CH626358A5 - Process for the preparation of 4-halodihydropyranones - Google Patents

Abstract

The compounds of formula II are obtained by reaction of a corresponding compound unsubstituted in position 4 with a halogenating agent, namely chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or their mixtures. The reaction takes place in a solvent such as water, a C1 to C4 alcohol or diol, a C2 to C10 ether, or a low molecular weight ketone, nitrile, ester or amide, at a temperature between -50 DEG and +50 DEG C. The symbols used in the formula II are explained in Claim 1. The compounds obtained are useful starting materials for organic syntheses, for example the preparation of maltols. <IMAGE>

Description

626,358

CLAIMS 1. Process for the preparation of a compound of formula

X

R '

R'o

in which R is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, phenyl or benzyl, R 'is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms or - COR ", where R "is a methyl, ethyl or phenyl group, R" 'is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms and X is chlorine or bromine, characterized in that it consists in reacting a compound of formula position 2 is described in US Patents Nos. 3130204;

3133089; 3140239; 3159652; 3365469; 3376317; 3468915; 3440183 and 3446629.

Maltol and ethylmaltol enhance the flavor and aroma of various food products. In addition, these compounds are used as ingredients in perfumes and essential oils. The (II) 2-alkenylpyromeconic acids described in US Pat. No. 3,644,635 and the 2-arylmethylpyromeconic acids described in US Patent No. 3,365,469 inhibit the growth of bacteria and fungi and are useful as flavor enhancers and flavor in foods and beverages and as flavor enhancers in perfumes.

The present invention provides a process for the preparation of a 4-halo-dihydropyrannone of formula (II)

(IV)

R'o

in which R, R 'and R' "are as defined above, in a solvent at a temperature of -50 to + 50 ° C. with at least one equivalent of a halogenated oxidizing agent chosen from chlorine, bromine, chloride of bromine, hypochlorous acid, hypo-bromous acid or mixtures thereof, until the reaction is essentially complete.

2. Method according to claim 1, characterized in that the solvent is water, an alkanol or a diol of 1 to 4 carbon atoms, an ether of 2 to 10 carbon atoms or a ketone, a nitrile, an ester or a low molecular weight amide.

3. Method according to claim 1 or 2, characterized in that R is an ethyl group and R 'is an alkyl group from 1 to

4 carbon atoms or —COR "where R" is a methyl, ethyl or phenyl group, and R '"and X are as defined in claim 1.

This invention relates to the preparation of novel intermediate 4-halo-dihydropyrannones.

Maltol (2-methyl-3-hydroxy-4H-pyran-4-one) is a natural substance found in the bark of young larches, pine needles and chicory. Ancient industrial production used destructive wood distillation. The synthesis of maltol from 3-hydroxy-2- (1-piperidylmethyl) -1,4-pyrone is described by Spielman and Freifelder, "J. Am. Chem. Soc. ”, 69.2908 (1947). Schenck and Spielman, "J. Am. Chem. Soc. ”, 67,2276 (1945), obtained maltol by alkaline hydrolysis of streptomycin salts. Chawla and McGonigal, "J. Org. Chem. ", 39, 3281 (1974) and Lichtenthaler and Heidel," Angew. Chem. ”, 81.998 (1969), reported the synthesis of maltol from protected carbohydrate derivatives. Shono and Matsumura, "Tetrahedron Letters", No. 17,1363 (1976) describe a five-step synthesis of maltol from methyl furfuryl alcohol.

The isolation of 6-methyl-2-ethyl-3-hydroxy-4H-pyran-4-one as one of the sweet aromatic components characteristic of final refinery molasses has been described by Hiroshi Ito, "Agr. Biol. Chem. ”, 40 (5), 827-832 (1976). This compound had previously been synthesized according to the method described in US Patent No. 3,468,915.

The synthesis of v-pyrones such as pyromeconic acid, maltol, ethylmaltol and other 3-hydroxy-v-pyrones substituted in

(II)

wherein R is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, phenyl or benzyl, R 'is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms or - COR " , where R "is a methyl, ethyl or phenyl group, R '" is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X is chlorine or bromine.

