NO145952B - PROCEDURE FOR MANUFACTURING GAMMA PYRONS. - Google Patents

Description

The present invention relates to a method for the production of gamma pyrones, for example maltol. Maltol is a naturally occurring substance that is found in the bark of young larch trees, in pine needles and in chicory. The early commercial production was from the destructive distillation of wood. Synthesis of maltol from 3-hydroxy-2-(1-piperidylmethyl)-1,4-pyrone was discussed by Spielman and Freifelder in J. Am. Chem. Soc, 6j), 2908 (1947). Schenck and Spielman, J. Am. Chem. Soc, 6J7, 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., 61, 999 (1969), wrote on the synthesis of maltol from protected carbohydrate derivatives.

Syntheses of gamma-pyrones, such as pyromeconic acid, maltol, . . . , ethyl maltol and other 2-substituted-3-hydroxy-gamma-pyrones> are described in U.S. Pat. Patents No. 3,130,204, 3,133,089, 3,140,239, 3,159,652, 3,376. 317, 3. 468 .915, 3'. 440.183 and 3. 446. 629 . '

Maltol and ethyl maltol give an increase in taste and aroma to a number of food products. These materials are also used as constituents in perfumes and essences. The 2-alkenylpyromeconic acids disclosed in U.S. Pat. Patent No. 3,644,635 and the 2-arylmethylpyromeconic acids disclosed in U.S. Pat. patent no. 3,365,469 inhibits the growth of bacteria and fungi and is useful for providing increased taste and aroma in food and drink and increased aroma in perfumes.

According to the present invention, a method for the production of gamma pyrones with the formula: where R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, phenyl or benzyl, whereby a compound of the formula:

where R is as defined above and R' is alkyl of 1 to 6 carbon-

atoms, are brought into contact with an acid during heating.

This invention gives rise to the production of 2-substituted-3-hydroxy-gamma-pyrones by using furfural as starting material. Furfural is a cheap raw material that is industrially produced from pentosans contained in straw and bran from cereal crops.

The reactions used, when starting from furfural, can be outlined as follows (where the last step is the method according to the invention):

Final product (5): R = H> pyromeconic acid

R = CH3*, maltol; R = CH2CH3; ethyl maltol ;The reaction of furfural with a suitable Grignard reagent ;is described in Chemical Abstracts, 44, 1092d (1949). The production of intermediate product 2 (R = H) by electrolysis in methanol is described in US patent no. 2,714,576 and Acta. Chem. Scand., 6, 545 (1952). The synthesis using bromine in methanol is discussed in Ann., 516, 231 (1935). The general regulation on the use of chlorine in an alcoholic solvent is also well known (for example British patent document no. 595,041). During the process according to this invention, it has been found that the reaction between intermediate product 1 and chlorine in an alcoholic solvent at a temperature between -70 and 50°C gives a clean conversion to the desired intermediate product 2, as the HCl by-product is neutralized with a base , such as ammonia, sodium carbonate or other alkali metal bases. Although the previous literature covering this turnover states dividends of up to approx. 50%, then the method according to the present invention results in yields in excess of 90%. ;Intermediate 2_ (R = CH^) is described in Acta. Chem. Scand., ;9, 17 (1955), and Tetrahedron, 27, 1973 (1971). Intermediate 2 (R = CI^CHg) is a new compound which can be prepared by the methods already described. ;The treatment of intermediate 2 with a strong organic acid ;is new, and it produces the desired 6-hydroxy derivative 3 directly in high yield and avoids formation of the corresponding*: hydroxy

derivative which is very unstable to further turnovers. Intermediate 2^ is brought into contact with an acid which is preferably 1 essentially anhydrous, although the presence of a protic solvent, such as an alcohol, or a small "

amount of water. By following this treatment, the product becomes a state of purity suitable for conversion to intermediate 3,

separated from the acidic medium by conventional extraction techniques.

Although it is preferred with formic acid and trifluoroacetic acid, . any acid with a pKa of approximately 4 or less will convert intermediate 2 to the desired intermediate 3. Other suitable organic acids include p-toluenesulfonic acid, methanesulfonic acid, citric acid, oxalic acid and chloroacetic acid, and suitable mineral acids include sulfuric acid, hydrochloric acid and phosphoric acid. Acidic resins, such as "Amberlite GC-120" and "Dowex 50W", can also be used.

The epoxidation of intermediate 3 to the epoxy ketone jl is a

new and hitherto unknown process. Intermediate 3 is dissolved in a

suitable solvent such as water or an alcohol such as iso-propyl alcohol or methanol. A base such as sodium bicarbonate or sodium hydroxide is added followed by the addition of "^O^

(30%). The desired intermediate £ can be isolated by conventional extraction techniques and is suitable for rearrangement to the desired pyrone 5 without further purification.

