NL8004974A - PROCESS FOR PREPARING GAMMA PYRONS. - Google Patents

Description

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Process for the preparation of γ-pyrons.

The invention relates to a process for the preparation of γ-pyrons, such as e.g. maltol. Maltol is a naturally occurring compound found in the bark of young larch trees, pine trees and chicory. Early industrial production consisted of destructive distillation of wood. Synthesis of maltol from 3-hydroxy-2- (1-piperidylmethyl) -1,4-pyron was described by Spielman and Freifelder, J.A.C.S.

69, 2908 (1947), Schenck and Spielman, J.A.C.S. 67, p.

2276 (1945), maltol was obtained by alkaline hydrolysis of 10 streptomycin salts. Chawla and MgGonigal, J. Org. Chem., 39, p.

3281 (1974) and Lichtenthaler and Heidel, Angew. Chem. 81, p.

999 (1969) described the synthesis of maltol from protected carbohydrate derivatives.

Syntheses of γ-pyrons, such as pyromeconic acid, maltol, ethylmaltol and other 2-substituted-3-hydroxy-γ pyrons are described in U.S. Pat. Nos. 3,130,204, 3,133,089, 3,140,239, 3,159,652, 3,376. 317, 3,468,915, 3,440,183, and 3,446,629.

Maltol and ethyl maltol enhance the taste and aroma of various food products. In addition, these materials are used as ingredients in perfumes and essences. The 2-alkenylpyromeconic acids described in US Patent 3,644,635 and the 2-arylmethylpyromeconic acids described in US Patent 3,365,469 prevent the growth of bacteria and fungi and are useful as flavor and flavor enhancers in food and beverages and flavor enhancers in perfumes.

8004974 2

According to the invention there is provided a process for the preparation of γ-pyrons of formula 1, wherein R is hydrogen, a short chain alkyl group of 1-6 carbon atoms, a short chain alkenyl group of 2-6 carbon atoms, a phenyl or benzyl group, wherein a compound of formula 2, wherein R is as defined above and Rf is a short chain alkyl group of 1-6 carbon atoms, is contacted with an acid to form the desired γ-pyron.

The invention also provides a process for the preparation of new compounds of formula 3 and formula 4, in which RS is an ethyl group and R 'is a short chain alkyl group with 1-6 carbon atoms.

The invention provides a process for the preparation of 2-substituted-3-hydroxy-γ-pyrons starting from furfural as starting material. Furfural is an inexpensive raw material, which is prepared on an industrial scale from pentosans, which are found in the straw of grains and in bran.

In this text, the term "short chain alkyl" and the short chain alkyl portion of an alkoxy group refers to both straight and branched chain alkyl groups of 1-6 carbon atoms; the term "short chain alkenyl" refers to straight and branched chain alkenyl groups of 2-6 carbon atoms; the term "aryl" refers to a mono-cyclic aromatic hydrocarbon of 6-8 carbon atoms and the term "aralkyl" refers to short chain alkyl groups in which an aryl group as defined above is substituted in place of a hydrogen atom.

The reactions which take place in the process according to the invention starting from furfural are described in scheme A. In the intermediates of scheme A, R 'is an alkyl group with 1-6 carbon atoms and R is hydrogen, an alkyl, aryl, alkenyl or aralkyl group. In the final product of formula 1, R is hydrogen, an alkyl, alkenyl, aryl or aralkyl group. When R = H, pyromeconic acid, R = CH ^, ismaltol and R = CH ^ CILl, ethyl-35 is maltol.

Furfural's reaction with the appropriate 8004974 ί 1 3

Grignard reagent is described in C.A. 44, column 1092d (1949).

