FI71315C - PROCEDURE FOR FRAMSTAELLNING AV 6-ALCOXY-3,6-DIHYDRO-2H-PYRAN-3-ONER - Google Patents

Description

1 71315

Process for the preparation of 6-alkoxy-3,6-dihydro-2H-pyran-3-ones

Divided separated from patent application 762039 5

The invention relates to a process for the preparation of 6-alkoxy-3,6-dihydro-2H-pyran-3-ones of the formula

a O

R

R '0 wherein R' is lower alkyl and R is hydrogen, methyl or ethyl.

These compounds are used as intermediates in the preparation of gamma-pyrones, e.g. maltol (3-hydroxy-2-methyl-4H-pyran-4-one). Maltol is a naturally occurring substance obtained from the bark of young larch, pine needles and chicory. In the past, it was obtained commercially by distilling wood, which destroyed the wood. The synthesis of maltol from 3-hydroxy-20si-2- (1-piperidylmethyl) -1,4-pyrone has been 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 from streptomycin salts. Chawla and McConigal, J. Org. Chem. 39, 3281 (1947) 25 and Lichtenhaler and Heidel, Angew. Chem. 81, 999 (1969) have described the synthesis of maltol from protected carbohydrate derivatives.

The process according to the invention is characterized in that the compounds of the formula 30 / = v ~

\ / iTHOH

where R and R 'are as defined above, is treated with a strong substantially anhydrous organic acid having a pKa of not more than 4.

2 71315

The term "lower alkyl" embraces both straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms.

The following reaction scheme shows the process according to the invention (conversion of compound 2 to compound 3j / preparation of the compound used as starting material in the process and use of compound _3 for the preparation of gamma-pyrones.

, -V / λ x2 / R’OH

10 / '' \ -3-> \ 0H or electrolysis v '\ / \ /

CHO 0 C-H

1 i / ^ / R 'R 0 X'0' '\: hoh 15 + | n H £ o v

JL 0H

, |) H + Ho0 f .. / „Λ I!

I I _2_ ^ mas / H ^ O

20 X ^ H2 ° 2 A

R R O R .RO UR

5 4 3

In the formulas included in the reaction scheme, R and R 'have the same meaning as above.

The reaction of furfural with a suitable Grignard reagent is described in Chemical Abstracts 44, 1092 d (1949).

The preparation of intermediate 2 (R = H) by electrolysis in methanol is described in U.S. Patent 2,714,576 and Acta Chem. Scand. 6, 545 (1952). The synthesis using bromine in methanol is described in Ann. 516, 231 (1935). The general way of using chlorine in an alcoholic solvent is also well known (e.g. British Patent 595,041). It has now been found that the reaction of intermediate 1 with chlorine in an alcoholic solvent at a temperature between -70 and 50 ° C causes very efficient conversion to the desired intermediate 2 and the HCl by-product is neutralized with a base such as ammonia, sodium carbonate or other alkali metal bases.

3,71315

Although the previous literature on this reaction mentions about 50% yields, the yields now obtained are as high as 90%.

Intermediate 2 (R 2 H 2) is described in Acta Chem.

5 Scand. 9, 17 (1955) and Tetrahedron 27, 1973 (1971). Intermediate 2 (R 2, CH 2) is a novel compound which can be prepared by the methods already described.

The process according to the invention, i.e. the treatment of compound 2 with a strong organic acid, is a new process, in which case the desired 6-alkoxy derivative 3 is obtained in very high yield directly and the formation of the corresponding hydroxy derivative is avoided, which is very unstable in further reaction. In the process of the invention, intermediate 2 is contacted with an acid, which is most preferably completely anhydrous, although the presence of a protic solvent such as alcohol or a small amount of water is in fact useful. After this treatment, the product, which is of a purity suitable for conversion to the final product 3, is isolated from the acidic medium by a conventional extraction technique.

Although formic acid and trifluoroacetic acid are preferred, any acid having a pKa of about 4 or less will convert Intermediate 2 to the desired end product 3. Other suitable organic acids include p-toluenesulfonic acid, methanesulfonic acid, citric acid, oxalic acid, and oxalic acid. Acid resins such as Amberlite GC-120 and DoweW can also be used.