The final rearrangements of the epoxy ketones 4^ to gamma-

pyrones _5 are new and they take place with good yield and give clean products i

The intermediate A is reacted in an acidic medium, and subsequent isolation of the desired gamma-pyrone :_5 is effected by conventional crystallization or extraction techniques. The pure gamma-pyrone can be recrystallized from a suitable solvent such as isopropanol, methanol or varian. Although the use of hot, aqueous mineral acid, such as sulfuric or hydrochloric acid, is the most convenient method for converting intermediate 4^ to product 5, the desired gamma-pyrone can be formed with Léwis acids, such as boron trifluoride etherate, zinc chloride and tin tetrachloride, with acidic ion exchange resins, such as "Amberlite GC-120"; or "Dowex 50W", and with strong organic acids such as p-toluenesulfonic acid or formic acid.

Compounds related to intermediate 21

(R = CH 2 OH or R = CH 2 O alkyl) can be prepared from carbohydrate sources, as described in Accounts of Chemical Research, 8, 192 (197.5). ■

'These compounds can be converted into intermediate product 4/ and product 5_ where R = CH2OH or CH2O-alkyl. Product 5 (R = CH 2 OH or v CH 2 O alkyl) can be converted to maltose, as described in U.S. Pat. patent documents. 3,130,204 or in Angew. Chem., 81, 998 (1969).

The following examples provide an illustration of the method according to the invention:

A. Intermediates:

Example' 1 " -"•••■» -;

To a round-bottomed 3-necked flask equipped with a magnetic stir bar, a jacketed addition funnel, a thermometer and a dry-ice condenser, was added 22.4 g (0.2 mol) of intermediate 1 (R = CH .j) , 100 ml of methanol and 21.1 g (0.2 mol) of sodium carbonate, and this mixture was cooled to 0°C using an ice-acetone bath. To this rapidly stirred solution was then added dropwise a cold (-30°C) solution of chlorine (11.0 ml, 0.24 mol) in methanol. The addition of chlorine was regulated to keep the reaction temperature below 40°C. For the addition, approx. 2 hours. After the addition, the reaction mixture was stirred at ice bath temperature for 30 minutes, and it was then allowed to warm to room temperature. The resulting slurry was filtered, the methanol was removed in vacuo and the residue was taken up in benzene and passed through an alumina plug as a final filter. Removal of benzene afforded 31.9 g (91%) of the desired dimethoxydihydrofuran 2 (R = CH 3 , R' = CH 3 ). This material can be used without further purification or it can be distilled,

k.p. 76-78°/5 mm [104-107°/10-11 mm, Acta Chem. Scand., 9, 17 (1955)]. Analysis:

Example 2

The procedure from Example 1 was repeated with intermediate 1 (R = H) to obtain intermediate 2 (R = H, R' = CH3),

k.p. 80-82°/5 mm [71°/l.0mm, Tetrahedron, 21_, 1973 (1971)].

Example 3

The procedure from Example 1 was repeated with intermediate 1 (R = H) to obtain intermediate 2 (R = H, R' = CH 3 ), b.p. 102°/10 mm.. Analysis:

Example 4

The procedure from example 1 was repeated using intermediate 1 (R = CH 3 ), replacing methanol with isopropanol 2 [R = CH 3 , R<1> = CH(CH 3 ) 2 ], b.p. 62-64°/0.05-mm..

Example 5 ■■

In a small glass electrolysis vessel with carbon anode and nickel cathode, 50 ml of methanol, 0.5 ml of concentrated sulfuric acid and 1.12 g (0.01 mol) of intermediate 2 (R = CH3, R<1> = CH3) and the solution is cooled to -20°C. An electrolysis was then performed using a potentiostat/galvanostat Princeton Applied Research Corporation Model 373 instrument set to provide a constant current of 0.6 amps. After a reaction time of 30 minutes, the reaction mixture was poured into water and the product 3 (R = CH3' R' = CH3) was isolated by a chloroform extraction process. This process is similar to that described in U.S. Pat. patent document no. 2,714,576, but sulfuric acid replaces ammonium bromide as the electrolyte.

IN

Example 6

To a 2-liter, 3-necked round-bottom flask equipped with a magnetic stirrer, dropping funnel and a thermometer, 400 ml of formic acid and 20 ml of methanol were added. To this solution was added a solution of intermediate product 2_

(R = CH 3 , R' = CH 3 ) (104.4 g, 0.6 mol) in 40 mL of methanol. The dropwise addition required 15 minutes. The reaction mixture was poured into 1 liter of water and extracted 3 times with 500 ml portions of chloroform. They collected

chloroform liquids were washed with an aqueous solution of sodium bicarbonate and with saline. The chloroform solution was evaporated to a crude yield of 76 g (89%) of intermediate 3 (R - CH 3 , .R' = CH 3 ) as a light brown product. The impure material can be used as such or distilled

by pressing on. 2 mm, 50-52°C [82-85°/30 mm, Tetrahedroh,

27, 1973 (1971)].

Example 7

Métpdén. i;ra Example 6 was repeated with analogous intermediate 2 (R = H, ■ R' = CH 3 ) to obtain intermediate 3 (R = H, R.' CH 3 ), b.p. 60-66°/14 mm [76-81°/23 mm, Tetrahedron, ^- ■ 27, • 197 3- 11971) ]'.

