FI72119C - Process for the preparation of 2-alkyl-3-hydroxy-4-pyrones. - Google Patents

Description

1 72119

Process for the preparation of 2-alkyl-3-hydroxy-4-pyrones

The invention relates to a process for the preparation of 2-alkyl-3-hydroxy-

For the preparation of 4-pyrones of formula I

O

ΠΓ ”(i) 10 R" wherein R is lower alkyl and R "'is hydrogen or lower alkyl. This method is the so-called. a one-pot process in which 2- (1-hydroxyalkyl) furans are directly converted to 2-alkyl-3-hydroxy-4-pyrones of formula (I) without isolation of intermediates.

Main application patent application 771934 relates to the preparation of 2-substituted 3-hydroxy-4-pyrones by hydrolysis of certain intermediates, some of which are novel, and which intermediates are prepared from suitable furfuryl alcohols using halogenated oxidants.

Maltol (2-methyl-3-hydroxy-4-pyrone) is a naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Previous technical production has taken place by dry distillation of wood. The synthesis of maltol from 3-hydroxy-2- (1-piperidylmethyl) -1,4-pyrone is described by Spielman and Freifelder in J. Am. Chem. Soc., 69 (1947) 2908. Schenck and Spielman, J. Am. Chem. Soc., 67 (1945) 2276 obtained maltol hydroly-30 by playing streptomycin salts in alkaline solution. Chawla and McGonigal, J. Org. Chem., 39, (1974) 39 and Lichtenthaler and Heidel, Angew. Chem., 81 (1969) 998, have described the synthesis of maltol from protected carbohydrate derivatives. Shono and Matsumura, Tetrahedron Letters No. 17, 35 (1976) 1363, have described a five-step synthesis of maltol starting from methyl furfuryl alcohol.

The isolation of 6-methyl-2-ethyl-3-hydroxy-4-pyrone as a typical sweet-scented ingredient in molasses processing is described by Hiroschi Ito in Agr, Biol. Chem. 40 (5) (1976) 827-832. These 5 compounds had been previously synthesized by the method described in U.S. Patent 3,468,915.

The syntheses of 3-hydroxy-4-pyrones such as pyromeconic acid, maltol, ethyl maltol and other 2-substituted-3-hydroxy-4-pyrones are described in U.S. Patent Nos. 10,330,204, 3,133,089, 3,140,239, 3,159,652, 3,365,459, 3,376,317, 3,468,915, 3,440,183 and 3,446,629.

Maltol and ethyl maltol increase the taste and aroma of various foods. In addition, these compounds are used as ingredients in perfumes and essences. 2-alkenyl-15 pyromeconic acids, described in U.S. Patent 3,644,635, and 2-arylmethylpyromeconic acids, described in U.S. Patent 3,365,469, inhibit the growth of bacteria and fungi and are useful in flavoring and flavor enhancers. and as scent enhancers in perfumes.

For the process according to the invention, 2-alkyl-3-hydroxy-

For the preparation of 4-pyrones of the formula I, it is characterized in that 2- (1-hydroxyalkyl) furan of the formula III

25 _____ Γ \ ^ 0Η (III)

R ^ -CKX R

wherein R and R "'have the same meaning as above, reacting in aqueous solution with at least two equivalents of a halogenated oxidant selected from chlorine, bromine, bromochloride, alachloric acid, alibromic acid or a mixture thereof at a temperature of -50 ° C to + 50 ° C, and the resulting 4-halide-hydropyran intermediate is hydrolyzed at elevated temperature to the compound of formula I.

This process according to the invention is a new and easy synthesis for the preparation of 2-11,372,199 alkyl-3-hydroxy-4-pyrones of the formula (I), in particular maltol (2-methyl-3-hydroxy-4-pyrone). and related compounds of the furfuryl alcohol of formula (III) by the one-pot method.

According to this one-pot process, the furfuryl alcohol in the aqueous medium is reacted with two equivalents of a halogen-containing oxidant and then the reaction mixture is heated to hydrolyze the obtained intermediate. The single vessel method 10 can be represented by the following equation: A-oh

JTL · * £ -> XX

15 R "'^ o 1 R"' ^ 0 ^ XR

X OH

(III) (I) wherein R is lower alkyl, R '"is hydrogen or lower alkyl and XY is Br2' clBr 'HOC1, HOBr or a mixture thereof.