The compound of formula (II) above is prepared by reacting so a compound of formula

.0

(IV)

wherein R, R 'and R' "are as defined above, in a solvent at a temperature of -50 to + 50 ° C, preferably at room temperature, with at least one equivalent of a halogenated oxidizing agent chosen from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or their mixtures, until the reaction is essentially complete.

Examples of suitable solvents for this reaction are water, an alkanol or diol of 1 to 4 carbon atoms, preferably methanol, an ether of 2 to 10 carbon atoms, preferably tetrahydrofuran or isopropyl ether , a lower molecular weight ketone, preferably acetone, a nitrile, an ester or an amide of lower molecular weight.

The starting compound of formula (IV) above can be prepared by reacting a furfuryl alcohol of formula

R

<

OH R

(III)

in which R and R '"are as defined above, in aqueous solution with at least one equivalent of a halogenated oxidizing agent chosen from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or their mixtures, at one

60 temperature from -50 to + 50 ° C, preferably at room temperature Until the reaction is essentially complete. The reaction can be carried out in the presence of a cosolvent which may be one of the solvents mentioned above for the preparation of the intermediate compound of formula (II).

65 If desired, the intermediate 4-halodihydropyrannone of formula (II) can be prepared directly from a furfuryl alcohol of formula (III) by reacting the latter in an aqueous solvent at a temperature of - 50 to + 50 ° C, with at least

3

626,358

two equivalents of one of the aforementioned halogenated oxidizing agents until the reaction is essentially complete.

In each of the reactions described above, the preferred halogenated oxidizing agent is chlorine or bromine chloride.

Lefebvre et al., In “J. Med. Chem. ”, 16.1084 (1973) have shown that furfuryl alcohols can be directly transformed into 6-hydroxy-2H-pyran-3 (6H) ones when a peracid such as peracetic acid or m-chloroperbenzoic acid. The first step of this process uses a peracid in an organic solvent and probably leads to a 6-acetoxy or 6-m-chlorobenzoyloxypyran derivative which is hydrolyzed to the 6-hydroxyl derivative during the aqueous treatment. Water is not used in the first step of the reaction and would in fact be harmful. In any case, the method of Lefebvre et al. cannot directly lead to the transformation of a furfuryl alcohol into a y-pyrone.

The halogenated oxidizing agent is chosen from chlorine, bromine, bromine chloride, hypochlorous or hypobromous acid or their mixtures. Bromine chloride is a commercially available gas. 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.

Hypochlorous or hypobromous acid can conveniently be formed in situ by adding aqueous acid (FC1, H2SO4 or HBr) to a solution of an alkali metal or alkaline earth metal hypochlorite or hypobromite, for example NaOCl , KOC1 or Ca (OCl) 2. Preferred halogenated oxidizing agents, for cost reasons, are chlorine and chlorine bromide prepared in situ.

6-Alkoxy-2H-pyran-3 (6H) -one can be prepared by the method described in "Tetrahedron Letters", No. 17,1363-1364 (1976). Anodic alkoxylation of a furfuryl alcohol to 2- (1-hydroxyalkyl) -2,5-dialkoxy-dihydrofuran is carried out. Treatment with a strong organic acid provides the desired 6-alkoxylated derivative. A 6-hydroxylated derivative can be prepared by conventional treatment of the 6-hydroxylated compound with the appropriate anhydride in the presence of pyridine.

A 6-acyl- or 6-alkoxy-2H-pyran-3 (6H) -one is dissolved in a solvent chosen from acetic acid, formic acid, trifluoroacetic acid, halogenated solvents, ethers, C1-C4 alkanols or diols, or ketones, nitriles, esters or lower molecular weight amides. The preferred solvent is acetic acid, formic acid or methanol. Adding at room temperature an equivalent of a halogenated oxidizing agent chosen from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid or their mixtures, at room temperature, and the mixture is heated reaction at 70-160 ° C, generally at 100-110 ° C, until the transformation into the desired y-pyrone is essentially complete (about 1 to 3 h). The y-pyrone can be obtained from the neutralized and cooled reaction mixture by standing or by extracting the reaction mixture with a solvent such as chloroform, which gives the y-pyrone by concentration.

