DK148020B - METHOD FOR PREPARING 6-ALCOXY-2H-PYRANE-3 (6H) -ON COMPOUNDS - Google Patents

Description

in 148020

This invention relates to a particular process for preparing known 6-alkoxy-2H-pyran-3 (6H) -one compounds of the formula set forth in the preamble of claim 1. These compounds have been found to be useful as intermediates for the preparation of γ-pyrones, including 3-hydroxy-4H-pyran-4-one (pyromeconic acid) and 3-hydroxy-2-methyl-4H-pyran-4-one (maltol ), by a process which is the subject of Danish Patent Application No. 1463/79.

6-Alkoxy-2H-pyran-3 (6H) -one compounds of this kind have been previously prepared by a two-step process described by 0. Achmatovi / icz et al., Tetrahedron, 27 (1971), p. 1996, wherein dialkoxydihydrofuran compounds of formula ή ~ r 'wherein R "'" means hydrogen, alkyl, alkenyl, phenyl or 2-benzyl, and R means alkyl, are hydrolyzed with acid under rearrangement to hydroxypyranones of formula wherein R 1 is as defined above and these are converted to the desired alkoxy pyranones for approx. 40¾ yield by treatment with alkyl orthoformate under Levi / ice acid catalysis. This process has the disadvantages of low yield, involves cumbersome isolation of the hydroxy pyranone and requires expensive reagents to convert it to the alkoxy pyranone.

2 148020

The object of the invention is to provide a process which allows direct conversion of the dialkoxydihydrofurans to the desired 6-alkoxy-2H-pyran-3 (6H) -ones in good yield.

This is achieved by the method according to the invention, which is characterized by the characterizing part of claim 1.

The dialkoxydihydrofuran starting materials are readily available in high yield from furfural, an inexpensive raw material manufactured industrially from pentosanes contained in straw and bran.

In this specification and claims, the terms "alkyl" and "alkenyl" shall include both straight and branched chains.

The reactions for preparing the starting compounds from furfural when R is alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, phenyl or benzyl, or from furfuryl alcohol when R is the hydrogen-like reaction of the process of the invention can be reproduced by the following reaction scheme : O Ovr ^ \ o - ^ \ / or electrolysis

CHO p — H

Oc 'XX

0 in R'O ^ ° ^ \ where: X = chlorine, bromine or iodine, X '= chlorine or bromine, R' = alkyl of 1-6 carbon atoms, R = hydrogen, alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, phenyl or benzyl, R "= alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, phenyl or benzyl.

When R is hydrogen, as mentioned, one is based on furfuryl alcohol (intermediate 1, R = H), which is a commercially available compound and proceeds according to the reaction scheme.

The reaction of furfural with the corresponding Grignard reagent is described in Chemical Abstracts 44, 1092d (1950).

The preparation of the intermediate 2 (R = H) by electrolysis in methanol is described in U.S. Patent No. 2,714,576 and Acta Chem. Scand. 6, 545 (1952). The synthesis using bromine in methanol is reported in Ann. 516, 231 (1935). The general idea of using chlorine in an alcoholic solvent is also well known (e.g., from GB Patent No. 595,041).

It has been found that the reaction of the intermediate 1 with chlorine in an alcoholic solvent at a temperature between -70 and 50 ° C gives a pure conversion to the desired intermediate 2 when the HCl by-product is neutralized with a base such as ammonia, sodium carbonate or other .alkali metal bases. Although the early literature on this reaction indicates yields of up to about 50%, the process disclosed herein results in yields in excess of 90? 6.

4 U8020

Intermediate 2 (R = CH 2) is described in Acta Chem. Scand.

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

As mentioned, the treatment of the intermediate 2 with a strong acid is unknown and gives the desired 6-alkoxy derivative 3 directly in high yield, avoiding the formation of the corresponding hydroxy derivative which is very unstable to further reactions. The intermediate 2 is contacted with an acid which is preferably substantially anhydrous, although the presence of a protic solvent such as an alcohol or a small amount of water is in fact beneficial. After this treatment, product 3 is separated from the acidic medium in a purity state suitable for further conversion by conventional extraction technique. Although formic acid and trifluoroacetic acid are preferred, any acid having a pKa of approximately 4 or less will convert the intermediate 2 to the desired intermediate 3. Other suitable organic acids include p-toluenesulfonic acid, methanesulfonic acid, citric acid, oxalic acid and chloroacetic acid; Suitable mineral acids include sulfuric acid, hydrochloric acid and phosphoric acid. Acidic resins such as "Amberlite ® GC-120" and "Dov / ex ® 50W" may also be used. Intermediate 3 (RsCl 2 CH 2) is a novel compound which can be prepared from the corresponding intermediate 2 (RCl 2 CH 2) by the process of the invention.