The conversion of the final product 3 to gamma-pyrone is carried out via epoxy ketone 4. Compound 3 is dissolved in a suitable solvent such as water or an alcohol such as isopropyl alcohol or methanol. A base such as sodium bicarbonate or sodium hydroxide is added, followed by the addition of H 2 O 2 (30%). The desired intermediate 4 can be isolated by a conventional extraction technique and is suitable for conversion to the desired pyrone 5 without further purification.

35 Finally, the conversion of epoxyketones 4 to gamma-pyrones 5 is a previously unknown process with a high yield of 4,71315 and a high purity. Intermediate 4 is reacted in an acidic medium and then the desired gamma-pyrone 5 is isolated using conventional crystallization and extraction techniques. Pure gamma-pyrone can be recrystallized from a suitable solvent such as isopropanol, methanol or water. Although a hot, aqueous mineral acid such as sulfuric acid or hydrochloric acid is the most suitable method for converting intermediate 4 to product 5, the desired gamma-pyrone is obtained with Lewis acids such as boron trifluoride-10 etherate, zinc chloride and tin tetrachloride; acidic ion-containing resins such as Amberlite GC-120 or Dowex 50W, and strong organic acids such as p-toluenesulfonic acid or formic acid.

The following examples illustrate the process of the invention, wherein Preparations 1-5 illustrate the preparation of starting materials and Examples 1-8 illustrate the preparation of final products.

Manufacture of starting materials

Preparation 1

To a round bottom 3-necked flask equipped with a magnetic stir bar, jacketed addition funnel, thermometer, and condenser with dry ice was added 22.4 g (0.2 moles) of intermediate 1 (R = CH.j; 2- (1-hydroxyethyl) furan), 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. A solution of cold (-30 °) chlorine (11.0 mL, 0.24 mol) in methanol was then added dropwise to this solution with vigorous stirring. The addition of chlorine was adjusted so that the reaction temperature remained below 40 ° C. The addition took 2 h. After the addition, the reaction mixture was stirred in an ice bath at 30 min. time and then allowed the temperature to return to room temperature. The resulting slurry was filtered, the methanol removed in vacuo, benzene added to the residue, and filtered through a pad of alumina, which was the final filter. Removal of benzene gave 31.9 g (91%) of intermediate 2 (R = CH 3, R '= CH 2; 2,5- (dimethoxy) -2- (1-hydroxyethyl) -2,5-dihydrofuran). This material can be used without further purification, or it can be distilled, b.p. 76-78 ° /.5 mm / 104-107 ° / 10-11 mm, Acta Chem. Scand. 9, 17 (1975).

Analysis: Calculated for C 9 H 18 N 2 O 2: C 55.22 H 8.11 δ Found C 55.34 H 8.04.

Preparation 2

The procedure of Preparation 1 was repeated using Intermediate 1 (R = H; 2- (hydroxymethyl) furan); and obtained intermediate 2 (R = H, R'-CH 2; 2,5- (dimethoxy) -2- (hydroxymethyl) -2,5-di-10-hydrofuran), b.p. 80-82 ° / 5 mm / 71 ° / 1.0 mm, Tetrahedron 27, 1973 (1971) 7.

Preparation 3

The procedure of Preparation 1 was repeated using intermediate 1 (R = C 2 H 2 -; 2- (1-hydroxypropyl) furan) to give intermediate 2 (R = C 2 H 9, R '= CH 3; 2,5- (dimethoxy) -2 - (1-hydroxypropyl) -2,5-dihydrofuran), b.p. 102 ° / 10 mm.

Analysis: Calculated for C 57.50 H 8.58 Found C 57.39 H 8.59.

Preparation 4 The procedure of Preparation 1 was repeated using intermediate 1 (R = CHg; 2- (1-hydroxyethyl) furan), and the methanol was replaced with isopropanol to give intermediate 2 (R = CHg, R '= CH (CH3) 2; 2.5 - (diisopropoxy) -2- (1-hydroxyethyl) -2,5-dihydrofuran), b.p. 62-64 ° / 0.05 mm.

