IE45642B1

IE45642B1 - Process for the preparation of 6-hydroxy-2h-pyran-3(6h)-ones useful in the synthesis of gamma-pyrones

Info

Publication number: IE45642B1
Application number: IE584/79A
Authority: IE
Original assignee: Pfizer
Priority date: 1976-08-02
Filing date: 1977-07-29
Publication date: 1982-10-20
Also published as: ES470746A1; EG13080A; FI72723B; YU40166B; PH13926A; FI831704L; NL182476C; JPS5436270A; SE433079B; DE2728499C2; DD132494A5; FI72722C; HK30681A; HU186026B; IE45641B1; DE2760220C2; FI831703L; HU185687B; IE790586L; PL115497B1

Abstract

The gamma-pyrones of formula I in which the symbols have the meaning given in Claim 1 are obtained by a simple and economic "one-pot" process by reaction of a furfuryl alcohol of formula III with at least 2 equivalents of a halogenated oxidising agent, in aqueous solution at a temperature of between -50 DEG and +50 DEG C, and then the reaction mixture is heated until hydrolysis of the intermediate formed is virtually complete. The gamma-pyrones obtained can be used as products which enhance flavour and fragrance in food and cosmetic preparations.

Description

This invention relates to a process for the preparation of gamma-pyrenes and is particularly concerned with a process for the preparation of maltol (3-hydroxy-2-methyl-4H-pyran-4one) and related compounds and with 6-hydroxy-2H-pyran-3(6H)one intermediates for use in the process.

According to Patent Specification No. 45641 · there is provided a process for preparing a gamma-pyrone of the general formula: wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; and R1 is hydrogen or alkyl of 1 to 4 carbon atoms which comprises contacting a furfuryl alcohol of the general formula: (ΙΪ) with at least taro equivalents of a halogen oxidant and heating at 70-160°C until the hydrolysis of the formed 4- 3 halo-6-hydroxy-2,6-dihydropyran-3-one is substantially complete.

The process is generally performed by treating the furfuryl alcohol, in aqueous medium, with two equivalents of oxidant and the reaction mixture is then heated to hydrolyse the intermediate formed. The overall reaction is represented as follows: wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl 10 or benzyl; R1 is hydrogen or alkyl of 1 to 4 carbon atoms; and XY is Cl2> Br2> CIBr, H0C1, HOBr or mixtures thereof.

The reaction pathway is shown in the following scheme: • k & I c=o I H—COH I R open chain tautomer open chain tautomer However, if desired, the intermediate 6-hydroxy-2Hpyran-3(6H)-one can be prepared by contacting the appropriate furfuryl alcohol with one equivalent of a halogen oxidant. The isolated product is readily converted to the - 5 desired gamma-pyrone by contacting it with an additional equivalent of a halogen oxidant and hydrolysing the formed 4-halogeno-6-hydroxy-2H-pyran-3(6H)-one as described in Patent Specification No. 45641. Ά process for preparing a compound of the formula: wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R' is hydrogen and R‘ is hydrogen or alkyl of 1 to 4 carbon atoms, comprises contacting a furfuryl alcohol of the formula (II) in aqueous solution with at least one but less than two equivalents of a halogen oxidant selected from chlorine, bromine, chlorine-bromide, hypochlorous acid, hypobromous acid or mixtures thereof at a temperature of -50 to 50°C until the reaction is substantially complete, and isolating the desired product of formula III* The process is reformed by dissolving the furfuryl alcohol in water or in water and a co-solvent. The cosolvent can be water miscible or water immiscible and can be selected from a wide range of solvents such as to C alkanols or diols; C? to ethers or nitriles; and to C ketones or esters. The preferred co-solvents are C, to 10 1 C alkanols and C_ to C ethers, with methanol the preferred rr XU solvent because of cost. The solution is kept at a temperature of -50 to 50°C, preferably -10 to 10°C. To this solution is charged a desired furfuryl alcohol while simultaneously adding a halogen oxidant(preferably one - 6 equivalent) to the reaction mixture. The temperature of the reaction mixture is maintained at -10 to 10°C. during halogen addition. If a low-boiling co-solvent is employed, it is preferably removed by distillation after all additions are complete, and the compound of formula (III) is isolated.

The halogen oxidant can be chlorine, bromine, chlorinebromide, hypochlorous or hypobromous acid or mixtures thereof. Chlorine-bromide is a commercially available gas. It can be prepared in situ by addition of chlorine to a solution of sodium or potassium bromide or by the addition of bromine to a solution of sodium or potassium chloride.

Hypochlorous and hypobromous acid can be conveniently generated in situ by the addition of aqueous acid (HCl, HjSO^, HBr, etc.) to a solution of the alkali or alkali earth metal hypohalite, e.g. NaOCl, K0C1 or Ca(OCl)2· The preferred halogen oxidants, based on cost factors, are chlorine and chlorine-bromide prepared in situ. Excess halogen oxidant (up to two equivalents) may be used but for optimum results one equivalent is employed.

According to the present invention the gamma-pyrones of formula (I) can be prepared by treating a compound of the formula III wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl and R' is hydrogen alkyl of 1 to 4 carbon atoms or -(f-R wherein R is methyl, ethyl o or phenyl; and R', is hydrogen or alkyl of 1 to 4 carbon atoms, with one equivalent of a halogen oxidant and heating at 7O-16O°C to hydrolyse the product.

A 6-alkoxy-2H-pyran-3(6H)-one of formula (III) wherein R' is alkyl of 1 to 4 carbon atoms is prepared by the method of Patent Specification No. 42789, A furfuryl - 7 45642 alcohol is anodically alkoxylated to the 2-(l-hydroxyalkyl)-2,5-dialkoxy-dihydrofuran. Treatment with a strong organic acid produces the desired 6-alkoxy compound. A 6acyloxy compound of formula (III) wherein R1 is -COR and R is methyl, ethyl or phenyl may be prepared by conventional treatment of the 6-hydroxy compound with the appropriate anhydride in the presence of pyridine.

