NO821850L - PROCEDURE FOR THE PREPARATION OF 4-HALOGEN-DIHYDROPYRANE DERIVATIVES - Google Patents

Description

The present invention relates to a method

for the production of 4-halo-dihydropyran intermediates suitable for the production of gamma-pyrones. In particular, the invention relates to the preparation and intermediate products from suitable 6-substituted dihydropyrans using . a. v halogen-containing oxidizing agents.

Maltpl (2-methyl-3-hydroxy-4H-pyran-4-one) is. er

naturally occurring substance found in the bark of young larch trees, pine needles and chicory. Early commercial production took place by destructive distillation of wood. The synthesis of maltol from 3-hydroxy-2-(1-piperidylmethyl)-1,4-pyrone was discussed by Spielman and Freifelder in J. Am. Chem. Soc, 69, 2908

(1947).- Schenck and Spielman, J. Am. Ghem.. Soc, 67, 2267

(194 5) 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); discussed, synthesis of maltol from protective carbohydrate derivatives. Shond and Matsumura, Tetrahedron Letters No. 17, 1363 (1976), described a five-step synthesis of maltol starting from methyl furyriaicohol.

The isolation of 6-methyl-2-ethyl-3-hydroxy-'4H-pyrari-

4-on as one of the characteristic sweet-aroma constituents in refined finished molasses was discussed by Hiroshi ito in Agr;

Biol. Chem., 40 (5), 827-832 (-1976). This compound was previously synthesized using the method described in US patent 3,468,915.

Syntheses of gamma pyrones such as pyromeconic acid) maltol, ethyl maltol and other 2-substituted 3-hydroxy-gamma-pyrones are described in US patents 3.13.0.204 > 3.133.089, 3.140.239, 3.159.652, 3.365.469, 3.376.317, 3.440.183 ,

3,446,629 and 3,468,915..

Maltol and ethyl maltol increase the taste and aroma of various foodstuffs. In addition, these compounds are used as ingredients in perfumes and essences. The 2-alkenylpyromecoric acids which are described in US patent 3,644,635 and the 2-arylmethylpyromeconic acids which are described in US patent 3:365,469 prevent the growth of bacteria and fungi and are useful as flavor and aroma enhancing agents in foodstuffs and beverages and aroma enhancers in perfumes.

Patent application 77.2193 describes i.a. a method for the preparation of a gamma pyrone of the formula

■ i

which comprises heating in acidic, aqueous solution, preferably at a temperature in the range of 70 to 160°C, until the hydrolysis is. substantially complete, of a 4-halodihydropyran of formula (II)

where R is hydrogen or alkyl of 1 to 4 carbon atoms,

RV is hydrogen, alkyl of 1 to 4 carbon atoms or -COR";

where R" is methyl, ethyl or phenyl, R<1>'' is hydrogen or alkyl of 1 to 4 carbon atoms and X is chlorine or bromine.

The acid required for the hydrolysis can be added to the reaction mixture, - e.g. by dissolving the intermediate of formula (II) in an aqueous, inorganic or organic acid before heating; or alternatively the acid can be generated in situ during the preparation of the intermediates as described later..

According to the invention, an intermediate product with formula (II) above is produced by reacting a compound with the formula:

where R, R' and R<1>'' 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 halogen-containing oxidizing agent selected from chlorine, bromine, bromine chloride, hypochloric acid, hypobromic acid or mixtures thereof until the reaction is essentially complete...