The preparation of the intermediate of formula 7 (R = H) by electrolysis in methanol is described in U.S. Pat. No. 2,714,576 and Acta. Chem. Scand. jS, 5 p. 545 (1952). The synthesis using bromine in methanol is described in Ann. 516, p. 231 (1935). The general principle of using chlorine in an alcoholic solvent is also known (see, e.g., British Patent 595,041). In carrying out the process according to the invention it has been found that the reaction of the intermediate of formula 6 with chlorine in an alcoholic solvent at a temperature between -70 ° C and + 50 ° C gives a smooth conversion to the desired intermediate of formula 7 wherein the HCl by-product is neutralized by a base such as ammonia, sodium 15 carbonate or other alkali metal base. Although the early literature pertaining to this reaction reports yields of up to about 50%, the process of the invention yields in excess of 90%.

The intermediate of formula 7 (R = CH 2) is described in Acta. Chem. Scand. 9, p. 17 (1955) and Tetrahedron 27, p. 1973 (1971). The intermediate of formula 7 (R = C 1 CH 2) is a new compound which can be prepared according to the methods described above.

The treatment of the intermediate of formula 25 with a strong organic acid is new and it directly yields the desired 6-alkoxy derivative of formula 8 in high yield and avoids the formation of the corresponding hydroxy derivative which is very unstable against further reactions. The intermediate of Formula 7 is contacted with an acid, which is preferably substantially anhydrous, although the presence of a protic solvent such as an alcohol or a small amount of water is beneficial in practice. After this treatment, the product is separated from the acidic medium according to conventional extraction techniques in a purity state suitable for conversion to the intermediate of formula 8. Although formic acid and trifluoroacetic acid are preferred, 8004974 4 causes any acid having a pKa of about 4 or less conversion of the intermediate of formula 7 to the desired intermediate of formula 8. Other suitable organic acids are p-toluenesulfonic acid, methanesulfonic acid, citric acid oxalic acid and chloroacetic acid; suitable mineral acids are sulfuric, hydrochloric and phosphoric acids. Acid resins such as Amberliet GC-120 (trademark) and Dowex 50W (trademark) can also be used.

The epoxidation of the intermediate of formula 8 to the epoxy ketone of formula 2 is a new method. The intermediate of formula 8 is dissolved in a suitable solvent, such as water or an alcohol, such as isopropyl alcohol or methanol. A base, such as sodium bicarbonate or sodium hydroxide, is added followed by addition of 30% hydrogen peroxide. The desired intermediate of formula 2 can be separated by conventional extraction techniques and is suitable for regrouping into the desired pyron of formula 1 without further purification.

The final rearrangement of the epoxy ketones of the formula II to the γ-pyrons of the formula I is new and proceeds in good yield and good purity. The intermediate of the formula II is reacted in an acidic medium and the subsequent isolation of the desired γ-pyron of the formula I is accomplished by conventional crystallization or extraction techniques. The pure γ-pyron can be recrystallized from a suitable solvent, such as isopropanol, methanol or water. Although warm aqueous mineral acid, such as sulfuric or hydrochloric acid, is the most suitable method for converting the intermediate of formula 2 into the product of formula 1, the desired γ-pyron may be formed by Lewis acids, such as boron trifluoride etherate, zinc chloride and tin tetrachloride, by acidic ion resins, such as Amberlite GC-120 or Dowex 50W and the strong organic acids, such as p-toluenesulfonic acid or formic acid.

Compounds related to the intermediate of formula 8 (R C 1 OH or R C 1 O alkyl) can be prepared from carbohydrate sources, as described in Accounts of

Chemical Research jl, p. 192 (1956). These connections can be 8004974

I. I

5 are converted by the process according to the invention into the intermediate of the formula II and the product of the formula I, wherein R = C 1 -H 2 OH or C 2 O-alkyl. The product of formula 1 (R = CH 2 OH or C 1 O alkyl) can be converted to maltol in the manner described in U.S. Patent 3,130,204 or Angew. Chem. 81, 998 (1969).

The examples below serve to illustrate the invention.

