CH626357A5 - Process for the preparation of 4-halodihydropyranones - Google Patents

Abstract

The compounds of formula II' - the meaning of the symbols used is explained in Claim 1 - are obtained by subjecting a furfuryl alcohol of formula III to a halogenating oxidation in the presence of water, at a temperature of between -50 DEG and +50 DEG C, and in one or two stages. The halogenated oxidising agent is chosen from chlorine, bromine, bromine chloride, hypochlorous acid, hypobromous acid and their mixtures. The compounds obtained are intermediates and lend themselves, by virtue of possessing various reactive centres, to many syntheses such as that of maltol. <IMAGE>

Description

This invention relates to the preparation of novel 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), indicated the synthesis of maltol from protected carbohydrate derivatives, s Shono and Matsumura,“ 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 sweet aromatic components characteristic of the 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 y-pyrones such as pyromeconic acid, is maltol, ethylmaltol and other 3-hydroxy-y-pyrones substituted in 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 2-alkenylpyromeconic acids described in US Patent No. 3644635 and the 2-arylmethylpyromeconic acids described in US Patent No. 3365469 inhibit the growth of bacteria and fungi and are useful as flavor and flavor enhancers aroma in foods and beverages and as flavor enhancers in perfumes.

The object of the present invention is to provide a process for the preparation of new pyrannones which are useful as intermediate products, in particular in the preparation of the compounds mentioned above.

These compounds correspond to the formula

(IV ')

(II ')

where 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, and X is chlorine or bromine.

The compound of formula (II ′) can be prepared above by reacting a compound of formula:

(IV)

55 in which R, 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 the solvents suitable 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 intermediate compound of formula (IV) above can be prepared by reacting a furfuryl alcohol of formula

3

626357

OH

R '

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 an ambient temperature of -50 to + 50 ° C., preferably at ambient 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 compound of formula (II ').

Alternatively, the 4-halo-dihydropyrannone of formula (II ') is 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 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.

The complete scheme of the reactions according to the invention is shown below:

oxidant

R

R1 '

OH

OH

(III)

R "'C = 0

CH (IV ')

halogenated oxidant

open chain tautomer

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 use of an aqueous solution of a halogenated oxidizing agent is decisive for the process for preparing the intermediates of the present invention. A furfuryl alcohol can be properly oxidized to 6-hydroxy-2H-pyran-3 (6H) -one using an equivalent of a halogenated oxidizing agent in water or in a mixture of water and organic solvent. We can consider a 6-hydroxy-2H-pyran-3 (6H) -one as the hemiacetal of an aldehyde and, therefore, we would think that it would undergo many unwanted side reactions, such as overoxidation or aldolic condensations. Using two equivalents of a halogenated oxidizing agent in water or a mixture of water and an organic solvent, the reaction is carried out regularly from a furfuryl alcohol to a y-pyrone. This new one-step process has the advantages of using low-cost products Cl2, Br2, BrCl, HOC1, HOBr or their mixtures, as halogenated oxidizing agents.

The process is carried out in one step by dissolving a furfuryl alcohol in water or in a mixture of water or a cosolvent. The cosolvent can be miscible or immiscible with water and can be chosen from a wide range of solvents, such as alkanols or diols in CrC4, for example methanol; C2-C10 ethers, for example tetrahydrofuran or isopropyl ether; low molecular weight ketones, for example acetone; low molecular weight nitriles; low molecular weight esters and low molecular weight amides. The preferred cosolvents are the C 1 -C 4 alkanols and the C 2 -C 10 ethers, methanol being the solvent of choice because of the price. The solution is maintained at a temperature of -50 to + 50 ° C, preferably of -10 to + 10 ° C. In this solution, the desired furfuryl alcohol is introduced, while simultaneously adding a halogenated oxidizing agent (two equivalents) to the mixture. The temperature of the reaction mixture is maintained at a value of -50 to + 50 ° C, preferably of -10a + 10 ° C, during the addition of the halogenated compound. If a low-boiling cosolvent is used, it is removed by elimination after all additions have been completed.

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 (CHI, 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.

As described above, the 6-hydroxy-2H-pyran-3 (6H) -one intermediate of formula (IV ') can be prepared by reacting the appropriate furfuryl alcohol with an equivalent of a halogenated oxidizing agent. The isolated intermediate is easily transformed into 4-halo-6-hydroxy-2H-pyran-3 (6H) -one of the desired formula (II ') by reacting it with an additional equivalent of a halogenated oxidizing agent.

Alternatively, a furfuryl alcohol in aqueous solution can be reacted with an optional co-solvent at a temperature of -10 to + 10 ° C with two equivalents of a halogenated oxidizing agent. After stirring at room temperature for 30 min, the pH of the reaction mixture is adjusted to 2 with a strong base and the reaction mixture is extracted with a solvent such as ethyl acetate. Removal of the solvent provides 4-halo-6-hydroxy-2H-pyran-3 (6H) -one of formula (II ').

