DE2359891A1 - PROCESS FOR THE PRODUCTION OF FURANONE DERIVATIVES - Google Patents

Description

DIPL-INQ. DIETER JANDER DR.-INQ. MANFRED BÖNINQ

Patent attorneys delivery address:

reply to:

8MUNCHENSO (BOGENHAUSEn) ■ 1 BERLIN 33 (DAHLEM)

KOLBERGER STRASSE 21 HOTTENWEG 15

Telephone: 0811/982704 Telon: 03 11/8324066

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2353891

New Screech ft J 1 Bcr! ^! n 15 i Cure. Cr; '.e-.damm 65 1 phone 833 50 7 1 I.
, i

97/15 170 DE

November 27, 1973

Patent application

of the company

NAARDM INTERNATIONAL N.7. Huizerstraatweg 28, Naarden bus sum, Netherlands

"Process for the preparation of furanone derivatives"

The present invention relates to a process for the preparation of dihydrofuranone compounds of the general

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Postal check account Berlin West 174384 Berliner Bank AG., Deposit kasse 1

DIPL.-INQ. DIETER JANDER DR.-INQ. MANFRED BONINQ

PATENT LAWYERS O O Γ Π Ο Π Τ

I ο ο r) ο α I

Formula I.

(I), wherein

R. a hydrogen atom, a hydroxy group, a COOH group or a GOO-alkyl group, which is straight or branched chain and contains 1-5 carbon atoms, R _p a straight or branched alkyl group with 1-4 carbon atoms and R-, a hydrogen atom or represents a straight or branched alkyl group having 1-7 carbon atoms.

Of the compounds of the general formula I in which R ^ is a COO-alkyl group, only two compounds have so far been described in the literature, namely those in which E ^ is a methyl group, R _{7 is} a hydrogen atom and R denotes a hydrogen atom or an ethyl group (HeIv. Chim. Acta 46, 1259 (1963), like. 48, 1322 (1965) and the citations given therein). The synthesis indicated is complicated, requires expensive reagents and gives unsatisfactory yields. In addition, only those compounds are obtained in pure form in which the radical R2 contains one more carbon atom than the radical R ₇ . When producing other homologues by this process, mixtures are inevitably obtained.

According to the present invention, dihydrofuran compounds of the formula I can be prepared without these disadvantages occurring.

It is known that the implementation of the ITodium compound of esters of a ß-keto acid with chloroacetyl chloride leads to no defined product and that a large part

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DIPL-INC-UIETERJANDER DR.-INQ. MANFRED BDNINQ PATENT LAWYERS

of the starting material does not react (Ber. 42, 3912 (1909))

Surprisingly, it has now been found that the reaction of the sodium compound of an acyl acetic acid ester with a chromocarboxylic acid halide leads to the formation of dihydrofuran compounds of the formula I, as the following scheme shows:

ROOC Na X 0

c c-

\ ■ Br C-HC

^R i

Compounds of the formula I in which R ^ is a COO-alkyl group are obtained directly via the sodium compounds R ₂ CO-CHN ₁ -COOR, in which R is an alkyl radical. Compounds of the formula I in which R ^ is a COOH group are obtained by the same reaction, but with a subsequent exchange of the radical R for hydrogen. This can be done, for example, by hydrolosis, for example in HeIy. Chim. Acta 46, 1259 (1963). The tert-butyl esters (formula I, R. = COO-tert-butyl) are preferably decomposed thermally. In contrast to the alkaline hydrolysis, for example of the ethyl ester, this reaction proceeds with a practically quantitative yield.

The invention relates to a process for the preparation of dihydrofuranone compounds of the general formula I

(I), wherein

R. a hydrogen atom, a hydroxyl group, a COOH group or a COO-alkyl group which is straight-chain or branched and contains 1-5 carbon atoms ", Rp a straight

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DIPU-INQ. DIETER JANDER DR-INQ. MANFRED BÖNINQ

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or branched alkyl group with 1-4 carbon atoms and R represents a hydrogen atom or a straight or branched alkyl group with 1-7 carbon atoms, which is characterized in that a 2-bromoalkanoyl halide R ^ CHBrCOX, in which R _{7 is} the above Has meaning and X is a halogen atom, with the sodium compound of an acyl acetic acid alkyl ester RpCOCHpGOOR, in which Rp has the meaning given above and R represents a straight or branched alkyl group with 1-5 carbon atoms, is optionally converted into the 2,5-substituted 5-keto- (2H) -furan-4-carboxylic acid alkyl esters converts the COOR group into the COOH group in a manner known per se or replaces it with a hydroxyl group or a hydrogen atom.