The prepared 6-alkoxy-2H-pyran-3 (6H) -one compounds (intermediate 3) can be epoxidized to the corresponding 4,5-epoxy compounds by treatment with hydrogen peroxide in a solvent in the presence of a base and the epoxy compounds converted into useful '/' pyrons by treatment with an acid, as described and exemplified in Danish Patent Application No. 1463/79.

5 148020

The following example serves to further elucidate the process of the invention, while the following preparation illustrates the preparation of the starting materials.

PREPARATION

Intermediate_1 -> _ Intermediate_2 1. In a 3-necked, round bottom flask equipped with a magnetic stirrer, sheath, thermometer and dry condenser addition funnel, 22.4 g (0.2 mole) of intermediate 1 (R = CH 2), 100 ml of methanol were charged. and 21.1 g (0.2 mole) 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 controlled so that the reaction temperature was kept below 40 ° C. The addition required about 2 hours. After the addition, the reaction mixture was stirred at ice bath temperature for 30 minutes and then allowed to warm to room temperature. The resulting slurry was filtered, the methanol removed in vacuo, the residue taken up in benzene and passed through an alumina plug as final filter. Removal of the benzene gave 31.9 g (91 ° ό) of the desired dimethoxydihydrofuran 2 (R = CH 2, R '= CH 2). This material can be used without further purification or it can be distilled, bp. 76-78 ° C / 5 mmHg [104-107 ° C / 10-11 mmHg, Acta Chem. Scand. 9 (1953)].

Analysis:

Calculated for C CH₂O₂C 55.22 - H 8.11

Found: C, 55.34 - H, 8.04.

6 The procedure of 1 was repeated with intermediate 1 (R = H) to obtain intermediate 2 (R = H, R '= CH 3), b.p. 80-82 ° C / 5 mmHg [71 ° C / 1.0 mmHg, Tetrahedron 27, 1973 (1971)].

3. The procedure of 1 was repeated with intermediate 1 (RrCh 2 CH 2) to give intermediate 2 (R = CH 2 CH 3, R's CH 3), b.p. 102 ° C / 10 mmHg.

Analysis:

Calculated for C CH ^HOO: C 57.50 - H 8.58

Found: C 57.39 - H 8.59.

4. The procedure of 1 was repeated using intermediate 1 (RrCH 2), replacing methanol with isopropyl alcohol, to give intermediate 2 [R = CH 3, R '= CH (CH 3) 21, bp. 62-64 ° C / 0.05 mmHg.

5. Place in a small glass electrolysis vessel with a carbon anode and nickel cathode 50 ml of methanol, 0.5 ml of concentrated sulfuric acid and 1.12 g (0.01 mol) of the intermediate 1 (R = CH 3) and the solution was cooled to -20 ° C.

An electrolysis was then performed using a potentiostat / galvanostat instrument Princeton Applied Research Corporation Model 373, set to deliver a constant current of 0.6 A. After a reaction time of 30 minutes, the reaction mixture was poured into water and the intermediate 2 ( R = CH3, R '= CH3) were isolated by a chloroform extraction procedure. The physical properties of the product were consistent with the product of 1. This procedure is similar to that described in U.S. Patent No. 2,714,576, since sulfuric acid replaces ammonium bromide as the electrolyte.

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EXAMPLE

Intermediate 2 — Intermediate 3 1. To a 2-liter 3-neck round bottom flask equipped with magnetic stirrer, drip funnel and thermometer was added 400 ml of formic acid and 20 ml: methanol. To this solution was added a solution of 104.4 g (0.6 mol) of intermediate 2 (R = CH 2, R 1 = CH) in 40 ml of methanol. The dropwise addition required 13 minutes. The reaction mixture was poured into 1 liter of water and extracted three times with 500 ml portions of chloroform. The combined chloroform solutions were washed with an aqueous sodium hydrogen carbonate solution and with brine. The chloroform solution was evaporated to give a crude yield of 76 g (89%) of intermediate 3 (R = CH 2, R '= CH 2). The crude material can be used as such or distilled at a pressure of 2 mmHg, 50-52 ° C [82-85 ° C / 30 mmHg, Tetrahedron 27, 1973 (1971)].

