CS203921B2 - Process for preparing gamma-pyrones - Google Patents

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. <IMAGE>

Description

The invention relates to a process for the preparation of γ-pyrons and in particular to the preparation of γ-pyrons by hydrolysis of certain products, some of which are prepared from the corresponding furfuryl alcohols using halogen-containing oxidizing agents.

Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) is a naturally occurring compound found in the bark of larch, pine needles and chicory. The first industrial production was the destructive distillation of wood. Synthesis of maltol from

3-hydroxy-2- (1-piperidylmethyl) -1,4-pyrone was reported by Spielman and Freifelder in J. Am. Chem. Soc., 69, 2908 (1947). Schenck and Spielman, J. Am. Chem. Soc., 67, 2276 (1945), obtained maltol by alkaline hydrolysis of strepromycin salts. Chawla and McGonigal, in J. Org. Chem. 39, 3281 (1974) and Lichtenthaler and Heidel, in Angew. Chem., 81, 998 (1969) report the synthesis of maltol from protected sugar derivatives. Shono and Matsumura, in Tetrahedron Letters No. 17, 1363 (1976), describe a five-step synthesis of maltol from methylfurfuryl alcohol.

The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one as one of the characteristic components of sweet aroma in molasses refining is reported in Hiroshi Ito, Agr. Biol. Chem., 40, (5), 827-832 (1976). This compound was previously synthesized as described in U.S. Patent 3,468,915.

The synthesis of γ-pyrons such as pyromeconic acid, maltol, ethylmaltol and other 2-substituted 3-hydroxy-γ-pyrones is described in U.S. Pat. Nos. 3130 204, 3133 089, 3 140 239, 3 159 652, 3 365 469, 3 376,317, 3,468,915, 3,440 183 and 3,446,629.

Maltol and ethylmaltol enhance the aroma and aroma of various food products. In addition, these compounds are useful as additives for perfumes and essences. The 2-alkenylpyromeconic acids disclosed in U.S. Patent No. 3,644,635 and the 2-arylmethylpyromeconic acids disclosed in U.S. Patent No. 3,365,469 inhibit bacterial and fungal growth and are useful for enhancing odor and flavor in foods and beverages and as flavor enhancers. perfume.

The invention relates to a process for the preparation of? -Pyrons of the general formula I

where

R. is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl;

R ’”. is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. 4 carbon atoms, characterized in that the 6-substituted-2H-pyran-3 (6H) -one, an intermediate of formula IV

(IV) wherein R and R "'are as defined above and R' is hydrogen, C 1 -C 4 alkyl or COR", wherein R "is methyl, ethyl or phenyl, reacted in an acidic aqueous solution with at least one equivalent of a halogen-containing oxidizing agent selected from the group consisting of chlorine, bromine, bromide, hypochlorous acid, hypobromic acid, or mixtures thereof. and optionally isolating the intermediate of formula (II)

where .R, R '.a. R ’”. are as defined above and X 'is an atom of chlorine or bromine, whereupon. the reaction mixture is heated at. a temperature in the range of 70 to 160. Until complete hydrolysis of the intermediate of formula II.

The acid required for the hydrolysis may be added to the reaction mixture, for example by dissolving an intermediate compound of formula. In aqueous inorganic or. organic. 'acid before. heating; or. Alternatively, it may. acid 'releasing in' 'sut' 'during. preparation of intermediates. . how . is described below.

The intermediate, compound 'of formula II' above 'can be prepared by reacting a compound of formula IV

wherein R, R 'and R' 'have the meaning given above in a solvent at a temperature of - 50 ° C to 50 ° C, preferably at room temperature with at least one equivalent. the halogen-containing oxidizing agent selected from the group consisting of chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or a mixture thereof until the reaction is complete.

Examples of suitable solvents for this reaction are water, C 1 -C 4 alkanol or diol, preferably methanol, C 2 -C 10 ether, preferably tetrahydrofuran. or isopropyl ether, a low molecular weight ketone, preferably acetone, a low molecular weight nitrile, ester or amide.

The intermediate compound of formula IV above may be prepared by reacting a furfuryl alcohol of formula III

(HD wherein R and R '' are as defined above in an aqueous solution with at least one equivalent of a halogen-containing oxidant selected from the group consisting of chlorine, bromine, bromine chloride, hypochlorous acid, hypobromic acid or mixtures thereof at a temperature from above The reaction is carried out in the presence of a solvent, which may be one of the solvents mentioned above for the preparation of the intermediate compound of formula II.