The process thus first leads to compounds of the formula I, which are then converted into 3- (2H) -furanones of the general Formula II

(H)

and 4 - hydroxy-3- (2H) -furanones of the general formula III

(III)

can be converted.

Many compounds of the general formula II or III have valuable organoleptic properties and are suitable are therefore used in the manufacture of flavored foods and beverages or perfumed articles and products.

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DIPL-INQ. DIETER JANDER DR.-INQ. MANFRED BONINC PATENT LAWYERS

Thus, 2,5-dimethyl-3 ~ (2H) -furanone (formula II, R ₂ = R ₅ = ^ is a flavoring substance of coffee (J.Agr. Food Chem. 19, 530, tf971)), while 2-n -Hexyl-5-methyl-3- (2H) -furanone (Formula II, Ep = CH ^, R ^ = n-CgH. ^) Is a component of onion oil (J. Agr. Food Chem «, 19, 984 ( 1971)) - 2,5-Dimethyl-4-hydroxy-3- (2H) -furanone (formula III, R ₂ = R ₅ = CH ^) was used as a flavoring substance in pineapple (J. Food Sci. 30, 280 (1965 )) and found in bouillon, in which 4-hydroxy-5-methyl-3- (2H) -furanone (formula III, R ₂ = CH ,, R, = H) occurs (J. Agr. Food Chem. 16, 1016 (1968)).

The preparation of compounds of formula III is common in the literature "(Proc.Am.Soc. Brewing Chem. 1963, 84; HeIv.Chim.Acta 49, 53 (1966); J.Org.Chem. 31, (1966)). Patent applications are also known for various processes (e.g. the laid-open Dutch Patent applications 68 083 77, 68 084 52 and 71 009 14).

However, for the above-mentioned procedures, they have to be very expensive Starting materials are used, or the synthesis is laborious, or the yields are low.

The conversion of compounds of formula I wherein R ^. is a COO-alkyl group, in compounds of the formula II can be carried out by treatment with dilute mineral acid (HeIv.Chim.Acta 46, 1259 (1963)). The yields are between 10 and 15 % of theory. A better and more economical process consists in treating compounds of the formula I in which R _{-1 is} the COOH group with sodium methylate and subsequent decarboxylation, yields of between 30 and 50 % of theory being obtained. By treating compounds of the formula I in which R. is a COOH group with hydrogen peroxide in a weakly alkaline medium (analogously to J.Org.Chem. 26, 250 (1961)) and

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DIPL-ING. DIETER JANDER DR.INQ. MANFRED BONINQ

PATENT Attorneys r \ Q C QOQ "1

subsequent decarboxylation under the influence of acid Compounds of the formula III obtained in a yield of 20-40 # of theory.

The process according to the invention is illustrated by Examples 1 to 8 inclusive. The conversion of compounds of the general formula I into compounds of the general formula II is described in Examples 9 to 12 inclusive. The conversion into compounds of the general formula III is shown in Examples 13 to 16. In the preparation of compounds of the general formula III, in which Rp £ R ₂ . isomeran mixtures are always obtained, as the IR and NMR spectra show.

example 1

Production of 2,5-dimethyl- ^z f -carbethoxy-3- (2H) -furanone (formula I, R ₁ = COOC ₂ H ₅ , R ₃ = R ₃ = CH ₅ ).