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

Some of the compounds that fall under the general formula (II) above are new, and according to the invention a compound with the formula is also provided:

4 where R is alkyl of 1 to 4 carbon atoms or -COR", where R" is methyl, ethyl or, phenyl,' R' '1 is hydrogen or alkyl. with 1 to 4 carbon atoms, and X is. chlorine or bromine, provided that when X is chlorine and R 1 is ethyl, R 11 is not hydrogen; The intermediate with formula (IV) can be prepared by reacting a furfuryl alcohol with the formula:

where R and R'<11> are as defined above, in aqueous solution with at least one equivalent of a halogen-containing oxidizing agent selected ■ from among chlorine, bromine, bromine chloride, - hypochloric acid, hypobromic acid or mixtures thereof at a temperature of -50 to. 50°C, preferably room temperature, until the reaction is essentially complete. The reaction can be carried out in the presence of a co-solvent which can suitably be one of the solvents such as

mentioned earlier in the preparation of the intermediate product of formula (II).

If desired, the intermediate product 4-halo-dihydropyran of formula (II) can be used. is prepared directly from a suitable furfiiryl alcohol of formula. (III) by reacting the latter in a solvent at a temperature of -50 to 50°C, with at least two equivalents of one of the aforementioned halogen-containing oxidizing agents until the reaction is substantially complete.

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

The halogen-containing oxidizing agent is selected from chlorine, bromine, bromine chloride, hypochlorous or hypobromoic acid

or mixtures thereof. Bromine chloride is a commercially available gas. It can be prepared in situ by the addition of chlorine to a solution of sodium or potassium bromide.d or by the addition of. bromine to a solution of sodium or potassium chloride. Hypochlorine and hypobromine acidification can conveniently be generated in situ by adding aqueous acid (HC1, H^ SO^. or HBr) to a solution of alkali metal or alkaline earth metal hypohalite, e.g. NaOCl, K0Cl or Ca(0Cl)2. The preferred halogen-holdigé oxidizers, based on cost factors, . chlorine and bromine chloride are produced in situ.

A 6-Alkoxy-2H-pyrah-3(6H)-one of formula (IV) can be prepared using the method described in Tetrahedron Letters No. 17, 1363-1364 (1976). A furfuryl alcohol is anodically alkoxylated to 2-(1-hydroxyalkyl)-2,5-dihydroxy-dihydrofuran. Treatment with a strong organic acid gives the desired 6-alkoxy compound. A 6-acyl compound can be prepared by conventional treatment of the 6-hydroxy compound with the appropriate anhydride in the presence of pyridine.

In one embodiment. for the invention, 6-acyl-.or 6-alkoxy-2H-pyran-3 (6H)-one ■ is dissolved in a solvent selected from water, ethers,. to C, alkanols or diols or low molecular weight ketones, nitriles, esters or amides. The preferred solvent is methanol. One equivalent of a halogen-containing oxidizing agent selected from chlorine, bromine, bromine chloride, uride chloride, hypobromine acidification, or mixtures thereof is added, and the 4-halo-dihydropyran compound is prepared and isolated by performing the halogenation at a temperature of -20 to 20°C,

preferably at 5 to 10°C, in the presence of an organic base so

as triethylamide. After approx. After 30 minutes, the reaction mixture is allowed to warm to room temperature, filtered to remove the triethylamide hydrochloride, and the solvent removed under vacuum to give the 4-halo-dihydropyran compound.

The following examples illustrate the production of the 4-halo-6-substituted-dihydropyran intermediates by the method according to the invention.

In the examples where spectral data are given, NMR chemical shift data are indicated using conventional literature symbolism, and all shifts are expressed as 6-units from tetramethylsilane: s = singlet d = doublet

q = quartet

Example 1.

4- chloro- 6- methoxy- r2- methyl- 2H- pyran- 3 ( 6H) - one

To a solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.05 mol) in 70 ml of dichloromethane at -10°C was added chlorine

(0.05 mol) through a gas intake tube. After this addition, triethylamine (0.05 mol) was added slowly while maintaining the temperature at -10°C. After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature, the reaction mixture was filtered to remove triethylamine hydrochloride and the solvent was removed under vacuum. Redissolution of the crude product in ether-benzene and filtration removed the last traces. triethylamiric hydrochloride. Removal of the solvent gave 4-chloro-6-methpxy- . 2-methyl-2H-pyran-3(6H)-one (yield, 99%). NMR analysis of the signals at 5.05 and 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 were 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 procedure from example 1 was repeated by . replace chlorine with bromine to obtain 4-bromo-6-m.ethoxy-2-methyl-2H-pyran-3(6H)-one in 93% yield. The two optical forms of the trans isomer were synthesized by Paulsenbg co-workers, Tetrahedron Letters 4377 (1974).

