GB1601934A - 2-carbalkoxy furan compounds - Google Patents

Description

(54) 2-CARBALKOXY FURAN COMPOUNDS (71) We, POLAK'S FRUTAL WORKS, B.V., formerly known as P. F. W.

Beheer B.V., a Corporation organised under the laws of The Netherlands, of Nijverheidsweg Zuid 7, Amersfoort, The Netherlands do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement:- The present invention relates to certain novel and useful intermediates in a novel process for preparing 4 - hydroxy - 5 - alkyl - 3 - oxo - 2H - furans and 4 hydroxy - 2,5 - dialkyl - 3 - oxo - 2H - furans having the general formula

or tautomeric forms thereof where R, represents an alkyl radical having 1 to 6 carbon atoms and R2 represents hydrogen or an alkyl radical having I to 4 carbon atoms. The novel process is described and claimed in our co-pending Applications Nos. 13636/77, and 52936/77 Serial No. 1,601,933.

In recent years furan derivatives of the above type have received considerable attention from researchers interested in the flavoring art. A survey of the literature reveals that these compounds are useful in a very wide range of foodstuff and beverage applications. For example, U.S. Patent 3,647,825 states that 4 - hydroxy 5 - methyl - 3 - oxo - 2H - furan has been added with beneficial results to bread, biscuits, candy, chocolate, meat and processed meat, milk products, processed food prepared from eggs, fresh and smoked fish and vegetable, also to powdered soup concentrates, dried fruits and nuts, canned fruits, soft drinks, liquer, wine, whiskey, instant coffee, but also cigars and cigarettes, chewing gum and oral hygiene preparations such as toothpastes, mouth washes and mouth wash concentrates.

U.S. Patent 3,887,589 teaches the use of 2,5 - diethyl - 4 - hydroxy - 3 - oxo 2H - furan in bakery products to provide a more pleasant taste and a fresher impression. U.S. 3,576,014 teaches using 4 - hydroxy - 2 - methyl - 5 - ethyl - 3 oxo - 2H - furan and 4 - hydroxy - 2 - ethyl - 5 - methyl - 3 - oxo - 2H - furan as a raspberry or gooseberry flavoring.

U.S. 3,709,697 teaches 4 - hydroxy - 2 - methyl - 5 - ethyl - 3 - oxo - 2H furan and 4 - hydroxy - 2,5 - diethyl - 3 - oxo - 2H - furan as additives to impart or enhance a meat flavor.

Many syntheses have been suggested for the preparation of furans of the above-identified type. However, all of these are either noneconomical multistep laboratory methods which cannot be profitably be applied to the production of the compounds on a commercial scale or they utilize very expensive natural products such as rhamnose (CF. Proc. Am. Soc. Brewing Chemists 84, (1963)) which can be obtained only in small insufficient quantities of unpredictable quality and which therefore are not suitable starting materials for production of the furans on a commercial scale. For techniques which have heretofore been proposed for preparing these compounds, reference can be had to J. Org. Chem. 31, 2391-4 (1966), J. Org. Chem. 38, 123-I 25(1973), and to U.S. 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: British Patent 1,440,270; Swiss Patent 565,168.

Our copending Applications Nos. 13636/77, and 52936/77 Serial No. 1.601.993 described how furan derivatives of the class above designated can be prepared in a technically very simple and commercially feasible manner. The present invention concerns novel intermediates in that process.

According to this invention we provide a 2 - carbalkoxy - 3,4 - dihvdroxy 5 - alkyl furan in which the alkoxy group has I to 4 carbon atoms and the alkyl group has 1 to 6 carbon atoms and a 2 - carbalkoxy - 4 - hydroxy - 2,5 - dialkyl 3 - oxo - 2H - furan in which the alkoxy group has I to 4 carbon atoms, the 5-alkyl group has 1 to 6 carbon atoms and the 2-alkyl group has 1 to 4 carbon atoms.