23 g of metallic sodium are dissolved in xylene at 90-100 ° C suspended. After cooling to about 20 ° C, the xylene is replaced by 30 ml of dry ether. 143 g of ethyl acetate are added to the mixture so quickly that the ether just boils. After the addition is complete the reaction mixture is heated on a water bath until practically all of the sodium has disappeared. The White The suspension is then cooled to -20 ° C. and a solution of 80 g of 2-bromopropionyl chloride in 100 ml of dry Ether was added over the course of an hour, the temperature being kept between -20 and -15 ° C. After the addition is stirred for a further hour at -20 ° C. Thereafter, the reaction mixture is stirred over the course of 12 Brought to room temperature for hours. 200 ml of water are added and the aqueous phase becomes from the ethereal Solution separated, then with lye and with water

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is washed. After drying over magnesium sulfate, the ether and excess acetyl acetic ester are removed by distillation. The residue is distilled under reduced pressure (2mm Hg) at 102-110.degree. The distillate solidifies on standing at -20 ° C. The pure compound is obtained by crystallization from hexane. Yield: 49 g (54 #), I ¹ P-: -51.5-53 ° C. NMRz ₀₁ : 1.33 (3H, t, J = 7 cps); 1.46 (3H, t, J = 7 cps);

⁴ 2.55 (3H, d, J = 0.8 cps); 4.25 (2H, q, J = 7 cps);

4.49 (1H, q, J = 7 cps).
IR: (CCl ₄ ): 5.83; 6.22; 7.10; 8.62.

Example 2-

5-Methyl-4-carbethoxy-3- (2H) -furanone (formula I, R ₁ = COOG ₂ H ₅ , R ₂ = CH ₅ , R, = H) was prepared in an analogous manner.

Yield 41 #, m.p .: 76-77 ° C

NMR: ^ ₀₀₁ : 1.32 (3H, t, J = 7 cps); 2.55 (3H, t, J = 0.8 cps);

⁴ 4.25 (2H, q, J = 7 cps); 4.48 (2H, q, J = 0.8 cps); IR: (CCl ₄ ): 5.82; 6.21; 7.01; 7.12; 8.69.

Example 3

2-n-Hexyl-5-methyl-4-carbethoxy-3- (2H) -furanone was prepared analogously to Example 1 (Formula I, R ₁ = COOC ₂ H ₅ , R ₂ = CH- ,, R ₅ = nC ₆ H ₁₅ ), yield 51 #, mp ^: about 25 ° C.

T: 0.8-1.1 (3H, m); 1.15-2.1 (13H, m); 2.57

(3H, d, J = 0.8 cps); 4.25 (2H, q, J =? Cps);

about 4.5 (1H, m).

Example 4

2-methyl-5-n-propyl-4-carbethoxy-3- (2H) -furanone (Formula I, R ₁ = COOC ₂ H ₅ , R ₂ = 11-C ₅ H ₇ , R ₅ = CH ₃ ) produced according to the process given in Example 1: Yield 48 #, boiling point 95-97 ° C./1 mm Hg, η 20 / D: 1.4810. . :

IR. (CCl ₄ ): 5.71; 5.82; 6.29; 8.64; 9.60,

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PATENT LAWYERS 0 Q RQ P Q 1

example 5

Preparation of 2,5-dimethyl-4-car'boxy-3- (2H) -furanone (formula I, R ₁ = COOH, R ₂ = R ₃ = CH ₃ ).

Analogously to Example 1, a suspension of 23 g of sodium in ether is prepared. 175 S tert-butyl acetylacetonate is added so quickly that the ether just remains at the boil. After the addition, the mixture is heated on the water bath for a further 4 hours until practically all of the sodium has disappeared. The white reaction mass is cooled to -20.degree. C. and a solution of 86 g of 2-bromopropionyl octiloride is added over the course of one hour at a temperature of between -20 and -25.degree. The mixture is stirred at this temperature for a further hour. The temperature of the solution is then brought to room temperature over the course of 12 hours while stirring. 200 ml of water are added, the ether phase is separated off, washed with lye and dried over magnesium sulfate. The ether and excess tert-butyl acetylacetonate are removed by distillation. The residue is then heated under reduced pressure (about 15 mm Hg). At 140 - I5O ⁰ C begins the decomposition of the tertiary-butyl ester which can be recognized by the pressure increase. The decomposition can be accelerated by adding a catalytic amount of p-toluenesulfonic acid. When the decomposition has ended after about 30 minutes, the residue is distilled at a pressure of 1 mm Hg. The free acid is obtained as a slightly yellow viscous liquid which slowly crystallizes on standing and can be obtained in pure form by crystallization from methanol. Yield 39 g (46 #), m.p .: 64-65 ° C

^NMR: ^ CCT ^{: 1.56 (3H} ' ^d » ^{J =} 7 cps); 2.68 (3H, d, J = 1.1 cps); * 4.78 (1H, q, J = 7 cps); 8.03 (iH, s).