When using organic acids or other protonic solvents such as formic acid, acetic acid, other organic acids and alkanols which have not been thoroughly dried, no additional water should be added in the reaction described above. However, with non-protonic solvents, water is necessary and is added for the transformation of the 4-halo-2H-pyran-3 (6H) -one substituted in the intermediate 6 position into py-rone. When a solvent with a low boiling point is used in the reaction, it is distilled off just before heating the reaction mixture to 100-110 ° C, for the hydrolytic transformation of the intermediate 4-halodihydropyran into y-pyrone.

If desired, 4-halodihydropyran can be prepared and isolated by carrying out the halogenation at a temperature of -20 to + 20 ° C, preferably 5 to 10 ° C, in the presence of an organic base such as triethylamine. After about 30 min, the reaction mixture is allowed to warm to room temperature, filtered to remove the triethylamine hydrochloride and the solvent is removed in vacuo to obtain 4-halodihydropyran. This compound is easily hydrolyzed to y-pyrone by heating it for approximately 1 h in aqueous solution, adding acid if necessary, preferably at a temperature between 70 and 160 ° C, better still between 100 and 110 ° C.

This process in which the 6-acyl- or 6-alkoxy-2H-pyran-3 (6H) -one is reacted in an organic solvent with an equivalent of a halogenated oxidizing agent and in which the intermediate 4-halodihydropyran is heated up to 'to a practically total transformation into the desired y-pyrone, differs from the multistage process described by Shono and Matsumura in "Tetrahedron Letters", 17, 1363 (1976), in which 6-alkoxy-2H-pyran-3 is treated (6H) -one with a methanolic solution of hydrogen peroxide or a solution of sodium hydroxide to obtain an epoxyketone. The isolated epoxyketone is then heated in water with a Dowex 50 ion exchange resin to obtain the desired y-pyrone.

The following examples illustrate the preparation of y-pyrones according to the process of this invention, and the preparation of various intermediate compounds.

In the examples where the spectral data are given, the chemical displacements in NMR are indicated with the symbols common in the literature, and all the displacements are expressed in S starting from tetramethylsilane:

s = singlet d = doublet t = triplet q = quartet m = multiplet la = large

Preparation 1

6-Hydroxy-2-methyl-2H-pyran-3 (6H) -one (IV)

To a solution of 25 g of 1- (2-furyl) -l-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 5 ° C., an equivalent of bromine is added. The temperature is maintained at 5-10 ° C throughout the addition. The pH of the solution is adjusted to 2.1 and the solution is extracted with ethyl acetate (3 x 50 ml). The ethyl acetate extract is dried and evaporated to give a yellow oil. The oil is chromatographed on silica gel and eluted with a 3/1 mixture of chloroform and ethyl acetate, which gives 4.8 g of clear oil, the spectral data of which show that it is identical to 6-hydroxy-2-methyl-2H-pyran-3 (6H) -one prepared by acid hydrolysis of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one ["Tetrahedron Letters" , 27.1973 (1971)].

IR (CHC13) 3700,3300.1700 cm "1

NMR (CDClj, S): 6.8-7.1 (1H, d of d); 6.0-6.2 (1H, d), 5.6 (1H, s la, exchanges with D2 o); 5.4-5.5 (1H, d); 4.8-5.0 (1H, q); 1.3-1.6 (3H, t).

Preparation 2

The process of Preparation 1 is repeated with a furfuryl alcohol of formula

OH

to get a compound of formula

O

where R is a hydrogen atom or an ethyl group.