2. The procedure of 1 was repeated with an analogous intermediate 2 (R = H, R'sCl3) to obtain intermediate 3 (R = H, R '= CH 3), b.p. 60-66 ° C / 14 mmHg [76-81 ° C / 23 mmHg, Tetrahedron 2_7, 1973 (1971)].

3. The procedure of 1 was repeated with an analogous intermediate 2 (R = CH2CH3, R '= CH3) to obtain intermediate 3 (R = CH2CH3, R' = CH3), b.p. 79-80 ° C 14 mmHg.

4. The procedure of 1 was repeated with 2,5-dihydro-2- (1-hydroxyethyl) -2,5-diisopropoxyfuran to give 6-isopropoxy-2-methyl-2H-pyran-3 (6H) -one. The yield of un-distilled product was 67¾ of the theoretical. 1 H-NMR / CDCl 3 / δ: 6.75 (H, cl of d); 6.05 (1H, d); 5.25 (1H, d); 4.55 (1H, q); 3.9-4.3 (1H, m) j 1.1-1.6 (9H, m).

8 The procedure of 4 was repeated, replacing formic acid with trifluoroacetic acid to give the same product in 76% yield.

6. The procedure of 1 was repeated using 5/0 (w / v) citric acid in formic acid instead of formic acid. The yield of the distilled product was 87¾} the yield of gas-liquid chromatographic test was 79¾.

7. The procedure from 1 was repeated using trifluoroacetic acid instead of formic acid. The yield of the distilled product was 88¾} the yield by gas-liquid chromatograph i was 85¾.

8. In a 3-necked, round bottom flask equipped with addition funnel, low temperature thermometer and magnetic stirrer, a solution of 5.0 g (0.029 mole) of 2,5-di-hydro-2- (1-hydroxyethyl) -2.5 was prepared. -dimethoxyfuran 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 minutes at -40 ° C, poured into water, forming 6-methoxy-2-methyl-2H-pyran-3 ( 6H) -one was isolated by the procedure of 1. The yield of the distilled product was 3.64 g (89? Ό)} the yield by gas-liquid chromatographic test was 57¾.

9. The procedure of 8 was repeated to convert intermediate 2 (R = methyl, R '= isopropyl) to intermediate 3 (R = methyl, R' = isopropyl). The yield of the exhibited product was 61¾. 1 H NMR was as above 4.

10. In a polyethylene container, a solution of 7.2 g of intermediate 2 (R = CH 2, R '= CH 2) in 15 ml of acetone was stirred under nitrogen, immersed in an ice bath at -10 ° C. Over 1 - 2 minutes, a cold (-10 ° C) solution of hydrogen fluoride (3 ml) in 5 ml of acetone was added from a polyethylene spray bottle. The reaction mixture turned to a brown solution shortly after the addition and the reaction was substantially complete after 20-30 minutes at this temperature (-10 ° C) as confirmed by thin layer chromatography. With stirring for a total of 2 hours, the temperature of the ice bath rose slowly to 16 ° C. The reaction mixture was diluted with 200 ml of methylene chloride, washed with 100 ml of water and then with 500 ml of water. The combined aqueous extracts were washed with 50 ml of fresh methylene chloride. The combined methylene chloride extracts were stirred vigorously with 200 ml of water while the pH was adjusted to 7.6 with 0.5 N sodium hydroxide solution. The layers were separated and the aqueous portion washed with 50 ml of methylene chloride. The methylene chloride extracts were combined and dried over anhydrous sodium sulfate, to which was added a small amount of activated charcoal. The mixture was filtered and concentrated to a yellow oil, 7.43 g. The crude oil was distilled under high vacuum in a Kugelrohr oven by immersing the flask containing the crude oil at 110 ° C. The distilled material was collected in a small round bottom flask which was cooled by wrapping in cotton dipped in dry ice / acetone at -72 ° C. The amount of distilled intermediate 3 obtained (R = CH3, R'rCH4) crystalline upon cooling with dry ice / acetone was 5.34 g (91%).