CS203922B2 - 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 young larch, pine needles and chicory. The first industrial production was the destructive distillation of wood. Synthesis of maltol from 3-hydroxy-2- (1-piperidylmethyl) -

I, 4-pyrone was introduced by Spielman and Freifelder v

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), disclose the synthesis of maltol from protected sugar derivatives. Shono and Matsumura, Tetrahedron Letters 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 No. 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. Patent Nos. 3,130,204, 3,133,089, 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

in aqueous acid ·· ®!

preferably in the thermal hydrolysis of 6.6 -? characterized in that it is heated in an aqueous acidic solution, with a temperature of 70 to 160 ° C, to

-oxybis [4-halo-2H-pyran-3 (6H) -one] of formula (V)

wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R '' is hydrogen or alkyl of 1 to 4 carbon atoms and X is chlorine or bromine.

The acid required for the hydrolysis may be added to the reaction mixture, for example by dissolving the compound of formula V, in aqueous inorganic or organic acid prior to heating, or alternatively, the acid may be released in situ during preparation as described below.

A compound of formula V can be prepared by dehydrating a compound of formula II.

X

where R and X are as defined above.

j In MS. No. 203,921 discloses the easy synthesis of γ-pyrons of formula I above, namely, maltol (2-methyl-3-hydroxy-4H-pyran-4-one) and related compounds by a process without isolation of intermediates using furfuryl alcohol as the starting material of formula III above. .

In this procedure, without isolation of the intermediates, furfuryl alcohol in an aqueous medium is treated with two equivalents of a halogen-containing oxidizing agent, and the reaction mixture is then heated to hydrolyze the resulting intermediate. This process without isolation of intermediates can be illustrated by the following formula:

wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R 'is hydrogen or alkyl of 1 to 4 carbon atoms and XY is C12, Brz, CIBr, HOC1, HOBr or a mixture thereof. The overall reaction is shown in the following scheme:

ai ")

R oxidizing agent

open-chain tautomer

D 41 -

R '~ C: O I C Γ7 I cm i C = O i H — COH I R

(I) open chain tautomer with

Lefebvre and collaborators J. Med. Chem., 16, 1084 (1973) have shown that furfuryl alcohols can be directly converted to 6-hydroxy-2H-pyran-3 (6H) -ones when a peracid such as peracetic acid or m-chloroperbenzoic acid is used as the oxidizing agent. The first step in Lefebre's work utilizes a peracid in an organic solvent and probably leads to a 6-acetoxy- or 6-m-chlorobenzoyloxy pyran derivative, which is then hydrolyzed to the 6-hydroxy compound during water treatment. Water is not used in the first stage of the reaction as it would adversely affect the course of the reaction. In any case, the procedure of Lefebvre and co-workers cannot directly lead to the conversion of furfuryl alcohol to χ-pyron.

The use of an aqueous halogen-containing oxidizing solution is critical to the process for preparing the products as indicated. Furfuryl alcohol can be pure oxidized to 6-hydroxy-2H-pyran-3 (6H) -one using one equivalent of a halogen-containing oxidizing agent in water or an aqueous organic solvent. It is surprising and unexpected that 6-hydroxy-2H-pyran-3 (6H) -ones can be converted to χ-pyrones. 6-Hydroxy-2H-pyran-3- (6H) -one can be regarded as the aldehyde semiacetal and as such can undergo a number of undesirable reactions such as further oxidation and aldol type condensation. Using two equivalents of the halogen-containing oxidizing agent in water or an aqueous organic solvent, the reaction proceeds smoothly from furfuryl alcohol to χ-pyron. This novel process without isolation of the intermediates has the advantage of using inexpensive halogen-containing oxidizing agents C12, Vg2, BrCl, HOCl, HOBr or mixtures thereof. Isolation of the desired .beta.-pyrone is greatly simplified since the solvent, oxidizing agent and mineral acid formed as a byproduct are volatile and can be removed in vacuo to give crude γ-pyron directly in high yield by simple concentration.