Ethyl compound: IR (CHC13) 3600, 3340.1706 cm-1 Hydrogenated compound: IR (CHC13) 3565, 3300.1703 cm-1

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626358

4

Example 1:

A solution of 0.01 mol of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one in 20 ml of acetic acid is treated with 0.01 mol of chlorine gas at room temperature.

Example 2:

The procedure of Example 1 is repeated, starting from a compound of formula

-O

R'O "

where R is a hydrogen atom or an alkyl group having from 2 to 4 carbon atoms, phenyl or benzyl; R 'is an alkyl group having 2 to 4 carbon atoms or —COR "where R" is a methyl, ethyl or phenyl group.

Example 3:

The procedure of Example 1 is repeated with comparable results, replacing the chlorine with bromine, hypochlorite or hypobromite of sodium or potassium, bromine chloride gas or bromine chloride prepared in situ by addition. chlorine to a solution containing sodium bromide or by adding bromine to a solution of sodium chloride.

Example 4:

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

To a solution of 0.05 mol of 6-methoxy-2-methyl-2H-pyran-3 (6H) -one in 70 ml of dichloromethane at - 10 ° C, 0.05 mol of chlorine is added by a tube gas inlet. After this addition, 0.05 mol of triethylamine is added slowly while maintaining the temperature at -10 ° C. After 30 min of stirring, the reaction mixture is allowed to warm to ambient temperature, it is filtered to remove the triethylamine hydrochloride and the solvent is removed in vacuo. Redissolution of the crude product in a mixture of ether and hexane and filtration remove the last traces of triethylamine. Removal of the solvent gives 4-chloro-6-methoxy-2-methyl-2H-pyran-3 (6H) -one (99% yield).

NMR analysis with signals at 5.05-5.25 clearly shows two doublets in a 3/1 ratio corresponding to the C-6 proton of the two possible isomers of the compound. The two optical forms of the trans isomer have been synthesized from a carbohydrate precursor by Paulsen, Eberstein and Koebernick, "Tetrahedron Letters", 4377 (1974).

Example 5:

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

The procedure of Example 4 is repeated, replacing the chlorine with the bromine to obtain 4-bromo-6-methoxy-2-methyl-2H-pyran-3 (6H) -one with a yield of 93%. The two optical forms of the trans isomer have been synthesized by Paulsen et al., "Tetrahedron Letters", 4377 (1974).

Example 6:

The procedure of Examples 4 and 5 is repeated respectively, starting from a compound of formula

.0

R'O "R

in which R is a hydrogen atom or an alkyl group having from 2 to 4 carbon atoms, phenyl or benzyl and R 'is an alkyl group from 2 to 4 carbon atoms, to obtain a compound of formula

30

R'o

in which R and R 'are as defined above and X is chlorine or bromine.

20 Example 7:

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

A dichloromethane solution of 6-acetyl-2H-pyran-3 (6H) -one, prepared by the method described in "Tetrahedron Letters", 27.1973 (1971), is brominated to obtain 4-bromo-6 -acetyl-25 2H-pyran-3 (6H) -one, pf 78-80 ° C. The mass spectrum of the compound presents the parent peaks expected at 234 and 236 mass units.

Example 8:

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

The procedure of Example 7 is repeated with 6-acetyl-2-methyl-2Hpyran-3 (6H) -one and 4-bromo-6-acetyl-2-methyl-2H-pyran- is obtained. 3 (6H) -one which has parent peaks at masses of 249.96 and 247.96 by mass spectroscopy, and the following NMR spectrum: (8, CDC13): 7.3 (1H, d); 6.4 (1H, d of d); 4.7 (1H, Q); 2.2 (3H, S); 1.4 (3H, S).

Example 9:

The procedure of Example 4 is repeated using chlorine instead of bromine, starting from a compound of formula:

O

R'o

in which R is a hydrogen atom or a C1-C4 alkyl, phenyl or benzyl group, R 'is a Q-C + or - COR alkyl group "where R" is a methyl, ethyl or phenyl group, which gives a compound of formula

55

R'o

in which R and R 'are as defined above and X is chlorine.