These compounds may be prepared by a process which comprises condensing a di- I to 4 carbon atom alkyl - alpha - 1 to 6 carbon atom alkyl diglycolic acid ester with an oxalic acid di - 1 to 4 carbon atom alkyl ester in the persence of an alkalone condensing agent and optionally alkylating the product of the condensation with a 1 to 4 carbon atom alkyl halide.

The process of this invention forms part of the process of copending Applications Nos. 13636/77 and 52936/77 which is represented schematically by the reaction schemes diagrammed in the drawing where R1 has the meaning specified above, R3 is an alkyl radical having I to 4 carbon atoms, R4 is an alkyl radical fitting the description of the alkyl radical represented by R2 above, and M is an alkali metal ion and X is a halogen.

Starting materials I and II are easily prepared compounds. Compound I is a dialkyl alpha-alkyl diglycolic acid ester. It can be prepared by reaction of an alkyl halo-acetate (bromo- or chloro-) and an alkyl ester of an alpha-hydroxy carboxylic acid. This synthesis is described by A. Soladie-Cavallo and P. Vieles in Bull. Soc.

Chim. France, 1967, Page 517 et seq. The diethyl and dimethyl esters are preferred.

Dialkyl oxalates (II) are cheap, commercially available compounds. The diethyl and dimethyl esters are very common and are accordingly preferred for use in the reaction. Other 1 to 4 carbon atom alkyl esters can, however, be used with equally good results.

The reaction between the alpha-alkyl diglycolic acid diester and the dialkyl oxalate produces the dialkali metal salt of 2 - carbalkoxy - 3,4 - dihydroxy - 5 alkyl furan, III. The reaction is usually carried out in an inert diluent or solvent in the presence of an alkaline condensing agent, preferably an alkali metal alkoxide of a 1 to 4 carbon alcohol or an alkali metal hydride. Condensing agents based on any of the alkali metals e.g. lithium, potassium and sodium, can be used. The preferred alkaline condensing agents are sodium methoxide, sodium ethoxide, and sodium hydride. Some of the intermediate compounds of the reaction are sometimes referred to hereinafter as sodium salts. It should be understood that these compounds could equally well be other alkali metal salts.

By an inert dilent or solvent is meant an organic liquid which does not itself enter into the reaction or which cannot react in another way with the other reactants. The diluent can be either polar or nonpolar. Thus, there can be used such organic liquids as aliphatic and aromatic hydrocarbons, alcohols, dimethyl formamide, dimethyl sulfoxide, ethers, and nitriles. The choice of diluent can effect the temperature at which the reaction is carried out but necessary conditions for a particular diluent are easily determined experimentally.

0 o o F.

II WO CM H CI R3 O-C C-O-R3 + C-O-R alkaline ) > T M Hs HOX F CH CH2 Z 3-0-R3 cony. agent R1 ,C, o-R3 Rl O C-O R RIP -O-ii3 cony. ogent ;1 3 ,, C 11 il il[ - IV MO ~~~ OM MC CM HO ) ~bOM MCH H --~ ) H Rl O CWO.R3 RJ 0 C7C-M R1 C 0 ,: R3 C III V Vl SCHEME A

SCHEME B In carrying out reaction scheme A usually equimolar quantities of the dialkyl alpha - alkyl diglycolic acid ester and the dialkyl oxalate, I and II, are added td a solution or suspension of two equivalents of the alkaline condensing agent in an inert diluent at low temperature. Reaction begins substantially immediately upon contact of reagents I and II. It is preferable to remove the alcohol formed by the condensation reaction as the reaction proceeds as this helps to force the reaction to completion, resulting in better yields. This is not critical to the formation of the intermediate disodium salt of 2 - carb - alkoxy - 3,4 - dihydroxy - 5 - alkylfuran.

When the reaction is complete, the disodium salt can be recovered as such, acidified to its 3,4-dihydroxy form and recovered or subjected immediately to the hydrolysis and decarboxylation steps to convert it to 4 - hydroxy - 5 - alkyl - 3 oxo - 2H - furan or it can be used in reaction scheme B without any intermediate recovery operations.