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 s

m

15

20

25

30

35

40

45

50

55

60

65

626357

4

Example 1:

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

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 (CHCI3) 3700,3300,1700 cm- ';

NMR (CDC13.8): 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).

Example 2:

The process of Example 1 is repeated with a furfuryl alcohol of

NMR (CDCI3, f (3H, m)

17.3 (1H, d); 5.6 (1H, d); 4.7-5.0 (1H, q); 1.1-1.5

formula

// w to obtain a compound of formula where R is a hydrogen atom or an ethyl group.

Ethyl compound: IR (CHC13) 3600,3340,1706 cm-i

Hydrogenated compound: IR (CHCI3) 3565, 3300.1703 cm-1

Example 3:

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

To a solution of 25 g of 1- (2-furyl) -l-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 0-5 ° C, 2.2 equivalents of bromine are added dropwise. During the whole addition, the temperature is maintained at 5-10 ° C. After the addition of bromine, the solution is stirred at room temperature for 30 min and the pH is adjusted to 2.1 with a 2N sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate (3 x 100 ml). The ethyl acetate extracts are combined, dried over MgSO4, filtered and brought to dryness. The residue is chromatographed on silica gel and eluted with a 95/5 mixture of chloroform and ethyl acetate. The product is an orange oil which is rechromatographed on silica gel, eluting with a 95/5 mixture of chloroform and ethyl acetate.

Example 4:

The procedure of Example 15 is repeated with a furfuryl alcohol of formula to obtain a compound of formula

X

where R is a hydrogen atom or an ethyl group.

Ethyl compound: 4-bromo-6-hydroxy-2-ethyl-2H-pyran-3 (6H) -one;

NMR (CDCl3, S) 7.4 (1H, d); 4.6-4.9 (1H, m); 1.8-2.2 (2H, m); 1.0-1.3 (3H, t).

Hydrogenated compound: 4-bromo-6-hydroxy-2H-pyran-3 (6H) -one; NMR (CDCI3.8) 7.4 (1H, d); 5.5 (1H, d); 4.6 (2H, d of d).

30 Example 5:

The process of Example 3 is repeated, using chlorine instead of bromine and the appropriate furfuryl alcohols, to obtain the following compounds:

Methylated: 4-chloro-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one; NMR (CDCl3, S): 7.1 (1H, d); 5.8 (1H, d); 4.6-5.0 (1H, m); 4.4 (1H, s la); 1.2-1.5 (3H, m).

Ethylated: 4-chloro-6-hydroxy-2-ethyl-2H-pyran-3 (6H-one; NMR (CDCl3> 8): 7.0-7.1 (1H, d); 5.6-6, 0 (2H, m); 4.4-5.0 (1H, m); 1.6-2.1 (2H, m); 0.9-1.1 (3H, t).

40 Hydrogenated: 4-chloro-6-hydroxy-2H-pyran-3 (6H) -one;

NMR (CDCI3.8): 7.1-7.2 (1H, d); 5.6 (1H, d); 4.4-4.9 (2H, d of d) (D20 added).

Example 6:

45 The process of Example 3 is repeated to obtain a compound of formula

55 in which R is a propyl, butyl, phenyl or benzyl group; X is chlorine or bromine.

Claims (4)

626,357 CLAIMS 1. Process for the preparation of a compound of formula X R1 (II ') 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 and X is chlorine or bromine, characterized in that it consists in reacting a compound of formula OH (III) in which R and R '"are as defined above, in aqueous solution at a temperature of -50 to + 50 ° C, with at least two equivalents of a halogenated oxidizing agent chosen from chlorine, bromine, chloride of bromine, hypochlorous acid, hypobromous acid or mixtures thereof, until the reaction is essentially complete. 2. Process for the preparation of a compound of formula II ', defined in claim 1, characterized in that the furfuryl alcohol of formula III is first reacted in aqueous solution with at least one equivalent of the agent halogenated oxidant according to claim 1, at a temperature between - 50 and + 50e C, to obtain a substituted 2H-pyran-3 (6H) -one 6- of formula 0 R . . , 7 ^ 0 R OH as an intermediate, which is then reacted in situ, in a solvent and at a temperature between - 50 and + 50 ° C, with at least one equivalent of one of the halogenated oxidizing agents defined above, until the reaction is essentially complete. 3. Method according to claim 2, characterized in that the solvent is water, an alkanol or a diol having from 1 to 4 carbon atoms, a C2 to C10 ether or a ketone, a nitrile, an ester or a low molecular weight amide. 4. Method according to claim 3, characterized in that the solvent is methanol, tetrahydrofuran, isopropyl ether or acetone.