The complete flow of 20 thion is shown in the following reaction scheme: X

jr \ ry—> R ”\ 0 ^ VR 2 R" 'k \ 0 / kR "" -'k A-r

25 'oh OH Ti OH O

R '"- 0 = 0" ΤΧ (III) CH. . . .

, open chain CH tautomer

C = O H-COH

30 ·

R

-fr ^ jfr "

35 ° F

Ti 'hll') (I) open chain tautomer 72119

In the article, Lefebre and colleagues presented in J. Med. Chem. 16 (1973) 1084 that furfuryl alcohols can be converted directly to 6-hydroxy-2,6-dihydro-3-pyrones using a peracid oxidant such as peracetic acid or m-chloroperbenzoic acid. In the first step of Lefebre's work, peracid is used in an organic solvent and probably results in the formation of a 6-acetoxy or 6-m-chlorobenzoyloxypyran derivative which is hydrolyzed to the 6-hydroxy compound upon further treatment with water. In the first stage of the reaction, no water is used and it would actually be harmful.

In any case, the method of Lefebvre and his colleague cannot directly lead to the conversion of furfuryl alcohol to 3-hydroxy-4-pyrone.

It has now surprisingly been found that by using two equivalents of a halogen-containing oxidant in water or a mixture of water and an additional organic solvent, the reaction proceeds smoothly from furfuryl alcohol to 3-hydroxy-4-pyrone.

This new one-pot process is advantageous because it is possible to use low-cost Cl 2, Br 2, BrCl, HOCl, HOBr or mixtures thereof as the halogen-containing oxidant. The isolation of the desired 3-hydroxy-4-pyrone is greatly simplified because the solvent, oxidant and by-product inorganic acid are all volatile and can be removed in vacuo to give crude 3-hydroxy-4-pyrone directly in maximum yields by concentration alone.

The operation in one vessel is carried out by dissolving furfuryl alcohol in water or water and co-solvent. The Li-30 salt solvent may be water-miscible or water-immiscible and may be selected from a variety of solvents, which may be, for example, lower alkonols, for example methanol; C 2 -C 10 ethers, for example tetrahydrofuran or isopropyl ether; acetonitrile; ethyl acetate or Alem-35 mat aliphatic ketones. Preferred co-solvents are lower alkanols and tetrahydrofuran, with methanol being the most preferred solvent due to its cost. The temperature of the solution is maintained between -50 ° C and + 50 ° C, preferably between -10 ° C and + 10 ° C. To this solution is added the desired furfuryl alcohol by simultaneously adding a halogenated oxidant (two equivalents) to the reaction mixture. The temperature of the reaction mixture is kept between -50 ° C and + 50 ° C, preferably between -10 ° C and + 10 ° C during the addition of the halogen. If a low-boiling co-solvent is used, it is removed by distillation after all additions have been made. The reaction mixture is then heated to a temperature at which the hydrolysis takes place at a reasonable rate, for example 70 ° C to 160 ° C. The commonly used hydrolysis temperature is 100 ° C to 110 ° C. Heating is continued until the resulting 4-halohydropyran intermediate is substantially completely hydrolyzed to the compound of formula (I) (usually 1-2 hours). The acid required for this final hydrolysis is evolved in situ upon release of the acid from the intermediates formed during the reaction. If desired, more acid can be added.

The halogen-containing oxidant is chlorine, bromine, bromide chloride, alachloric acid or alibromic acid or a mixture thereof. Bromine chloride is a gas obtained as a technical product. It can be prepared in situ by adding chlorine to a solution of sodium or potassium bromide or by adding bromine to a solution of sodium or potassium chloride. Alichloroacid and alibromic acid can be conveniently prepared in situ by adding an aqueous solution of the acid (HCl, h 2 SO 4 or HBr) to a solution of an alkali metal or alkaline earth metal hypohalide, e.g. NaOCl, KOCl or Ca (OCl) 2. The preferred halogen-containing oxides, based on cost factors, are chlorine and bromochloride prepared in situ.

The following examples illustrate the preparation of 3-hydroxy-4-pyrones by the process of this invention.