25 Preparation 5

To a small glass electrolysis vessel with a carbon anode and a nickel cathode were added 50 ml of methanol, 0.5 ml of concentrated sulfuric acid and 1.12 g (0.01 mol) of intermediate 1 (R = CH 2; 2- (1-hydroxyethyl) furan) , and the solution was cooled to 30-20 ° C. Electrolysis was performed using a potentiostat / galvanostat, a Model 373 instrument set from Princeton Applied Research Corporation, which provides a constant current of 0.6 A. 30 min. after the reaction time, the reaction solution was poured into water, and the product 2 (R = CH 3, R '= CH 3; 2,5- (di-35-methoxy) -2- (1-hydroxyethyl) -2,5-dihydrofuran) was isolated by extraction with chloroform. This method is similar to that described in U.S. Patent 2,714,576, but with sulfuric acid replacing ammonium bromide as the electrolyte.

r Ό 71315

Manufacture of finished products

Example 1 To a 2 L round bottom 3-necked flask equipped with a magnetic stirrer, dropping funnel and thermometer were added 400 mL of formic acid and 20 mL of methanol. To this solution was added a solution of 104.4 g (0.6 moles) of intermediate 2 (R = CH 3, R '= CH 3> · 2,5-dimethoxy) -2- (1-hydroxyethyl) -2.5 -dihydrofuran), in 40 ml of methanol. The addition by dropwise took 15 min. The reaction mixture was poured into 1 liter of water and extracted 3 times with 500 ml portions of chloroform. The combined chloroform extracts were washed with aqueous sodium carbonate solution and brine. The chloroform solution was evaporated to dryness to give a residual crude yield of 76 g (89%) of compound 3 (R = CH 3, R '= CH 3; 6-methoxy-2-methyl-3,6-dihydro-2H-pyran-3-one) light brown substance. The crude product can be used as it is or it can be distilled at a pressure of 2 mm at 50-52 ° C. / 82-85 ° / 30 mm, Tetrahedron 27, 1973 (1971) 7.

Example 2

The procedure of Example 1 was repeated using anological intermediate 2 (R = H, R '= CH 3; 2,5- (dimethoxy) -2-hydroxymethyl) -2,5-dihydrofuran) to give compound 3 (R = H, R' = CH 3; 6-methoxy-3,6-dihydro-2H-pyran-4-one), b.p. 60-66 ° / 14 mm / 76-81 ° / 23 mm, Tetrahedron 27, 1973 (1971) / · The yield of the non-distilled product was 45%.

Example 3

The procedure of Example 1 was repeated using intermediate 2 (R 2, CH 2, R '(2,5-dimethoxy) -2- (1-hydroxypropyl) -2,5-dihydrofuran) to give compound 3 (R , R '= CH 2); 6-methoxy-2-ethyl-3,6-dihydro-2H-pyran-4-one), b.p.

79-80 ° / 14 mm. The yield of the crude product was 85% and the yield of the distilled product was 57%.

Example 4

The procedure of Example 1 was repeated using intermediate 2 (R = CH 3, R '= isopropyl; 2,5- (diisopropoxy) -2- (1-hydroxyethyl) -2,5-dihydrofuran) to give compound 3 (R = CH 3 , R'-isopropyl; 6- (isopropoxy-2-methyl-3,6-dihydro-1,4-pyran-3-one) The yield of the distilled product was 67% of theory, pnmr / CDCl3: £ 6. , 75 (H, dd), 6.05 (1H, d), 5.25 (1H, d), 2.55 (1H, q), 3.9-4.3 (1H, m), 1.1 -1.6 (9 H, m).

Example 5

The procedure of Example 3 was repeated using 5 trifluoroacetic acid instead of formic acid. The yield of the distilled product was the same as theoretically calculated. The yield of the distilled product was 37%, the boiling point was the same as that of the product of Example 3.

The procedure of Example 1 was repeated using 10% (w / v) citric acid in formic acid instead of formic acid. The yield of the distilled product was 87%, and the yield of the product purified by gas chromatography was 79%.

The procedure of Example 1 was repeated using trifluoroacetic acid instead of formic acid. The yield of the distilled product was 88%, and the yield of the product purified by gas chromatography was 83%.

