IE45645B1

IE45645B1 - Process for the preparation of 6-alkoxy and 6-acyloxy-4-halo-2h-pyrones and their use in the synthesis of gamma-pyrones

Info

Publication number: IE45645B1
Application number: IE587/79A
Authority: IE
Original assignee: Pfizer
Priority date: 1976-08-02
Filing date: 1977-07-29
Publication date: 1982-10-20
Also published as: DK153483C; IE790587L; EG13080A; NO151365C; PT66694A; FI831702A0; NO150042C; ES470744A1; ES459994A1; HU186026B; FI831701A0; HK30381A; CH625798A5; TR19652A; IE790585L; NO151365B; NO150559B; DK326186A; YU146977A; SU1015826A3

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-pyrones 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-alkoxy and 6-acyloxy5 4-halo-2H-pyran-3(6H)one intermediates for use in the process, According to Patent Specification No. 45642 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 R‘ is hydrogen or alkyl of 1 to 4 carbon atoms which comprises treating a compound of the formula: ζγ° A Λ 0/. 0 R (IV) - 3 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 -C-R wherein R is methyl, ethyl or phenyl; and R' is # hydrogen or alkyl of 1 to 4 carbon atoms, with 1 equivalent 5 of a halogen oxidant and heating at 7O-16O°C to hydrolyse the product The intermediate 4-halogeno-6-substituted-2H-pyran-3(6H)one may also be isolated and hydrolysed in a separate Step, thus according to the present invention there is provided a process for preparing a compound of the general formula: wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl; R' is hydrogen, allyl of 1 to 4 carbon atoms or -C-R wherein R is methyl, ethyl or phenyl; R‘ is hydrogen I or alkyl of 1 to 4 carbon atoms; and X is bromine, or chlorine 15 which comprises contacting a compound of the formula (IV) in a reaction inert solvent at a temperature of -50 to 50°C with at least one equivalent of a halogen oxidant selected from chlorine, bromine, chlorine-bromide, hypochlorous acid, hypobromous acid or mixtures thereof in the presence of an organic base until the reaction is substantially complete.

Suitable reaction-inert solvents are water, alkanols or diols of 1 to 4 carbon atoms, ethers and nitriles of 2 to 6 4 3 - 4 10 carbon atoms, and ketones, esters and amides of 3 to 10 carbon atoms.

Excess halogen oxidant may be employed but for optimum results and efficiency of operation 1 equivalent is used. The 4-halo-dihydropyran of formula (V) may be prepared and isolated by conducting the halogenation at about -20 to 20°G., preferably 5-I0°C., in the presence of an organic base such as triethylamine. After about 30 minutes the reaction mixture is allowed to warm to room temperature, filtered to remove triethylamine hydrochloride and the solvent removed under vacuum to yield the 4-halodihydropyran of formula (V). Hydrolysis of the 6-hydroxy4-halo-dihydropyrans of formula (V) where R' is hydrogen to yield gamma-pyrones is described and claimed in Patent Specification No. 45644.

According to the present invention there is provided a process for the preparation of a gamma-pyrone of the formula (I) which comprises hydrolysis of a 4-halogeno intermediate, of formula (V) wherein R' is alkyl of 1 to 4 carbon atoms or -g-R, wherein R is methyl, ethyl or phenyl by heating in aqueous solution until hydrolysis is substantially complete. 6-Alkoxy-2H-pyran-3(6H)-ones of formula (IV) where R is alkyl of 1 to 4 carbon atoms are prepared by the method of Patent Specification No. 42789. A β-acyloxy compound of formula (IV) where R' is -COR and R is methyl, ethyl or phenyl may be prepared by conventional treatment of the 6hydroxy compound with the appropriate/anhydride in the presence of pyridine.

The hydrolysis reaction is performed with the 4- 5 43645 halogeno-6-acyloxy or 6-alkoxy~2H-pyran~3(6H)-one dissolved in a reaction-inert solvent selected from acetic acid, formic acid, trifluoroacetic acid, halogenated solvents, C2 to nitriles and ethers, to C4 alkanols or diols, and C3 to C^Q ketones, esters and amides. The preferred solvents are acetic acid, formic acid or methanol, and the reaction mixture is heated to 7O-16O°C., generally 1OO-11O°C., until the conversion to the desired gamma-pyrone is substantially complete (approximately 1-3 hours). The gamma10 pyrone may be obtained from the cooled, neutralized reaction mixture on standing or by extracting the reaction mixture with a solvent such as chloroform which yields the gammapyrone 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 as necessary and is added for the conversion of the formed 4-halogeno-6-substituted-2H-pyran20 3(6H)-one to the γ -pyrone.

Certain 4-halo-dihydropyran intermediates of the formula: R'O 436 ·1ΰ - 6 wherein R is ethyl; R' is alkyl of 1 to 4 carbon atoms or -C-R wherein R is methyl, ethyl or phenyl; R' is hydrogen IL or alkyl of 1 to 4 carbon atoms; and X is chlorine or bromine are novel compounds according to the invention.