■' Example 1 8

The procedure of Example 6 was repeated with intermediate 2 (R = CH 2 CH 3 , R' = CH 3 ) to obtain intermediate 3 (R = CH 2 CH 3 , R' = CH 3 ), b.p. 79-80°/14mm.

Example 9

In a 3-neck round-bottom flask equipped with an addition funnel, a low-temperature thermometer, and a stirring bar, a solution of 5.0 g (0.029 mol) of intermediate 2 (R = CH3, R ' = CH3) in diethyl ether (10 ml), and the solution was cooled to -40°C. To this solution was added dropwise 1.6 ml of concentrated sulfuric acid and the black mixture was stirred for 5 minutes at -40°C, poured into in water and the desired intermediate 3 (R = CH3, R' = CH3) was isolated by the method from example 6.

Essentially the same results can be obtained by replacing sulfuric acid with hydrochloric or phosphoric acid.

Example 10

To a dry flask was added 1.05 grams (0.0074 mol)

of intermediate 3 (R = CH3, R<1> = CH3O) dissolved in 20 ml of isopropyl alcohol, and the flask was cooled to 0°C. Then 0.5 g (0.0059 mol) of sodium bicarbonate and 2.0 ml (0.023 mol) of 30% hydrogen peroxide were added, and the reaction mixture was stirred at room temperature for approx. 2 hours. The reaction mixture was poured into 100 ml of water and the water was extracted with chloroform, followed by concentration to obtain an oil which could

distilled at 70-90°/3 mm. An analytical sample was purified

by chromatography.

Analysis:

Example 11

The procedure from Example 10 was repeated with intermediate 3 (R = H, R<1> = CH3) to obtain intermediate 4^

(R = H, R' = CH 3 ).

Analysis:

Example 12

The procedure from example 10 was repeated with intermediate 3 (R = CH 2 CH 3 , R' = CH 3 ) to obtain intermediate 4 (R = CH 2 CH 3 , R' = CH 3 ).

Analysis:

Example 13

2.84 g (0.02 mol) of intermediate 3 (R = CH 3 , R' = CH 3 ), 10 ml of water and 10 ml of isopropanol were added to a 75 ml flask. The solution was cooled to 0-5°C and the pH was adjusted to 7.0-9.0 with 1N NaOH. Then 2.1 ml of 30% hydrogen peroxide was added drop by drop, and if necessary NaOH was also added to keep the pH constant. Cooling was required to keep the container temperature below 10°C. After the addition of peroxide, the reaction mixture was stirred at 8-10°C for approx. 1 hour, was poured into water and the solution was extracted with chloroform. Removal of the solvent gave 2.99 g (94.5%) of intermediate A_ (R = CH 3 , R' = CH 2 ) as a clear oil. A reaction temperature above 15°C and a pH value above 9.5 or below 6.5 results in a lower yield of intermediate 4.

Essentially the same results are obtained when isopropanol is replaced with water.

B. End products:

Example 14

To a flask with a condenser was added .3.7 g

(0.023 mol) of intermediate _4 (R = CH 3 , R' = CH 3 ) and 50 ml of 2M I^SO^. After heating this biphasic solution for 1 1/2 hours at reflux, the reaction mixture was cooled, adjusted to a pH of 2.2 with 6N NaOH, extracted 3 times with 100 ml volumes of chloroform and the combined solvent extracts were concentrated to give product _5 (R = CH3, maltol) in 69% yield. By using phosphoric acid instead of sulfuric acid, a yield of 75% is achieved.

Example 15

The procedure from example 14 can be repeated with intermediate 4_ where R is hydrogen or ethyl and R<1> is methyl, ethyl, isopropyl or hexyl to give product 5 where R is hydrogen or ethyl, in a yield of 56 and 70% respectively.

Example 16

To a 250 cm 3 Wheaton pressure flask was added 3.16 g (0.02 mol) of intermediate 4^ (R = CH 3 , R' = CH 3 ) and 50 cm 3 of 2M H 2 SO 4 . The bottle was closed and heated to 140-160° for 1-2 hours. After cooling, the reaction mixture was worked up as in Example 19 to give maltol (R = CH3) in a yield of 73%.

Example 17

The procedure in Examples 14 and 15 can be repeated with comparable results by replacing sulfuric acid with hydrochloric acid, "Dowex 50W" or "Amberlite GC-120", yields according to

show 31 and 46%.

Example 18

1.58 g (0.01 mol) was added to a small flask

with intermediate _4 (R = CH^, R' = CH^) and 25 ml of benzene followed

of 3.7 ml of boron trifluoride etherate. After stirring for 2 4 hours

at 25°C the solvent was removed, the residue was extracted with chloroform and the chloroform was removed to give maltol (R = CH 3 ), yield 10%.

Substantially the same results were obtained when boron trifluoride etherate was replaced by p-toluenesulfonic acid, formic acid, zinc chloride or stannous tetrachloride.

Claims (1)

Procedure for the production of gamma pyrones with the formula: where R is hydrogen, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, phenyl or benzyl, characterized in that a compound with the formula: where R is as above, oa R<1> is alkyl with 1 to 6 carbon atoms, is brought into contact with an acid while heating.