In carrying out reaction scheme B in which the intermediate compound III is alkylated to form a 2,5 - dialkyl substituted product any solvents or diluents used in scheme A can be used, but it is preferable to employ a dipolar, aprotic diluent or solvent. The reaction proceeds more rapidly in the presence of such a solvent.

Preferred solvents are dimethyl sulfoxide, dimethyl formamide, a mixture of at least 10% by weight of one of these in an inert organic liquid such as toluene or another polar or apolar organic liquid or an alcohol.

Prior to carrying out the alkylation, it is helpful to convert the disodium salt to the monosodium salt by adding the calculated amount of an anhydrous organic acid or a mineral acid to the reaction mixture. The monosodium salt has been found to be more soluble in the organic reaction medium and the alkylation reaction proceeds more rapidly and more selectively when carried out on this salt than with the disodium salt.

The alkylation reaction is usually carried out using an equimolar amount, based on compound III of an alkyl halide of 1 to 4 carbon atoms. Any alkyl halide fitting this description can be used, e.g. the alkyl chlorides, alkyl bromides, and alkyl iodides. The reaction can be conducted at about 20 to 800 C. and takes place in about 1 to 20 hours depending upon the temperature. Completion of the alkylation reaction is indicated by a steady pH reading of about 6.5 to 7.5.

As mentioned above in the case of compound III, the initial alkylation product VII, can be recovered as such, or subjected immediately to the hydrolysis and decarboxylation steps without any intermediate recovery steps.

Conversion of the intermediate compounds to their intended final products is effected in the same way for both reaction schemes A and B. In each case, the ester is hydrolyzed to its alkali metal salt form and thereafter decarboxylated.

Hydrolysis of the ester can be carried out by the use of an alkali metal hydroxide in a manner known to the art for effecting hydrolysis of an ester. The resulting de-esterified carboxylic acid group is not stable and decarboxylation takes place spontaneously upon neutralization or acidification thereof.

As suggested hereinabove, the intermediate reaction products IV and VII can be isolated and recovered if desired. These can be further processed as described hereinabove at a later time by hydrolyzing and decarboxylating as described. In particular, it is useful to recover product IV in the intermediate state as it can thereafter be used to prepare either the alkylated final product as needed.

These intermediate products, 2 - carbalkoxy - 3,4 - dihydroxy - 5 - alkyl furan (IV) which may exist to a small extent in its keto-enol tautomeric forms, and 2 - carbalkoxy - 4 - hydroxy - 2,5 - dialkyl - 3 - oxo - 2H - furan (VII) are novel compounds. In addition to their utility as intermediates in the process of copending Applications Nos. 13636/77, and 52936/77 Serial No. 1,601,993 they have been found to be useful additives to several types of flavors because of their ability to enhance the sweetness causing a richer, more balanced taste by improving the body notes. In this respect they are useful in a variety of applications such as, e.g.

pastries, soft drinks, confectioneries, and as components of artificial sweetener compositions.

The following examples illustrate the invention.

Example 1 2-Carbethoxy-5-methyl-3,4-dihydroxy-furan In a 6 L. three-necked flask fitted with a mechanical stirrer, a dropping funnel.

a thermometer, a 30 cm. Vigreux column connected to a deflegmator and a gas inlet tube, is placed a suspension of 408 g. of sodium ethoxide in 3 L. of dry toluene. To the stirred suspension is added, under nitrogen at 0 C., 438 g. of diethyl oxalate over a period of 75 minutes. To the yellow reaction mixture is then added, at 0- 2 C., 612 g. of diethyl alpha - methyldiglycolate (A. Solladie-Cavallo and P. Vieles.