Example I

In a three-necked round bottom equipped with a magnetic stir bar, a jacketed addition funnel, a thermometer and a dry ice cooler, 22.4 g (0.2 mol) of the intermediate of formula 6 (R = CH2), 100 ml of methanol and 21 1 g (0.2 mol) of sodium carbonate and this mixture was cooled to 0 ° C using an ice-acetone bath. To this rapidly stirred solution was then added dropwise a cold (-30 ° C) solution of chlorine (11.0 ml, 0.24 mol) in methanol.

The addition of chlorine was controlled to keep the reaction temperature below 40 ° C. The addition took about 2 hours. After the addition, the reaction mixture was stirred at ice bath temperature for 30 min and then allowed to warm to room temperature. The resulting slurry was filtered, the methanol removed in vacuo, the residue taken up in benzene and passed through an alumina plug as a final filter. Removal of the benzene gave 31.9 g (91%) of the desired dimethoxydihydrofuran of formula 7 (R = CH 2, R 1 = CH 2). This material can be used without further purification or it can be distilled; kpt. = 76-78 ° C / 5 mm / T04-107 ° C / 10-11 mm,

Acta Chem. Scand. 9, p. 17 (1955) J.

30 Analysis:

Ber, for CoH 4, C 55.22 H 8.11 8 14 4

Found: C 55.34, H 8.04

Example II

The method of Example I is repeated with the intermediate of formula 6 (R = H) to give the intermediate of formula 7 (R = H, R '= CH 3) at bp = 80-82 ° C / 8004974 6 5 mm / 71 ° C / 1.0 mm, Tetrahedron 27, 1973 (1971) 7.

Example III

The procedure of Example I was repeated with the intermediate of formula 6 (R = H), whereby the intermediate 5 of formula 7 (R = H, RT = CHg) was obtained with bpt. * 102 ° C / 10 mm.

Analysis:

Ber. for C-Η ,, Ο .: C 57.50 H 8.58

Found: C 57.39, H 8.59

Example IV

The method of Example I was repeated using the intermediate of formula 6 (R = CH 2) replacing the methanol with isopropanol to give the compound of formula 7 / R = CH 2, R '= CH (CH 2) 2 -7 was obtained at 15 kpt. 62-64 ° C / 0.05 mm.

Example V

The method of Example I can be repeated using bromine instead of chlorine and using the intermediate of formula 6 to yield the intermediate of formula 7 wherein R is hydrogen, a methyl, ethyl, hexyl, phenyl, vinyl, 1-butenyl, allyl or 1-hexenyl group and R 'is methyl, ethyl, isopropyl or hexyl.

Example VI

A small glass electrolysis vessel with a carbon-anode and a nickel cathode was charged with 50 ml of methanol, 0.5 ml of concentrated sulfuric acid and 1.12 g (0.01 mol) of the intermediate of formula 7 (R = CH 2 R = CH2) and the solution was cooled to -20 ° C. Electrolysis was performed using a potentiostat / galvanostat instrument set to deliver a constant current of 0.6 A. After a reaction time of 30 min, the reaction mixture was poured into water and the product of formula 8 (R = CH 2, R '= CH 2) was isolated by a chloroform extraction. This method is similar to the method described in U.S. Patent 2,714,576 with sulfuric acid in place of ammonium bromide as the electrolyte.

8004974 f, 1

Example VII

7

The method of Example VI can be repeated with the intermediate of formula 7 to yield an intermediate of formula 8 wherein R is hydrogen, an ethyl, hexyl, phenyl, benzyl, vinyl, allyl, 1-butenyl or 1-hexenyl group and R 'is an ethyl, isopropyl or hexyl group.

