,4—dihydroxy-5-alkylfuran(IV) 11) 2-carbalkoxy-4-hydroxy-2,5-dialkyl-3-} oxo-2H-phorane (VII). Milan, for PFWBV, the Representative NDTAHìJAÌÌTCLO & CAVASI STUDIO LE.'LTI E MA.IC.'II 20Ϊ22 MILAN - Viale Bianca Marie, 33 INVENTOR'S DECLARATION 81719 A / 78 The undersigned p^fW BV....................................................................................................................................................................... with registered office in Amersioprt .(.0lan.da.)....Ni4.verheidsweg... Zuid, 7......................................... declares that of the patent application no. filed on .................. The inventor relating to the invention entitled: Process for preparing -4-hydroxy-5-alkyl- and 4-hydroaxes............ , 5 ” of alkyl 1 - 3 -oxo. - 2 H-furani 11 * xBOMxkSggx is Mr. Amnon Mordechai COHEN The applicant PFWBV Mr. HA Lok ACCEPTANCE OF THE INVENTOR'S DECLARATION The undersigned Mr. Amnon Mordechai..- COttEN..........................resident at Spreeuwenstraat 201 Λ Amersfoort (Holland)......................... ............ declares to accept the indication of inventor, made in favor of the Company .....P»F...W»BV...... in relation to the patent application filed in the name of the aforementioned, concerning the invention entitled: Process for preparing 4-hydr©xy“2y5“ dialkyl-3-oxa-2H-furans. The Inventor is Mr. AM Cohen.