Bull. Soc. Chim. France 1967, 517), over a period of 90 minutes. The reaction mixture is stirred at room temperature for an additional 2 hours. The reaction mixture is then warmed up gradually and an ethanol-toluene mixture is distilled off until the vapor temperature reaches 107"C. The reaction mixture is cooled to room temperature and stirred for 30 minutes with 2 L. of water. The reaction mixture is transferred to a separatory funnel, the toluene layer is separated off and the water layer is washed successively with diisopropyl ether and pentane. The aqueous solution is acidified with concentrated hydrochloric acid. The temperature is maintained at OOC. throughout the acidification. The solid product is filtered off and dried, yielding 425 g. 76% of 2 - carbethoxy - 5 - methyl - 3,4 - dihydroxy furan; recrystallized from alcohol, m.p. 120121 C. NMR (CDCI). 1.40 (3H. t).

2.28 (3H, s), 4.40 (2H, q), 6.0 (2H, broad).

Example 2 2-Carbethoxy-5-methyl-3 ,4-dihydroxy furan In a 2 L. three-necked flask fitted with a mechanical stirrer, a thermometer, a nitrogen inlet tube and a reflux condenser protected by a calcium chloride tube, is placed a solution of 102 g. of diethyl alpha-methyl dilycolate and 73 g. of diethyl oxalate in 1 L. of dry dimethylformamide. To the stirred reaction mixture is added at room temperature 24 g. of sodium hydride and 0.5 ml. of ethanol. The reaction mixture is then heated under nitrogen to 900 C. when an exothermic reaction accompanied by hydrogen evolution is observed. The temperature is maintained at 110"C. for an additional 15 minutes. The reaction mixture is cooled then to room temperature and the solvent is removed under vacuum. The residue is dissolved in water and the aqueous solution is acidified with concentrated hydrochloric acid.

The temperature is maintained at OOC. throughout the acidification. The solid product is filtered off and dried. Yielding 39.5 g. (42.50/,) or 2 - carbethoxy - 5 methyl - 3,4 - di - hydroxy furan m.p. 119--120"C.

Example 3 2-Carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan In a 0.5 L. three-necked flask fitted as described in Example 1, is placed a suspension of 27.2 g. of sodium ethoxide in 180 ml. of dry toluene and 20 ml. of dry dimethyl formamide. To the stirred suspension is added at 0 C. 29.2 g. of diethyl oxalate over a period of 15 minutes. To the yellow reaction mixture is then added at 0--50C 40.8 g. of diethyl alpha-methyl diglycolate over a period of 15 minutes. The reaction mixture is stirred at room temperature for an additional 30 minutes. The reaction mixture is then warmed up gradually and the ethanol-toluene mixture is distilled off until the vapor temperature reaches 107"C. The reaction mixture is then cooled to OOC. and 9.2 g. of formic acid is added followed by a solution of 9.2 g. ethanol and 0.5 g. of sodium iodide in 60 ml. of dimethyl formamide. Gaseous methyl bromide is bubbled through the vigorously stirred reaction mixture at 40 50"C. until the pH of the reaction mixture reaches 7.7.5. The solvents are removed under vacuum (complete removal of the dimethyl formamide is essential for an optimal isolation of the solid product) and the residue is dissolved in ether.

The sodium bromide is filtered off, the ether solution is 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, yielding 24 g. (70%) of 2 - carbethoxy - 2,5 - dimethyl - 3 - oxo - 4 hydroxy - 2H - furan, recrystallized from cyclohexane. M.p. 89.2--89.5"C. NMR (CDCl3), 1.27 (3H, t), 1.65 (3H, s), 2.32 (3H, s), 4.22 (2H, q), 6.00 (1H, broad).

Example 4 2-Carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan Example 3 is repeated substituting methyliodide for methyl bromide. There is obtained 22 g. (64%) of 2 - carbethoxy - 2,5 - dimethyl - 3 - oxo - 4 - hydroxy 2H furan. M.p. 89.8-90.20C.