If desired, the intermediate 4-halo dihydropyran of formula II can be prepared directly from the corresponding furfuryl alcohol of formula III by reaction at -50 ° C to 50 ° C, with at least two equivalents of one of the aforementioned halogen-containing oxidizing agents. complete reaction.

In each of the above reactions, chlorine or bromine chloride is used as the halogen-containing oxidant.

Patents Nos. 203 922, 203 923, 203 924 and 203 925 describe the easy synthesis of γ-pyrons of the formula. I. above, 'namely' maltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds. without isolation of intermediates,. whereas . it is used as the starting material. furfuryl alcohol of formula III above.

In this procedure 'without. isolation of intermediates. furfuryl alcohol. in an aqueous medium. to respond. with two equivalents of oxidation. halogen-containing reagents. and the reaction mixture is then heated. wherein the 'intermediate' is 'hydrolysed'. . This process' without 'isolation' of intermediates can be illustrated by the following equation:

where 'R is'. hydrogen, C 1 -C 4 alkyl, phenyl or C 1 -C 4 alkyl; benzyl, R '' 'is a' hydrogen or C1-C4 alkyl 'and XY is C12, Br, CIBr, HOCl, HOBr or a mixture thereof. The overall reaction is shown in the following scheme:

203321

(III)

I CH i 0-0 i

H —COH i

R

open-chain tautomer

The following examples illustrate the preparation of the γ-pyrons of the invention and the preparation of various intermediates.

In the examples where spectral data is given, NMR shifts are reported in accordance with conventional symbols and all shifts are in δ units using tetramethylsylan as standard.

s = singlet d - doublet t = triplet q = quartet m = multiplet br = wide.

He did

A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyron-3 (6H) -one is prepared by dissolving the compound in either an aqueous, inorganic or aqueous organic acid. The solution was then heated to boiling, cooled to room temperature and adjusted to pH 2.1 with 6 N sodium hydroxide solution, then extracted with chloroform. Concentration yields maltol. The acids used, the reaction time and the yields of maltol are as follows:

acid concentration (%) reaction time (h) yield ('%) HCl 32 2 68 HCl 32 5 52 HCl 18 5 35 HCl 25 3 49 HBr 18 5 24 H2SO4 35 2 26 H3PO4 35 2 29 СНзСООН 35 2 69 CF3COOH 100 ALIGN! 3 36 HN03 35 3 0.4 CF3COOH 100 ALIGN! 3 70 СНзСООН 100 ALIGN! 3 77 нсоон 100 ALIGN! 3 24 H2SO4 35 5 48

Alternatively, solvents such as benzene and toluene may be used together with acidic materials such as p-toluenesulfonic acid and an ion exchanger ("Amberlite" IR 120).

Example 2

A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one (0.0025 mol) in 20 ml of 35% phosphoric acid was heated at reflux for 5 hours. Maltol (34%) was isolated as described in Example 1.

wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl. Comparative results are obtained.

Example 3

Example 5

A solution of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one (0.01 mol) in 20 mL acetic acid was treated with chlorine gas (0.01 mol) at room temperature. The reaction mixture was then heated under reflux for one hour, cooled to room temperature, diluted with 20 ml of water, adjusted to pH 7.0 by addition of 50% sodium hydroxide, and extracted with chloroform. The chloroform extract is concentrated and the resulting maltol is recrystallized from methanol to give the pure product (56%), m.p.

160.5 ° C.

Example 4

The procedure of Example 3 was repeated using the starting compound of the formula

where R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl, R 'is alkyl of 2 to 4 carbon atoms or “COR”, where R ”is methyl, ethyl or phenyl to give the χ-pyran of formula

The procedure of Example 3 is repeated and comparable results are obtained when acetic acid is replaced with any of the following solvents:

formic acid methanol ethanol tetrahydrofuran benzene ethylene glycol trifluoroacetic acid acetone acetonitrile

Example 6

The procedure of Example 3 is repeated and comparable results are obtained when chlorine is replaced by bromine, sodium or potassium hypochlorite, sodium or potassium bromate, bromine gas or bromine prepared in situ by adding chlorine to a solution containing sodium bromide or bromine to sodium chloride solution. .