In the examples where spectral data are reported, the values of the chemical shifts of the NMR spectra are given by the symbolic symbols commonly used in the literature and all shifts are expressed in <5 units (from tetramethylsilane): 6 72119 s = singlet t = triplet q = quartet Example To a 15 3-necked round bottom flask equipped with a magnetic stirrer, gas inlet tube, thermometer and addition funnel were added 20 mL of tetrahydrofuran and 50 mL of water. The solution was cooled to 0-10 ° C. A solution of 1- (2-furyl) -1-ethanol (0.089 mol) in 20 ml of tetrahydrofuran was placed in an addition funnel and added dropwise to the stirred reaction mixture in the flask, to which chlorine was simultaneously introduced via a gas inlet tube ( 0.30 moles). The addition took place at a rate such that the total amount of alcohol was added over the same period of time as the first 1.3-1.5 equivalents of chlorine (over about 30 minutes), and keeping the temperature below 10 ° C.

The reaction mixture was heated to reflux and tetrahydrofuran was removed by distillation. When the reaction mixture reached a temperature of about 105 ° C, a condensing condenser was added and boiling was continued for about two hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2.2 and the reaction mixture cooled to 5 ° C. Crystallization and filtration gave 3.43 grams of crude 2-methyl-3-hydroxy-4-pyrone (maltol). The aqueous filtrate was extracted with chloroform to give another batch of 2.58 grams of maltol. Distillation of the combined solids and recrystallization from methanol gave 5.5 g (40%) of pure white maltol, m.p. 159.5 ° -160.5 ° C.

Example 2

The procedure of Example 1 for the preparation of 4-pyrones of formula (I) was repeated under varying conditions as shown in Table I and using 0.089 moles of furfuryl alcohol of formula

II

72119 7 cv

R

5 and optionally an amount of additional solvent corresponding to the amount of tetrahydrofurans.

Table 1. Single vessel process using chlorine as oxidant 10 R Co-solvent Oxidation heat Hydrolysis Yield State (° c) Ignit state (%) CH 2 methanol 10 100 45 CH 2 methanol 5 110 56 CH 2 methanol -5 104 60 15 CH 3 methanol -10 104 77 CH 2 methanol -20 106 62-67 CH 3 THF 10 105 49 CH 3 acetone -5 110 36 CH 3 CH 3 CN -5 110 29 20 CH 3 Et OAc 0 110 26 CH3 no additional solvent 10 110 17-30 CH3 benzene 10 110 26 CH3 methyl -isobutyl-5 110 44 liketone 25 CH-isopropylalko- 0 110 49 J h CH2CH3 methanol 5 110 49 CH2CH3 methanol -10 110 58 CH2CH3 THF 10 110 47 30 H methanol -10 110 57 CH3 methanol -30 110 50 THF = tetrahydrofuran EtOAc = ethyl acetate 72119

Melting point of the compound of formula (I): R Sp. (° C) H 117-118 CH 3 160 5 CH 2 CH 3 90

Example 3 To a 3-necked round bottom flask equipped with a stirrer, a gas inlet tube and an addition funnel were added 20 ml of tetrahydrofuran, 50 ml of water and sodium bromide (0.20 mol). The solution was cooled to 0 ° -20 ° C. A solution of 1- (2-furyl) -1-ethanol (0.18 mol) in 20 ml of tetrahydrofuran was placed in an addition funnel and this was added dropwise rapidly to the stirred reaction mixture in 15 flasks while simultaneously introducing gaseous chlorine through a gas inlet tube ( 0.40 moles). The rate of addition of alcohol was maintained so that the mixture remained yellow-orange in color. The temperature was kept below 20 ° C by cooling in an ice bath. After both alcohol and chlorine were added to the reaction flask, the temperature was raised to boiling point to distill off tetrahydrofuran. The isolation method of Example 1 was then used to isolate 12.47 g of pure maltol 25 (55% yield), m.p. 160 ° C.

Substantially the same results were obtained by replacing sodium bromide with potassium bromide.

Example 4

The procedure of Example 3 was repeated to prepare compounds of formula (I) under the varying conditions shown in Table 2 using 0.18 moles of furfuryl alcohol of formula

35 / ~ Λ ^ 0H

- "" I

R

II

9 72119 and possibly an amount of additional solvent corresponding to the amount of tetrahydrofurans.