Example 5 2-Carbethoxy-2, 5-dimethyl-3-oxo-4-hydroxy-2H-furan Example 3 is repeated substituting methyl chloride for methyl bromide. There is obtained 23 g. (67%) of 2 - carbethoxy - 2,5 - dimethyl - 3 - oxo - 4 - hydroxy 211 - furan. M.p. 89.790C C.

Example 6 2-Carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan In a 250 ml. three-necked flask fitted with a mechanical stirrer and a gas inlet tube is placed a solution of 3.4 g. of sodium ethoxide in 100 ml. of ethanol. To the stirred solution is added at room temperature, under nitrogen, 9.3 g. of 2 carbethoxy - 5 - methyl - 3,4 - dihydroxy - furan and 0.5 g. of sodium iodide.

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. The solvent is removed under vacuum and the residue is dissolved in ether. The sodium bromide is filtered off, the ether solution is concentrated under vacuum and the residue is distilled through a short Vigreux column; 2 - carbethoxy - 2,5 - dimethyl - 3 oxo - 4 - hydroxy - 2H - furan is collected at 102-1050C./0.2 mm. Yield 8.1 g.

(81%), recrystallized from cyclohexane, m.p. 89.8--90.1"C.

Example 7 Two cream flavors were prepared by mixing the following ingredients: A B acetoin 3.0 3.0 diacetyl 2.0 2.0 vanilline 2.0 2.0 ethylbutyrate 1.0 1.0 malto 0.5 0.5 a-decalactone 1.0 1.0 ethyllactate 5.0 5.0 butyric acid 5.0 5.0 caproic acid 0.5 0.5 2-carbethoxy-5-methyl-3,4-dihydroxy furan - 50.0 propylene glycol 980.0 930.0 1000.0 1000.0 Mixtures A and B were separately added to an 8% sugar solution at a level of 0.2 g.

per liter. The test solutions were tested and compared. The panel preferred the test solution containing mixture B over the test solution containing mixture A because the test solution containing mixture B has a richer, sweeter and creamier character than the test solution containing mixture A.

Example 8 Two strawberry flavors were prepared by mixing the following ingredients: A B ethylacetate 2.0 2.0 ethylbutyrate 5.0 5.0 ethylformate 1.5 1.5 ethyl isovalerate 1.0 1.0 ethyl caproate 0.5 0.5 y-undecalactone 0.8 0.8 ethylphenylglycidate 10.0 10.0 ethylbenzoate 2.5 2.5 dimethylanthranilate 2.0 2.0 methylisopropylphenylpropionaldehyde 10% solid 0.5 0.5 methyloctincarbonate 10% sol.X 0.5 0.5 maltol 3.5 3.5 acetoin 10.0 10.0 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan - 12.5 propylene glycol 960.2 947.7 x) in propylene glycol 1000.0 1000.0 Mixtures A and B were separately added to a drink containing 8"" sugar and 0.05%citric acid. The drinks were tasted and compared. The panel preferred the drink containing mixture B over the drink containing mixture A because the drink containing mixture B had a fuller. sweeter and more balanced strawberry character than the drink containing mixture A.

WHAT WE CLAIM IS: 1. A 2 - carbalkoxy - 3,4 - dihydroxy - 5 - alkyl furan in which the alkoxy group has 1 to 4 carbon atoms and the alkyl group has 1 to 6 carbon atoms.

2. A 2 - carbalkoxy - 4 - hydroxy - 2,5 - dialkyl - 3 - oxo - 2H - furan in which the alkoxy group has I to 4 carbon atoms, the 5-alkyl group has I to 6 carbon atoms and the 2-alkyl group has 1 to 4 carbon atoms.

3. A process for the preparation of a furan as claimed in Claim I or 2 which comprises condensing a di-l to 4 carbon atom alkyl - alpha - I to 6 carbon atom alkyl diglycolic acid ester with an oxalic acid di- I to 4 carbon atom alkyl ester in the presence of an alkaline condensing agent and optionally alkylating the product of the condensation with a 1 to 4 carbon atom alkyl halide.