Example VIII

To a 2 L three-necked flask equipped with a magnetic stirrer, dropping funnel and a thermometer were added 400 ml formic acid and 20 ml methanol. To this solution was added a solution of the intermediate of formula 7 (R = CH 2, R 1 = CH 2) 104.4 g; 0.6 mol in 40 ml of methanol. The dropwise addition took 15 minutes. The reaction mixture was poured into 1 liter of water and extracted 3 times with 15 aliquots of 500 ml each of chloroform. The combined chloroform washes were washed with an aqueous sodium bicarbonate solution and with brine. The chloroform solution was evaporated to a crude intermediate of formula 8 (R = CH 2, R '= ΟΗ ^) in a yield of 76 g (89%) as a light brown product. The raw material can be used as such or distilled at 2 mm pressure, 50-52 ° G / ~ 82-85 ° C / 30 mm, Tetrahedron 27, 1973 (1971) 7.

Example IX

The procedure of Example VIII was repeated with a corresponding intermediate of formula 7 (R = H, R '* CH 2), whereby intermediate of formula 8 (R = H, R' - CH 2) was obtained with bpt. 60-66 ° C / 14mm / 76-81 ° C / 23mm, Tetrahedron 27, 1973 (1973) 7.

Example X.

The method of Example VIII was repeated with the intermediate of formula 7 (R = C 2 CH 2 R 3 = CH 2) whereby the intermediate of formula 8 (R = CE 2 C 2 R 3 = CH 2) is obtained with bpt. = 79-80 ° C / l4 mm.

Example XI

The method of Example VIII can be repeated with the intermediate of formula 7 to yield the intermediate of formula 8 wherein R is a hexyl, phenyl, benzyl, vinyl, allyl, 1-butenyl or 1-hexenyl group and R is an isopropyl or hexyl group.

Example XII

The method of Example VIII can be repeated

with similar results by replacing the formic acid with an organic acid such as citric acid, oxalic acid, chloroacetic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid. Example XIII

In a three-necked round bottom equipped with an addition funnel, low temperature thermometer and stirring bar, a solution of 5.0 g (0.029 mol) of the intermediate of formula 7 (R = CH-, R '= 0Ho) indiethyl ether ( 10 ml) and the solution was cooled to -40 ° C. To this solution was then added dropwise 1.6 ml of concentrated sulfuric acid and the black mixture was stirred at -40 ° C for 5 min, poured into water and the desired intermediate with formula 8 (R = CHg, R1 = CH ^) was isolated according to the method of Example VIII.

Substantially the same results can be obtained by replacing the sulfuric acid with hydrochloric or phosphoric acid.

Example XIV

Into a dry flask, 1.05 g (0.0074 mol) of intermediate of formula 8 (R = CH 2, R 1 = CH 2 O) dissolved in 20 ml of isopropyl alcohol are placed and the flask was cooled to 0 ° C. Then 0.5 g (0.0059 mol) of sodium bicarbonate and 2.0 ml (0.023 mol) of 30% hydrogen peroxide were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into 100 ml of water and the water was extracted with chloroform, followed by concentration to obtain an oil which can be distilled at 70-90 ° C / 3 mm. An analytical sample was purified by gas chromatography.

35 Analysis:

Ber. for C ^ H ^ O ^: C 53.16 H 6.37

Found: C 52.90 H 6.27 8004974

Example XV

9

The procedure of Example XIV was repeated with the intermediate of formula 8 (R = H, R '- CH 2) to give the intermediate of formula 2 (R = H, R' = CH 2).

5 Analysis:

Ber. for C15 Hg O: C 50.00 H 5.59

Found: C 50.09, H 5.81

Example XVI

The method of Example XIV was repeated with the intermediate of formula 8 (R = C 1 -CH 2, R 1 = CH 2) to give the intermediate of formula 2 (R = CH 2 CH 2, R '= CH 2).

Analysis:

Ber. for C 8 H 15 O 55.81 H 7.02 15 Found: C 55.95 H 7.04

Example XVII

The procedure of Example XIV can be repeated with intermediate of formula 8, whereby intermediate of formula 2 is obtained, in which R is a hexyl, phenyl, benzyl, vinyl, allyl, 1-butenyl or 1-hexenyl group and R 'is an isopropyl or hexyl group.