Example 6

In a round bottom 3-necked flask equipped with 20 addition funnels, a low temperature gauge and a stir bar, a solution of 5.0 g (0.029 mol) of intermediate 2 (R = CH 3, R 2 Cl 2; 2,5- (dimethoxy) was prepared. ) -2- (1-hydroxy-ethyl) -2,5-dihydrofuran) in diethyl ether (10 ml), and the solution was cooled to -40 ° C. To this solution was then added dropwise 1.6 ml of concentrated sulfuric acid, and the black mixture was stirred for 5 min. at -40 ° C, poured into water and the desired compound 3 (R = CH 3, R '= CH 2; 6-methoxy-2-methyl-3,6-dihydro-2H-pyran-3-one) was isolated according to Example 1. method. The yield of the distilled product was 3.64 g (89%), 30 and the yield of the product purified by gas chromatography was 57%. This procedure was repeated to convert intermediate 2 (R = CH3, R '= isopropyl; 2,5- (diisopropoxy) -2- (1-hydroxyethyl) -2,5-dihydrofuran) to compound 3 (R = CH3, R '= isopropyl; 6-isopropoxy-2-methyl-3,6-dihydro-2H-pyran-3-one.

35 The yield of the distilled product was 61%, pnmr as above.

8. · VV 7 71 31 5

Example 7

A solution of intermediate 2 (R = CH3, R '= CH3; 2,5- (dimethoxy) -2- (1-hydroxyethyl) -2,5-dihydrofuran) (7.2 g) in 15 ml of acetone, was stirred in a polyethylene vessel under the protection of nitrogen gas while the reaction vessel was immersed in an ice bath at -10 ° C. A cold solution (-10 ° C) of hydrofluoric acid (3 mL) in 5 mL of acetone was added to the reaction mixture over a period of 1-2 minutes from a polyethylene syringe bottle. Shortly after the addition, the reaction mixture turned to a brown solution, and thin layer chromatography-10 indicated that the reaction was substantially complete after 20-30 minutes at this temperature (-10 ° C). After stirring the mixture for another two hours, the temperature of the ice bath slowly rose to 16 ° C. The reaction mixture was diluted with 200 ml of methylene chloride, washed with 100 ml of water and then with 50 ml of water.

The aqueous extracts were combined and washed with 50 mL of fresh methylene chloride. The methylene chloride extracts were combined and mixed vigorously with 200 ml of water, and the pH of the mixture was adjusted to 7.6 with 0.5 N sodium hydroxide solution.

The layers were separated and the aqueous phase was washed with 50 mL of methylene chloride. The methylene chloride extracts were combined and dried over anhydrous sodium sulfate to which a small amount of activated carbon had been added. The mixture was filtered and concentrated to a yellow oil (7.4 3 g). The crude oil was distilled under high vacuum in a Kugelrohr oven at 110 ° C. The distilled material was collected in 25 containers wrapped in a dry ice / acetone dipped cotton swab (-72 ° C). The obtained distilled oily compound 3 (R = CH3, R '= CH3; 6-methoxy-2-methyl-3,6-dihydro-2H-pyran-3-one) weighed 5.34 g. (The product was crystalline on dry ice / chilled with acetone.) 30 Example 8

To a solution of 20 ml of formic acid and 1 ml of methanol at 10 ° C was added dropwise 5.0 g of intermediate 2 (R = CH 3, R '= CH 3; 2,5- (dimethoxy) -2- (1- hydroxyethyl) -2,5-di-tetrahydrofuran). The mixture was stirred at 10 ° C for 30 minutes, and the desired product 3 (R = CH 3, R '= CH 3; 6-methoxy-2-methyl-3,6-dihydro-2H-pyran-3-one) was isolated according to Example 1. method.

Claims (2)

71 31 5 A process for the preparation of 6-alkoxy-3,6-dihydro-2H-pyran-3-ones of the formula R '0 0 R 10 wherein R' is lower alkyl and R is hydrogen, methyl or ethyl, characterized in that compounds of the formula / - Λ / * 'R'0 ---- \ X-CHOH 15 N, / i wherein R and R 'are as defined above, is treated with a strong substantially anhydrous organic acid having a pKa of not more than 4. Process according to Claim 1, characterized in that formic acid, trifluoroacetic acid or citric acid is used.