4. A process according to Claim 3 wherein the alkaline condensing agent is selected from alkali metal alkoxides of I to 4 carbon alcohols and alkali metal hydrides.

5. A process according to Claim 3 or 4 wherein the optional alkylation is carried out in the presence of an organic liquid selected from (a) dimethyl formamide, (b) dimethyl sulfoxide, (c) a mixture of inert organic liquids containing at least 10% of (a) or (b) and (d) an alcohol.

6. A process according to Claim 3, 4 or 5 wherein one half of the alkaline condensing agent is acidified prior to the alkylation step.

7. A process according to Claim 3, 4. 5, or 6 wherein the alpha-alkyl group is selected from methyl, ethyl and n-hexyl groups.

8. A 2 - carbalkoxy - 3,4 - dihydroxy - 5 - alkyl furan according to Claim I substantially as described herein and exemplified.

9. A 2 - carbalkoxy - 4 - hydroxy - 2,5 - dialkyl - 3 - oxo - 2H - furan according to Claim 2 substantially as described herein and exemplified.

10. A process according to Claim 3 substantially as described herein.

11. A compound of Claim 1 or 2 when prepared by the process of Claim 3 or 4.

12. A food flavoring comprising a compound according to Claim 1, 2, 8, 9 or II.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (12)

**WARNING** start of CLMS field may overlap end of DESC **. Mixtures A and B were separately added to a drink containing 8"" sugar and 0.05%citric acid. The drinks were tasted and compared. The panel preferred the drink containing mixture B over the drink containing mixture A because the drink containing mixture B had a fuller. sweeter and more balanced strawberry character than the drink containing mixture A. WHAT WE CLAIM IS:

1. A 2 - carbalkoxy - 3,4 - dihydroxy - 5 - alkyl furan in which the alkoxy group has 1 to 4 carbon atoms and the alkyl group has 1 to 6 carbon atoms.

2. A 2 - carbalkoxy - 4 - hydroxy - 2,5 - dialkyl - 3 - oxo - 2H - furan in which the alkoxy group has I to 4 carbon atoms, the 5-alkyl group has I to 6 carbon atoms and the 2-alkyl group has 1 to 4 carbon atoms.

3. A process for the preparation of a furan as claimed in Claim I or 2 which comprises condensing a di-l to 4 carbon atom alkyl - alpha - I to 6 carbon atom alkyl diglycolic acid ester with an oxalic acid di- I to 4 carbon atom alkyl ester in the presence of an alkaline condensing agent and optionally alkylating the product of the condensation with a 1 to 4 carbon atom alkyl halide.

4. A process according to Claim 3 wherein the alkaline condensing agent is selected from alkali metal alkoxides of I to 4 carbon alcohols and alkali metal hydrides.

5. A process according to Claim 3 or 4 wherein the optional alkylation is carried out in the presence of an organic liquid selected from (a) dimethyl formamide, (b) dimethyl sulfoxide, (c) a mixture of inert organic liquids containing at least 10% of (a) or (b) and (d) an alcohol.

6. A process according to Claim 3, 4 or 5 wherein one half of the alkaline condensing agent is acidified prior to the alkylation step.

7. A process according to Claim 3, 4. 5, or 6 wherein the alpha-alkyl group is selected from methyl, ethyl and n-hexyl groups.

8. A 2 - carbalkoxy - 3,4 - dihydroxy - 5 - alkyl furan according to Claim I substantially as described herein and exemplified.

9. A 2 - carbalkoxy - 4 - hydroxy - 2,5 - dialkyl - 3 - oxo - 2H - furan according to Claim 2 substantially as described herein and exemplified.

10. A process according to Claim 3 substantially as described herein.

11. A compound of Claim 1 or 2 when prepared by the process of Claim 3 or 4.

12. A food flavoring comprising a compound according to Claim 1, 2, 8, 9 or II.