In the process for preparing gamma-pyrones of formula (I) from a compound of formula (III), wherein OR’ is a hydroxy group, the reaction with a halogen oxidant is performed as described above. The reaction mixture is then heated as described in Patent Specification No. '.45641 to effect hydrolysis of the formed 4-halo-6-hydroxy-2,6dihydropyran-3-one intermediate.

In the process for preparing gamma-pyrones of formula (I) from a compound of formula (III) wherein R‘ is an alkyl group or an acyl group the 6-aCyloxy or 6-alkoxy-2H-pyran3(6H)-one is dissolved in a reaction-inert solvent selected from acetic acid, formic acid, trifluoroacetic acid, halogenated solvents, ethers, C^ to C^ alkanols or diols, C3~C10 ketones, nitriles, esters and amides. The preferred solvents are acetic acid, formic acid or methanol. An equivalent of a halogen oxidant such as chlorine, bromine, chlorine-bromide, hypochlorous acid or hypobromous acid is added at room temperature and the reaction mixture is heated to 7O-16O°C., generally 100-110°C., until the conversion to the desired gamma-pyrone is substantially complete (approximately 1-3 hours). The gamma-pyrone may be obtained from the cooled, neutralized reaction mixture on standing or by extracting the reaction mixture with a solvent such 3 6 4 3 - a - _ as chloroform which yields the gamma-pyrone on concentration.

With organic acids and other protic solvents such as formic acid, acetic acid, other organic acids and alkanols that have not been vigorously dried, no additional water is added in the above described reaction. However, with nonprotic solvents, Water is necessary and is added for the conversion of the formed 4-halogeno-6-substituted-2H-pyran3(6H)-one to the y -pyrone. When a low boiling solvent is employed in the reaction, it is preferably removed by dis10 filiation just before the reaction mixture is heated to 100110°C. for the hydrolytic conversion of the formed 4-halodihydropyran to the gamma-pyrone.

The process for the preparation of compounds of the formula III and their conversion to gamma-pyrones is illustra15 ted by the following Examples: Example 1 6-hydroxy-2-methyl-2H-pyran-3 (6H) -one To a solution of 25 g of 1(2-furyl)-1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 5°C. was added 1 equivalent of bromine. The temperature Was maintained at -lO°C. throughout the addition. The solution was adjusted to pH 2.1 and extracted with ethyl acetate (3 X 50 ml).

The ethyl acetate extract was dried and evaporated to give a yellow oil. The oil was chromatographed on silica gel and eluted With chloroform-ethyl acetate (3:1) to give 4.8 g of clear oil which was shown by spectral data to be identical with 6-hydroxy-2-methyl-2H-pyfan-3(6H)-one prepared from 6-methoxy-2-methyl-2H-pyran-3(6H)-one by acid hydrolysis [Tetrahedron 27, 1973 (1971)] . - 9 IR (CIiCl3 ) 3.700 , 3300, 1700 cm-1 NMR (CDC13, ,5 ): 6.8-7.1 (IH, d of d); 6.0-6.2 (IH, d), .6 (IH, br. s, exchanges with D^O); 5.4-5.5 (IH, d); 4.8-5.0 (IH, q) ; 1.3-1.6 (3H, t).

Example 2 The method of Example 1 was repeated with a furfuryl alcohol of the formula to yield a compound of the formula wherein R is hydrogen or ethyl.

Ethyl compound: IR (CHC1 ) 3600, 3340, 1706 cm-1 Hydrogen compound: IR (CHCip 3565, 3300, 1703 cm Example 3 A solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.01 mole) in 20 ml of acetic acid was treated with gaseous chlorine (0.01 mole) at room temperature. The reaction mixture was then heated to reflux for about one hour, cooled to room temperature, diluted with 20 ml of water, the pH adjusted with 50% NaOH solution to 7.0 and the 3 6 4 2 - 10 reaction mixture extracted with chloroform. The chloroform extract was concentrated to yield maltol which was recrystallized from methanol to give the pure product (56%), mp 159.5-160.5°C.

Example 4 The method of Example 3 may be repeated starting with a compound of the formula wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl 10 and benzyl; R‘ alkyl of 2 to 4 carbon atoms and —Cj—R wkere R is methyl, ethyl or phenyl to yield a ganma-pyrana of the formula wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl 15 or benzyl.

Example 5 The method of Example 3 may be repeated with comparable results replacing acetic acid with each of the following solvents; - 11 4SG42 formic acid methanol ethanol tetrahydrofuran 5 benzene ethylene glycol trifluoroacetic acid acetone acetonitrile Example 6 The method of Example 3 may be repeated with comparable results replacing chlorine with bromine, sodium or potassium hypochlorite or hypobromite, gaseous chlorine-bromide or chlorine-bromide prepared in situ by the addition of chlorine to a solution containing sodium bromide or bromine to a solution of sodium chloride.

Claims

1. A process for preparing a gamma-pyrone of the general formula: 5 which comprises treating a compound of the general formula: wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R' is hydrogen, alkyl of 1 to 4 carbon atoms or -C-R wherein R is methyl, ethyl or phenyl; and R' is 10 Cl hydrogen or alkyl of 1 to 4 carbon atoms; with 1 equivalent of a halogen oxidant and heating at 7O-16O°C to hydrolyse the product.

2. A process as claimed in claim 1 substantially as 15 hereinbefore described with reference to Examples 3 to 6.