Examples 6 with 8

In the manner indicated in Example 5, the following were analogous

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Substances made:

2-ethyl-5-methyl-4-carboxy-3 - (2H) -furanone (! Formula I, E ₁ = COOH, R ₂ = C ₂ H ₅ , R ₃ = CH ₃ ). Yield 48 #, m.p .: 55-56 ° C: 1.04- (3H, t, J = 7cps); 1.60-2.30 (2H, m); 2.72 (3H, d, J = 1.2 cps); 4.78 (1H, t, J = 7cps).

2-Isopropyl-5-methyl-4-carboxy-3- (2H) -furanone (Formula -I, R ₁ = COOH, R ₂ = 1-C ₃ H ₇ , R ₅ = CH ₃ ). Yield 39 #, m.p .: 49-50 ° C.

NMR: </ " _GDC1 : 0.99 (3H, d, J = 12 cps); 1.11 (3H, d, J = 12 cps); ³ 1.90-2.60 (1H, m); 2 , 72 (3H, d, J = 1.2 cps); 4.66 (1H, m).

2-n-Butyl-5-methyl-4-carboxy-3- (2H) -furanone (Formula ^, 1, R ₁ = COOH, R ₂ = nC ^ Hg, R ₃ = CH ₃ ), yield 45 ^, Melting point: 67 - 68 ° C. ·

NMR: CT ₀₃₀₁ : 0.70-2.20 (9H, m); 2.71 (3H, d, J = 1.1 cps); ³ 4.60-5.00 (1H, m).

Example 9

Preparation of 2,5-dimethyl-3- (2H) -: furanone (formula II, R ₂ = R ₃ = CH ₃ ).

a) From 2,5-dimethyl-4-carbethoxy-3- (2H) -furanone.

18.4 g of the starting material are heated to boiling with 250 ml of 2N sulfuric acid. After cooling, the reaction mixture is extracted with ether. The. The ether layer is washed with NaHCO ^ solution and then with water until it reacts neutral. Then it is dried over magnesium sulfate. After the ether has been distilled off, it is fractionated. 2.4 g of (22 #) 2,5-dimethyl-3- (2H) -furanone, boiling point: 66-80 ° C / 15 mm Hg, n20 / D: 1.4755 are obtained. NMR: ^ ₀₀₁ : 1.35 (3H, d, J = 7 cps); 2.18 (3H, t, J = 0.8 cps); ^ 4.34 (iH, q, J = 7 cps); 5.29 (iH, s).

b) From 2,5-dimethyl-4-carboxy-3- (2H) -furanone.

15.6 g of starting material become a solution of 32 g

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DIPL-INC /. DIETER JANDER DR.-INQ. MANFRED BoNINC /

PATENT LAWYERS 2 3 5989

Given sodium methylate in 100 ml of methanol. The mixture is left to stand at room temperature for 24 hours. Afterward it is cooled to 0 ° C and slightly diluted hydrochloric acid is added until it is neutral to litmus reacted. The volume is brought to 500 ml with water. The product is isolated in a known manner by means of ether extraction and fractionation. The yield is 3.3 g (30 #). Bp: 67-68 ° C / 15mm "Hg, n ^ O / D: 1.4-756. NMR: see under a.

Examples 10 with 12

Analogously to example 9b, the following were produced:

2-n-Hexyl-5-methyl-3- (2H) -furanone (Formula II, ₂

R ₃ = UC ₆ H ₁₃ ), yield: 35 #, boiling point: 79-81 ° C / 3mm Hg, n20 / D: 1

2-ethyl-5-methyl-3- (2H) -furanone (formula II, R ₂ = GH ₃ , R = G ₂ H ₅ ), yield 33 #, boiling point: 78 - 79 ° C / 15 mm Hg, n20 / D: 1,4-744-,

2-n-Butyl-5-methyl-3- (2H) -furanone (Formula II, R ₂ = CH ^, R,, yield 28 #, b.p .: 101-103 ° C / 15 mm Hg, n20 / D :

1.4-720.