Example 3

The procedure of Examples 1 and 2, respectively, was repeated starting from a compound of the formula: where R is hydrogen or alkyl of 2 to 4 carbon atoms, and R' is alkyl of 2 to 4 carbon atoms to give a compound the formula:

where R. and R<1> are as defined above, and X is chlorine or bromine;

Example 4'

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

A solution in dichloromethane of 6-acetyl-2H-pyrari-3(6H)-oil, prepared by the method described in Tetrahedron 2.7, 1973

(1971), was brominated using the procedure of Example 6 to give 4-bromo-6-acetyl-2H-pyran-3(&H)-one, m.p. 78 to 80°C. Mass spectrum for the compound showed the expected peaks at 234 and 236 mass units.

Example 5

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

The procedure from. Example 4 was repeated with 6-acetyl-2-methyl-2H-pyran-3(6H)-one to give 4-brom-6-acetyl-2-methyl-2H-pyran-3(6H)-one which showed masses of 249.96 and 257.96

by mass spectroscopy and the following NMR spectrum:

(6, CDCl 3 ): 7.3 (1H, d); 6.4 (1H, d of d); 4.7 (1H, q);

2.2 (3H, p).; 1.4 (3H, s) .

Example- 6

The procedure from Example 1 was repeated using chlorine instead of bromine and starting from a compound with the formula:

where R is hydrogen or alkyl of 1 to 4 carbon atoms, R' is alkyl of 1 to 4 carbon atoms or -COR" where R" is -"methyl, ethyl or phenyl to give a compound of the formula:

where R and R 1 are as defined above, and X is chlorine.

Claims (5)

.1.. Process for the preparation of a 4-halo.n-dihydropyran compound with the formula: where Rer is hydrogen or alkyl of 1 to 4 carbon atoms, R' is hydrogen, alkyl of 1 to 4•carbon atoms or -COR", where R" is methyl, ethyl or phenyl, R'1' is hydrogen or alkyl of 1 to 4 carbon atoms, and X is chlorine or bromine, characterized in that a compound with the formula: .where R,R' and R' <11> are as indicated above, reacted in a solvent at a temperature from -50 to 50°C, with at least one equivalent of. a halogen-containing oxidizing agent which is chlorine, bromine, bromine chloride, hypochloric acid, hypobromic acid or a mixture thereof until the reaction is almost complete. . 2. Method according to claim 1, characterized in that the solvent used is water, an alkanol or diol with 1 to 4 carbon atoms; one ether with 2 to 10 carbon atoms, or a low molecular weight ketone, nitrile,. ester or amide.. 3. Method according to claim 2, characterized in that methanol, tetrahydrofuran, isopropyl ether or acetone are used as solvents. 4. Method according to one of the preceding claims, characterized in that the halogen-containing oxidizing agent. chlorine or bromine chloride is used. 5. Method according to one of the preceding claims, characterized in that R is ethyl and R' is alkyl with 1 to 4 carbon atoms or -COR" where R" is methyl, ethyl. or phenyl and R1'' and X are as stated in claim 1. 6. 4-halo-dihydropyran compound for use as an intermediate in the production of gamma-pyrones. characterized' by the formula: 4 where R is alkyl with 1 to 4 carbon atoms or -COR" where . R" is methyl, ethyl or phenyl, R"'' is hydrogen or alkyl of 1 to 4 carbon atoms, and X is chlorine or bromine, provided that when X is chlorine and R is ethyl, R1'' is not hydrogen.