The process without isolation of the intermediates is carried out by dissolving furfuryl alcohol in water or water together with an organic solvent. As such a solvent, a water-miscible or water-miscible solvent may be used and may be selected from a wide variety of solvents such as C 1 -C 4 alkanols or C 1 -C 4 diols, for example methanol, C 2 -C 10 ethers carbon ketones such as tetrahydrofuran or isopropyl ether; low molecular weight ketones such as acetone, low molecular weight nitriles, low molecular weight esters and low molecular weight amides. Preferred solvents are C 1 -C 4 alkanols, C 2 -C 10 ethers, and methanol is most preferred. The solution is maintained at a temperature of -50 ° C to 50 ° C, preferably -10 ° C to 10 ° C. The desired furfuryl alcohol is added to this solution, and a halogen containing oxidizing agent (two equivalents) is added simultaneously to the reaction mixture. The temperature of the reaction mixture is maintained at -50 to 50 ° C, preferably at -10 to 10 ° C during the halogen addition. If a low boiling solvent is used, it is removed by distillation after the addition is complete. The reaction mixture is then heated to a temperature at which the hydrolysis proceeds to a sufficient extent, for example 70 to 160 ° C. Generally, a temperature of 100 to 110 ° C is used for the hydrolysis. Heating is continued until complete hydrolysis of the 4-halo-dihydropyran intermediate (usually 1 to 2 hours). The acid necessary to catalyze this final hydrolysis is liberated in situ by cleavage of the acid from the intermediate during the course of the reaction. If desired, additional acid may be added.

The halogen-containing oxidizing agent is selected from the group consisting of chlorine, bromine, bromide, hypochlorous acid or hypobromic acid or mixtures thereof. Bromine chloride is a commercially available gas. It can be prepared in situ by adding chlorine to a sodium or potassium bromide solution or by adding bromine to a sodium or potassium chloride solution. Preferably, hypochlorous acid and hypobromic acid can be liberated in situ by adding aqueous acid (HCl, H2SO4 or HBr) to a solution of an alkali metal or alkaline earth metal hypochlorite or hypobromite, such as NaOCl, KOCl or Ca (OCl) 2. Preferred halogen atom-containing oxidizing agents according to their cost are chlorine and bromine chloride prepared in situ.

The furfuryl alcohol in aqueous solution with any solvent present may be reacted at -10 to 10 ° C with two equivalents of halogen-containing reagents. After stirring at room temperature for 30 minutes, the pH of the reaction mixture was adjusted to 2 by adding a strong base, and the reaction mixture was extracted with a solvent such as ethyl acetate. Removal of the solvent affords the 4-halo-6-hydroxy-2H-pyran-3 (6H) -one of formula II which can be hydrolyzed to the desired χ-pyron. The 4-halo-dihydropyran can be dehydrated by heating under vacuum to give 6,6´-oxybis [4-halo-2H-pyran-3 (6H) -one). This dimer provides the desired χ-pyron by hydrolysis optionally with the addition of an acid.

The following examples illustrate the preparation of the χ-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 < 5 units using tetramethylsilane as standard.

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

Example 1

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

To a solution of 25 g of 1- (2-furyl) -1-ethanol in 125 ml of tetrahydrofuran and 125 ml of water at 0-5 ° C was added dropwise 2.2 equivalents of bromine. The temperature is maintained at 5-10 ° C during the addition. After the addition was complete, the solution was stirred at room temperature for 30 minutes and the pH was adjusted to 2.1 with 2N sodium hydroxide. The reaction mixture was extracted with ethyl acetate (3 X 100 mL). The ethyl acetate extracts were combined, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 95: 5 mixture of chloroform and ethyl acetate. The product is an orange oil that was. rechromatographed on silica gel, eluting with a mixture of chloroform and ethyl acetate. (95: 5).

NMR (CDCl 3, δ) 7.3 (1H, d), 5.6 (1H, d), 4.7-5.0 (1H, q), 1.1-1.5 (3H, m) .