Table 2. Single vessel process using BrCl as oxidant, developed by adding chlorine in situ to 5 NaBr R Co-solvent Oxidation temperature Hydrolysis Yield, o „v temperature (%) potxla (C) Λ ^ _ra_ CH3 THF 20 104 55 10 CH3 THF 27 110 54 CH3 THF 15 110 52 CH3 isopropyl ether 25 110 46 CH3 ethyl ether 20 110 43 CH3 acetone 15 105 47 15 CH3 CH3OH 15 110 32 CH2CH3 THF 16 113 47 H_THF_20_109_48 THF = tetrahydrofuran 20

Example 5 To a 3-necked round bottom flask equipped with a magnetic stirrer, a gas inlet tube, a thermometer and an addition funnel were added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0 ° C and chlorine (0.10 moles) was slowly introduced into the reaction flask while adding 1- (2-furyl) -1-ethanol (0.09 moles) dropwise. The temperature of the reaction mixture was not allowed to rise above 10 ° C. Bromine (0.10 moles) was then added and the reaction mixture was heated to reflux. After isolation according to Example 1, 5.7 g of maltol were obtained in m.p. 160 ° C.

Example 6 A 4-necked round bottom flask equipped with a thermometer, condenser and two addition funnels was charged with 50 mL of tetrahydrofuran and 50 mL of water and the solution was cooled to 10 ° C. To this well-stirred 10 721 L solution was added bromine (0.20 moles) and 1- (2-furyl) -1-ethanol (0.09 moles) in two addition funnels simultaneously. The temperature of the mixture was maintained at 15 ° C throughout the double addition. The reaction mixture was then heated at 75 ° C for 10 hours. Maltol was isolated by the method of Example 1 (53% yield), m.p. 160 ° C.

Example 7

The procedure of Example 6 for the preparation of compounds of formula (I) under varying conditions mentioned in Table 3 using 0.09 moles of furfuryl alcohol of formula r \ 15 was repeated.

XJ I

R

and optionally an amount of additional solvent equivalent to the amount of tetrahydrofuran.

Table 3 20 R Co-solvent Oxidation temperature Hydrolysis Yield Temperature (%) _ (° C) _ (¾_ CH3 THF 15 75 53 CH3 CH3OH 5 105 47 25 CH3 no co-solvent 15 100 30 CH2CH3 THF 25 105 47 H THF 15 100 45 CH3 THF 50 100 20

Example 8

A 2.8 solution of sodium hypochlorite was prepared by introducing chlorine gas (42.6 g) into a solution of 48 g of sodium hydroxide in 150 ml of water at 0 ° C.

A solution of 1-35 (2-furyl) -1-ethanol (0.05 mol) in 15 ml of tetrahydrofuran and 15 ml of water was prepared in a 3-necked flask and cooled to 5 ° C. By keeping

II

11 72119 pH 1.0-0.8 with 6 m HCl, 21.7 ml of hypochlorite solution was added dropwise to the reaction flask over about 33 minutes, keeping the temperature below 5 ° C. A 15 ml portion of concentrated hydrochloric acid was then added to the reaction mixture, followed by heating to remove tetrahydrofuran by distillation. Heating was continued for another hour. Maltol was isolated as described in Example 1, m.p. 160 ° C.

Substantially the same results are obtained when sodium hypobromite is used instead of sodium hypochlorite.

Example 9

To a solution of 1- (2-furyl) -1-ethanol (0.05 mol) in 15 ml of tetrahydrofuran and 15 ml of hydrogen at 5 ° C was added 21.7 ml of 2.8 sodium hypochlorite solution. . Chlorine (0.05 moles) was introduced into the reaction flask through a gas inlet tube, keeping the temperature below 5 ° C. The reaction mixture was then heated to reflux and the tetrahydrofuran was removed by distillation.

20 Heating was continued for another hour. The reaction mixture was cooled and maltol was isolated by the method described in Example 1, m.p. 160 ° C.

Example 10 A solution of 50 ml of water and 20 ml of tetrahydrofuran was placed in a 3-necked round bottom flask and the solution was cooled to 0 ° C. A solution of 1- (2-furyl) -1-ethanol (0.89 mol) in 25 ml of tetrahydrofuran was placed in an addition funnel and this solution was added dropwise to the reaction flask while gas was added via an inlet tube to BrCl (0 , 30 moles). The rate of addition was such that the total amount of furyl alcohol was added first

With 1.3-1.5 equivalents of BrCl and the temperature was then kept below 30 ° C. The reaction mixture was heated to reflux and tetrahydrofuran was removed by distillation. After the temperature rose to 105 ° C, a condenser was added to the flask and the reaction mixture was heated to reflux for about two hours. The reaction mixture was cooled and maltol was isolated by the method of Example 1, m.p. 160 ° C

12 721 1 9

Example 11 A 3-necked round bottom flask equipped with a magnetic stir bar, a thermometer and two addition funnels was charged with 25 mL of tetrahydrofuran-5 and 50 mL of water. To this solution was added 1- (2-furyl) -1-ethanol (0.89 mol) in 25 ml of tetrahydrofuran, while adding bromine (0.16 mol) dropwise and keeping the temperature below 15 ° C. At the end of the additions, chlorine (0.10 mol) was added via a gas inlet and the reaction mixture was heated to reflux.