Example 7

4-Chloro-6-methoxy-2-methyl-2 H -pyran-3 (6 H) -one

To a solution of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one (0.05 mol) in 70 ml dichloromethane at -10 ° C was introduced chlorine (0.05 mol) via a gas inlet. Triethylamine (0.05 mol) was then added slowly while maintaining the temperature at -10 ° C. After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature, triethylamine hydrochloride was removed by filtration, and the solvent was removed in vacuo. The crude product was redissolved in ether / benzene and the last triethylamine hydrochloride was removed by filtration. Removal of the solvent gave 4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one (yield 99%).

NMR analysis of the signals at 5.05 to 5.25 showed two 3: 1 doublets corresponding to the proton at position 6 of the two possible isomers of the compound. Both optical forms of the trans-isomer were synthesized from a sugar precursor [Paulsen, Eberstein and Koebernick, Tetrahedron Letters 4377 (1974)].

Example 8

4-Bromo-6-methoxy-2-methyl-2 H -pyran-3 (6 H) -one

The procedure of Example 7 was repeated by substituting chlorine for bromine to give 4-bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one in 93% yield. Two optical forms of the trans-isomer were synthesized by Paulsen et al., Tetrahedron Letters 4377 (1974).

Example 9

The procedures of Examples 7 and 8 were repeated using the compound of formula as starting compound

A solution of 6-acetyl-2H-pyran-3 (6H) -one in dichloromethane prepared by the method described in Tetrahedron 27, 1973 (1971) was brominated according to the procedure of Example 7 to give

4-bromo-6-acetyl-2H-pyran-3 (6H) -one, m.p. 78-80 ° C. The mass spectrum of the compound contains the expected base bands at 234 and 236 mass units.

Example 11

4-Bromo-6-acetyl-2-methyl-2 H -pyran-3 (6 H) -one

The procedure of Example 10 was repeated with 6-acetyl-2-methyl-2H-pyran-3 (6H) -one to give 4-bromo-6-acetyl-2-methyl-2H-pyran-3 (6H) -one. which, according to mass spectroscopy, contains bands at masses 249.96 and

247.96 and shows the following NMR spectrum: (δ, CDCl 3); 7.3 (1H, d), 6.4 (1H, dd), 4.7 (1H, Q), 2.2 (3H, S), 1.4 (3H, S).

Example 12

4-Chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one and acetic acid were added to a round-bottomed flask equipped with a condenser and the reaction mixture was heated at reflux for one hour. Cooling gave maltol (65%).

Example 13

The procedure of Example 12 was repeated with comparable results using formic acid instead of acetic acid.

Example 14

The procedure of Example 12 was repeated using the compound of formula

wherein R is hydrogen, alkyl of 2 to 4 carbon atoms, phenyl or benzyl and R 'is alkyl of 2 to 4 carbon atoms. As a product, a compound of the formula is obtained in a comparable result

wherein R and R 'are as defined above and X is a chlorine or bromine atom.

Example 10

4-Bromo-6-acetyl-2H-pyran-3 (6H) -one wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R 'is alkyl of 1 to 4 carbon atoms or a group —COR Where R "is methyl, ethyl or phenyl and X is a bromine or chlorine atom to give a compound of formula

wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl in a comparable result.

203821

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of? -Pyrons of the general formula I wherein R is hydrogen, C 1 -C 4 alkyl, phenyl or benzyl; R '' is hydrogen or C1-C4 alkyl, characterized in that the 6-substituted 2H-pyran-3 (6H) -one, an intermediate of formula IV (IV) wherein R and R '' have the above and R 'is hydrogen, C 1 -C 4 alkyl or the group "COR" where R "is methyl, ethyl or phenyl, is reacted in an acidic aqueous solution with at least one equivalent of halogen containing oxidizing agents selected from the group consisting of chlorine , bromine, bromochloride, hypochlorous acid, hypobromic acid or mixtures thereof, and optionally isolating the intermediate of formula II X o R (U) where R; R 'and R' are as defined above and X is chlorine or bromine, whereupon the reaction mixture is heated at a temperature in the range of 70 to 160 ° C until complete hydrolysis of the intermediate of formula II. 2. The method of item 1, for preparing γ-pyrons of formula IA O (IA) wherein R is as defined in point 1, characterized in that the 4-halo-dihydropyran of formula IIA wherein R, R 'and X are as defined in point 1 is heated at a temperature of from 70 ° C to 160 ° C, in an acidic aqueous solution until complete hydrolysis. 3. A process according to claim 1, wherein the isolated intermediate of formula (II) ## STR3 ## wherein R, R &apos;, R &apos; and X have the meanings given in item 1 is heated at 70-160 [deg.] C. solution until complete hydrolysis.