Example 2

The procedure of Example 1 was repeated using the furfuryl alcohol of formula

CV

R to give a compound of formula

wherein R is hydrogen or ethyl.

4-Bromo-6-hydroxy-2-ethyl-2H-pyran-3 (6H) -one ethyl compound, NMR (CDCl 3, δ) 7.4 (1H,

d), 4.6 to 4.9 (1H, m), 1.8 to 2.2 (2H, m), 1.0 to 1.3 (3H, t).

Compound with hydrogen 4-bromo-6-hydroxy-2H-pyran-3 (6H) -one,. NMR (CDCl 3, δ) 7.4 (1H, d),

5.5 (1H, d1), 4.6 (2H, dd).

Example 1 - a d 3

A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one is prepared by dissolving the compound in either 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 CH3COOH 35 2 69 CF3COOH 100 ALIGN! 3 36 HN03 35 3 0.4 CF3COOH 100 ALIGN! 3 70 CH3COOH 100 ALIGN! 3 77 HCOOH 100 ALIGN! 3 24 H2SO4 35 5 48

Alternatively, organic 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 4

The process of Example 1 was repeated using chlorine instead of bromine and using the appropriate furfuryl alcohols. The following compounds were prepared:

Methyl:

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

NMR (CDCl 3, δ): 7.1 (1H, d), 5.8 (IH, d),

4.6-5.0 (1H, m), 4.4 (1H, broad s), 1.2-1.5 (3H, m).

Ethyl:

4-chloro-6-hydroxy-2-ethyl-2 H -pyran-3 (6 H) -one

NMR (CDCl 3, δ): 7.0 to 7.1 (1H, d), 5.6 to 6.0 (2H, m), 4.4 to 5.0 (IH, m), 1.6 to 7.1 2.1 (2H, m), 0.9-1.1 (3H, t).

Compound with hydrogen:

4-chloro-6-hydroxy-2 H -pyran-3 (6 H) -one

NMR (CDCl 3, δ): 7.1-7.2 (1 H, d), 5.6 (1 H,

d), 4.4 to 4.9 (2H, dd) (addition of D 2 O).

Example 5

The process of Example 1 is repeated to prepare compounds of the formula wherein R is propyl, butyl, phenyl or benzyl,

X is bromo or chloro.

Example 6

4-Bromo-6-hydroxy-2-methyl-2H-pyran-3 (6H) -one was heated under vacuum at 40 ° C for 16 hours. The resulting oily solid was crystallized from isopropyl alcohol to give 6,6'-oxybis- [4-bromo-2-methyl-2H-pyran-3 (6H) -one] m.p. 125 ° C.

Example 7

The process of Example 6 was repeated using the starting material of the formula

and a compound of formula is prepared

wherein R is hydrogen, ethyl, propyl, butyl, phenyl or benzyl, X is bromine or chlorine.

R ____________________________________ X ________________________________ 1.1. (° C)

See footnotes 177 to 179

CH2CH3 Cl 132-135

Example 8

The phosphoric acid compound and the solution are heated for about 5 hours. A compound of formula is obtained

where R is hydrogen, methyl, ethyl, propyl, butyl, phenyl or benzyl and X is an atom wherein R is as defined above, of bromine or chlorine, is dissolved in 20 ml of 35%

Claims (2)

SUBJECT A process for the preparation of? -Pyrons of the general formula I Ж (I) I invent 2. A process for the preparation of? -Pyrons of the general formula IA In ⁴ /? (IA) wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, R '' is hydrogen or alkyl of 1 to 4 carbon atoms, characterized in that 6,6'-oxybis- [4] -halogen-2H-pyran- (6H) -one] of the general formula V wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or benzyl, characterized in that 6,6'-oxybis- [4-halogen] -2H-pyran-3 (6j-one) of the general formula V wherein R is as defined above and X is a chlorine or bromine atom, heated to 70-160 ° C in aqueous acidic solution until complete hydrolysis. wherein R is as defined above and X is a chlorine or bromine atom, heated to 70-160 ° C in aqueous acidic solution until complete hydrolysis.