Maltol was isolated from the cooled solution by the method of Example 1, m.p. 160 ° C.

Example 12 6-Methyl-2-ethyl-3-hydroxy-4-pyrone To a 3-necked round bottom flask were added 28 mL of methanol and 38 mL of water. The solution was cooled to -15 ° C and 0.166 moles of 5-methyl-2- (2-hydroxypropyl) furan (J. Org. Chem., 26 (1960) 1673) and 0.416 moles of chlorine were added simultaneously. During the addition, the temperature was maintained between -16 ...- 8 ° C. At the end of the addition, the solution was heated to 80 ° C and boiled for about three hours. After cooling to room temperature, the pH was adjusted to 2.1 and the mixture was extracted with chloroform (3 x 100 mL). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to dryness to give a thick, dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of a white solid. Sublimation gave the pure product, m.p. 157-159 ° C.

Analysis for cgH 2 Q ° 3:

Calculated: C 62.33; H 6.54

Found: C, 62.05; H 6.44.

NMR (CDCl 3, δ); 6-CH. 2.33 (3 H, s); 2-CH 3, 1.30 (3H, t); 35 2-CH 2 -, 2.75 (2H, quartet), 5H, 6.23 (1H, s).

li 13 721 1 9

Example 13 2,6-Dimethyl-3-hydroxy-4-pyrone

To a 3-necked round bottom flask were added 28 mL of water and 32 mL of methanol and the mixture was cooled to 5-15 ° C. The solution was treated simultaneously with 0.167 moles of 5-methyl-2- (X-hydroxyethyl) furan (J. Org.

Chem., 26 (1960) 1673) and 0.416 moles of chlorine. The temperature was maintained between -15-10 ° C during the addition. The mixture was allowed to warm to room temperature over 30 minutes and heated to reflux for three hours. The pH of the cooled solution was adjusted to 2.1 and extracted with chloroform (3 x 100 mL). The chloroform extracts were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue, a dark oil, was chromatographed on silica gel eluting with methylene chloride / ethyl acetate (95: 5). The product was separated by evaporation, recrystallized from methanol as a tan solid (25% yield). Sublimation gave white crystals, m.p. 161-163 ° C.

Analysis for C 12 H 9 O 2:

Calculated C 59.99; H 5.75

Found: C, 59.83; H 5.82.

NMR (CDCl 3), δ, δ-CH 3, 2.33 (3H, s); 2-CH 2, 2.26 (3H, s); 5-H, 6.10 (1H, s).

Claims (5)

7211 9 A process for the preparation of 2-alkyl-3-hydroxy-4-pyrones of formula III (I) wherein R is hydrogen or lower alkyl and R "'is hydrogen or lower alkyl, characterized in that that 2- (1-hydroxyalkyl) furan of formula III 15 R "--- 1 [\ _ ^ 0H (III) Vo / \ R wherein R and R" 'are as defined above, is reacted in aqueous solution with at least two equivalents of a halogenated oxidant which is chlorine, bromine, bromochloride, alachloric acid , alibromic acid or a mixture thereof, at -50 ° C to + 50 ° C and the resulting 4-halide-hydropyran intermediate are hydrolyzed at elevated temperature to give the compound of formula I. Process according to Claim 1, characterized in that the temperature at which the hydrolysis is carried out is in the range from 70 to 160 ° C. Process according to Claim 1 or 2, characterized in that the reaction is carried out in the presence of an additional solvent which is a lower alkanol, tetrahydrofuran, isopropyl ether, acetonitrile, ethyl acetate or a lower aliphatic ketone. Process according to Claim 3, characterized in that the additional solvent is methanol, tetrahydrofuran, isopropyl ether or acetone. Process according to any one of Claims 1 to 4, characterized in that the halogen-containing oxidant is chlorine or bromide chloride. li