Example 13

Preparation of 2,5-dimethyl-4-hydroxy-3- (2H) -furanone (formula III, R ₂ = R = CH ₃ ).

15.6 g of 2,5-dimethyl-4-carboxy-3- (2H) -furanone are suspended in 60 ml of water and the pH is adjusted to 8.5 with 4N NaOH. 12.5 ml of 30% hydrogen peroxide solution are added over the course of 30 minutes. The pH is kept between 8.0 and 8.5 by adding 1N NaOH. The reaction temperature is set from 30 to 40 ⁰ C. After the addition, the mixture is stirred for a further 30 minutes, then it is cooled to 0 C and acidified with dilute hydrochloric acid.

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Continuous ether extraction for 6 hours and working up in the usual way gives 4.0 g (30 % ") of the crossed product, melting point 79-80 ° G. NMR _{CT 03301} : 1.42 (3H, d, J = cps ); 2.21 (3H, d, J, = 1, Ö cps); ⁵ 4.50 (1H, q, J = 7cps); ca 7 (1H, s, broad).

Examples 14 with 16

The following isomer mixtures were prepared analogously to Example 13 :

2-methyl-5-ethyl-4-hydroxy-3- (2H) -furanone and 2-ethyl- _T 5-methyl-4-hydroxy-3- (2H) -furanone (ratio 1: 2), formula III, R ₂ = C ₂ H, R-, = CH, or R ₂ = CH ₅ , R ₅ = C ₃ H ₅ , yield 37 #, b.p .: 79-83 C / 0.2 mm Hg.

2-methyl-5-isopropyl- and 2-isopropyl-5-methyl-4-hydro3cy-3- (2H) -furanone (ratio 2: 3), formula III, R ₂ = 1-C ₅ H ₁₇ , R ₃ =, CH ₅ or R ₂ = CH _{1, R 5} = 1-C ₇ H ₇ , yield 40 ^, b.p .: 85-93 ° C / 0.5 mm Hg.

2-methyl-5-n-butyl- and 2-n-buty4-5-methyl-4-hydroxy-3- (2H) -furanone (ratio 1: 1), formula III, R ₂ = nC ^ Hq, R , = GR-, or R ₂ = CH ₃ , R ₃ = nC ^ H ₉ , yield 35 #, boiling point: 98-104 ° C / 0.3 mm Hg.

The NMR and IR spectra were consistent with the activity the mixtures of the compounds. The presence of two components was proven by means of liquid-liquid chromatography. The fflR spectrum of the mixture from Example 14 is correct with that published in Swiss patent specification 491.904 Spectrum match.

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Claims (2)

Patent claims: ~ Λ » Process for the preparation of dihydrofuranone derivatives of the general formula I. I, in which R. a hydrogen atom, a hydroxy group, a COOH group or a GOO-alkyl group, which is straight or branched chain and contains 1-5 carbon atoms, R ₂ a straight or branched alkyl group with 1-4 carbon atoms and R ₇ a hydrogen atom or represents a straight or branched alkyl group with 1-7 carbon atoms, characterized in that a 2-bromoalkanoyl _{halide R 7} CHBr-COX, in which R _{7 has} the meaning given above and X is a halogen atom, with the sodium compound of an alkyl acylacetate RpCOCEUCOOR, in which Rp has the meaning given above and R represents a straight or branched alkyl group with 1-5 carbon atoms, converts and optionally in the 2,5-substituted 3-keto- (2H) -furan-4-carboxylic acid alkyl esters the COOR group known per se Manner converted to the COOH group or replaced by a hydroxyl group or a hydrogen atom. 2. The method according to claim 1, characterized in that the compound with R ^ = COO-tert-butyl is prepared and this is then converted thermolytically with or without acid catalysis into the free acid (formula I, R _x . = COOH), DJ: DG 409823/1 170