The process for the preparation of the compounds of the formula (V) and their conversion to gamma-pyrones is illustrated by the following Examples:Example 1 4-chloro-6-methoxy-2-methyl-2H-pyran-3(6H)-one To a solution of 6-methoxy-2-methyl-2H-pyran-3(6H)one (0.05 mole) in 70 ml of dichloromethane at -10°C. was added chlorine (0.05 mole) via a gas inlet tube. Following this addition, triethylamine (0.05 mole) was added slowly maintaining the temperature at -10°C. After 30 minutes of stirring the reaction mixture was allowed to warm to room temperature, filtered to remove triethylamine hydrochloride ana the solvent removed under vacuum. Redissolving the crude product in ether-benzene and filtration removed the last traces of triethylamine hydrochloride. Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2H-3(6H)-one (yield, 99%). NMR analysis of the signals at 5.05 to 5.25 clearly showed two doublets in a 3 to 1 ratio corresponding to the proton at C-6 of the two possible isomers of the compound. Both optical forms of the trans isomer had been synthesized from a carbohydrate precursor by Paulsen, Eberstein and Koebernick, Tetrahedron Letters 4377 (1974).

Example 2 4-bromo-6-methoxy-2-methyl-2H-pyran-3(6H)-one The method of Example 1 was repeated replacing chlorine v/ith bromineto obtain 4-bromo-6-methoxy-2-methyl-2H-pyran- 7 4564S 3(6H)-one in 93% yield. The two optical forms of the trans isomer had been synthesized by Paulsen and co-workers. Tetrahedron Letters 4377 (1974).

Example 3 The methods of Examples 1 and 2 may be repeated starting with a compound of the formula: wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl; R’ is alkyl of 2 to 4 carbon atoms to yield a compound of the formula wherein R and R' are as defined above; and X is chlorine or bromine.

Example 4 4-bromo-6-acetoxy-2H-pyran-3(6H)-one A solution of dichloromethane of 6-acetoXy-2H-pyran‘3(6H)-one, prepared by the method described in Tetrahedron 27, 1973 (1971), was brominated by the method of Example 2 to yield 4-bromo-6-acetoxy-2H-pyran-3(6H)-one, mp 78-8O°C. 6 Ί 5 - 8 The mass spectrum of the compound showed the expected parent peaks at 234 and 236 mass units.

Example 5 4-bromo-6-acetoxy-2-methyl-2H-3(6H)-one 5 The method of Example 4 was repeated with 6-acetoxy2-methyl-2H-pyran-3(6H)-one to yield 4-bromo-6-acetoxy-2methyl-2H-3(6H)-one which showed parent masses of 249.96 and 247.96 by mass spectroscopy and the following NMR spectrum: (δ, CDCl3): 7.3(lH,d>; 6.4(lH,d of d); 4.7(1H,Q); 2.2(3H,S); 1.4(3H,S).

Example 6 The method of Example 1 may be repeated starting with a compound of the formula wherein R is hydrogen, alkyl Of 1 to 4 carbon atoms, phenyl or benzyl? R' is alkyl of 1 to 4 carbon atoms or -C-R where a R is methyl, ethyl or phenyl to yield a compound of the formula - 9 wherein R and R‘ are as defined above and X is chlorine.

Example 7 To a round bottom flask equipped with a stirring bar and a condenser was added 4-chloro-6-methoxy-2-methy1-2H5 pyran-3(6H)-one and acetic acid and the reaction mixture heated to reflux for ap hour. Maltol (65%) was obtained on cooling.

Example 8 The method of Example 7 was repeated with comparable results adding formic acid in place of acetic acid.

Example 9 The method of Example 7 may be repeated starting with a compound of the formula wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl 15 or benzyl; R' is alkyl of 1 to 4 carbon atoms or -C-R where R s is methyl, ethyl or phenyl; X is bromine or chlorine to yield a compound of the formula 645 - 10 where R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl

Claims

1. A process for preparing a compound of the formula wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl 5 or benzyl; R' is hydrogen, alkyl of 1 to 4 carbon atoms or -fj-R wherein R” is methyl, ethyl or phenyl; R‘ is hydrogen 0 or alkyl of 1 to 4 carbon atoms; and X is bromine, or chlorine which comprises contacting a compound of the formula 10 where R, R* and R' are as previously defined in a reactioninert solvent at a temperature of -50 to 50°Cwith at least one equivalent of a halogen oxidant selected from chlorine, bromine, chlorine-bromide, hypochlorous acid, hypobromous acid or mixtures thereof in the presence, of an organic base.until 15 the reaotion is substantially complete.

2. The process of claim 1 wherein said reaction-inert solvent is selected from water, alkanols or diols of 1 to 4 o645 -12 4 carbon atoms, ethers and nitriles of 2 to 10 carbon atoms, and ketones, esters and amides of 3 to 10 carbon atoms.

3. A process for preparing a gamma-pyrone of the formula 5 which comprisas heating at 70 to 160°C in aqueous solution until hydrolysis is substantially complete a compound of the formula wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl 10 or benzyl? R' is alkyl of 1 to 4 carbon atoms or -C-R wherein R is methyl, ethyl or phenyl; R 1 is hydrogen or alkyl of 1 to 4 carbon atoms; and X is chlorine or bromine. A compound of the general formula

4. - 13 4S645 wherein R is ethyl; R' is alkyl of 1 to 4 carbon atoms or -C-R wherein R is methyl, ethyl or phenyl; R' is hydrogen i or alkyl of 1 to 4 carbon atoms; and X is chlorine or bromine.

5. 5. A process as claimed in claims 1 to 3, substantially as hereinbefore described with reference to the Examples.