Example XVIII

2.84 g (0.02 mol) of the intermediate of formula 8 (R = CHg, R'-CHg), 10 ml of water and 10 ml of isopropanol were placed in a 75 ml flask. The solution was cooled to 0-5 ° C and the pH was adjusted to 7.0-9.0 with 1N NaOH. Then 2.1 ml of 30% hydrogen peroxide were added dropwise, while NaOH was also added as needed to keep the pH constant. Cooling was required to keep the pot temperature below 10 ° C. After the addition of the peroxide, the reaction mixture was stirred at 8-10 ° C for 1 hour, then poured into water and the solution was extracted with chloroform. Removal of the solvent gave 2.99 g (94.5%) of the compound of formula 2 (R-CHg, RT = CHg) as a clear oil. A reaction temperature above 15 ° C and a pH above 9.5 or below 6.5 results in lower intermediate yields of 80049/4 of formula 2.

10

Virtually the same results are obtained when replacing isopropanol with water.

Example XIX

In a flask equipped with a cooler, 3.7 g (0.023 mol) of intermediate of formula 2 (R ** CH 2, R 1 ** CH 2) and 50 ml 2 molar sulfuric acid were placed. After this two phase solution was heated at reflux for hours, the reaction mixture was cooled, the pH adjusted to 2.2 with 6N NaOH, extracted 3 times with volumes of 100 ml each of chloroform and the combined solvent extract concentrated to yield the product of formula 1 (R = CH 2, maltol) was obtained.

Example XX

The method of Example XIX can be repeated with the intermediate of formula 2, wherein R is hydrogen, an ethyl, hexyl, phenyl, benzyl, allyl, vinyl, 1-butenyl or 1-hexenyl group, and Rf is a methyl, ethyl is isopropyl or hexyl group to give a product of formula 1 wherein R 20 is hydrogen, an ethyl, hexyl, phenyl, benzyl, allyl, vinyl, 1-butenyl or 1-hexenyl group.

Example XXI

In a 250 cc Wheaton pressure bottle, 3.16 g (0.02 mol) of intermediate of formula 2 (R * CH 2, R '= CEL) and

3 J J

25 50 cm 2 of molar sulfuric acid. The vessel was sealed and heated to 140-160 ° C for 1-2 hours. After cooling, the reaction mixture was treated as in Example XIX to give maltol (Formula 1, R = CHg).

Example XXII

30 The method of example XIX and of example

XX can be repeated with similar results when replacing the sulfuric acid with hydrochloric acid, Dowex 50Wc £ Amberlite GC-120. Example XXIII

Into a small flask, 1.58 g (0.01 mol) of intermediate of formula 2 (R = CH 2, R 1 CH 2) and 25 ml of benzene, followed by 3.7 ml of boron trifluoride etherate were charged. After stirring at 25 ° C for 11 hours, the solvent was removed, the residue extracted with chloroform and the chloroform removed to give maltol (formula], R = CH 2),

Virtually the same results are obtained when the boron trifluoride etherate is replaced with p-toluenesulfonic acid, formic acid, zinc chloride or tin tetrachloride.

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Claims (3)

1. Process for the preparation of γ-pyrons of the general formula 1, wherein R represents H, lower alkyl of 1-6 carbon atoms, lower alkenyl of 2-6 carbon atoms, phenyl 5 or benzyl, characterized in that a compound having Formula 2, wherein R has the meanings indicated above and Rf represents lower alkyl of 1-6 carbon atoms, contacts an acid to form the desired γ-pyron. 2. Process according to claim 1, characterized in that compounds of the formula 2a, in which X represents H, alkyl, aryl, alkenyl, aralkyl, -C 1-4 alkyl or -Cl 2 O-alkyl, are prepared from compounds of the formula 8a in an aqueous medium by treatment with a base and hydrogen peroxide. 3. Methods as described in description 15 and / or examples. 8004974