Preparation process of 1-alkyl-4-methyl-2, 3-diol-1, 4-butanedione

Abstract

The invention relates to the field of organic synthesis, particularly discloses a preparation process of 1-alkyl-4-methyl-2, 3-diol-1, 4-butanedione, and provides a preparation process of 1-alkyl-4-methyl-2, 3-diol-1, 4-butanedione by taking 1, 3-dihydroxyacetone (compound 1) and a hydroxy ketone compound (compound 2) as raw materials and by adding a catalyst (compound 3). The invention relates to a preparation process of 1-alkyl-4-methyl-2, 3-diol-1, 4-butanedione (compound 3), which comprises the following steps of: performing condensation reaction in a water-containing medium under the catalysis of an acid catalyst to obtain the 1-alkyl-4-methyl-2, 3-diol-1, 4-butanedione (compound 3), and has the advantages of abundant raw material source, simple reaction operation, mild reaction condition, higher yield and low cost; water is used as a reaction solvent, a homogeneous catalyst is simple in treatment and small in pollution, and if a heterogeneous catalyst is used, the heterogeneous catalyst can be repeatedly used after being simply filtered.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a process for preparing 1-alkyl-4-methyl-2,3-diol-1,4-butanedione. BACKGROUND

[0002] 1-alkyl-4-methyl-2,3-diol-1,4-butanedione (compound 3) can be used as a starting material for certain flavorants in the flavor and fragrance industry, such as 4-hydroxy-2,5-dimethyl-3(2H)-furanone (known as furaneol or pineapple ketone, FEMA 3174), 5-ethyl-4-hydroxy-2-methyl-3(2H)-furanone (soy sauce ketone FEMA 3623).

[0003] The reported synthesis methods of compound 3 are mainly as follows: Method one: using methylglyoxal as raw material, using various catalysts to couple to obtain compound 3, mainly electrochemical method (EP 368211 B1), zinc powder method (J. Org. Chem, 1973, 38, 123), TiCl3catalytic method (J. Org. Chem., 1989, 54, 3872), Cu(I) catalytic method (J. Am. Chem. Soc., 1966, 88, 5498) and hydroxymethyl sulfonate catalytic method (WO2006048792).

[0004] Method two: 2,5-dimethylfuran reacts with bromine in methanol to obtain 2,5-dimethyl-2,5-dimethoxy-2,5-dihydrofuran, and then is oxidized with potassium chlorate and osmium tetroxide in aqueous tetrahydrofuran to obtain almost quantitative erythro 3,4-dihydroxyhexane-2,5-dione. This method uses the highly toxic osmium tetroxide (J. Org. Chem., 1978, 43, 4245).

[0005] Method three: using tartaric acid as raw material, four steps are needed to synthesize 3,4-dihydroxyhexane-2,5-dione (J. Chem. Soc. Perkin. Trans. I, 1985, 795). Method four: using ketone aldehyde and hydroxy ketone to obtain by Aldol condensation, for example, under the catalysis of zinc (magnesium) acetate (WO2006048795), or under the catalysis of various acids (WO2008142592), or under the catalysis of organic amine salt (CN110511129).

[0006] 1,3-dihydroxyacetone is a naturally occurring ketose, has biodegradability, edible and non-toxic to the human body and the environment, is a multifunctional additive, which can be used in cosmetics, pharmaceuticals and food industry. According to literature research, there is no process report on the synthesis of 1-alkyl-4-methyl-2,3-diol-1,4-butanedione using 1,3-dihydroxyacetone as a raw material.

[0007] The method reported in the prior art has the defects of more steps, low yield, use of harmful heavy metal salt, complicated product purification and environmental unfriendliness. Therefore, an efficient and environmentally friendly synthesis process is needed for preparing the compound. SUMMARY

[0008] In order to solve the problems existing in the prior art, the first aspect of the present application provides a preparation process of 1-alkyl-4-methyl-2,3-diol-1,4-butanedione, characterized in that the reaction formula is as follows:

[0009] The compound 1, the compound 2, the reaction medium and the acidic catalyst are mixed to obtain a mixture, and the reaction obtains the compound 3. The R is a substituted or unsubstituted alkyl group. The reaction medium comprises water, and the mass fraction of water in the mixture is greater than 30wt%.

[0010] In some embodiments, the mass fraction of water in the mixture is optionally greater than 30wt%, 40wt%, 50wt%, 60wt%, 70wt%, 80wt%, 90wt%.

[0011] In some embodiments, the R is a linear or branched alkyl group.

[0012] In some embodiments, the R is a C1 to C10 alkyl group.

[0013] In some embodiments, the R is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group or a heptyl group.

[0014] In some embodiments, the R is a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.

[0015] In some embodiments, the acidic catalyst is selected from a liquid acid or a solid acid, and the liquid acid is selected from any one of phosphoric acid, sulfuric acid, hydrochloric acid, formic acid, nitric acid or oxalic acid.

[0016] In some embodiments, the acidic catalyst is selected from a solid acid, and the solid acid is selected from any one of tartaric acid or an acidic resin.

[0017] In some embodiments, the acidic resin is Amberlyst® 15.

[0018] In some embodiments, the reaction medium comprises water or a mixture of water and an organic solvent.

[0019] In some embodiments, the reaction occurs under acidic conditions.

[0020] In some embodiments, the pH of the reaction is 0-5, in some specific embodiments of the first aspect, the pH of the reaction is optionally 1, 2, 3, 4.

[0021] In some embodiments, the reaction occurs in a homogeneous or heterogeneous phase.

[0022] In some embodiments, the mass of the catalyst charged per 1 L of reaction medium is 8.69-200 g, in some specific embodiments of the first aspect, the mass of the catalyst charged per 1 L of reaction medium is optionally 10 g, 30 g, 50 g, 70 g, 90 g, 110 g, 130 g, 150 g, 170 g, 190 g.

[0023] In some embodiments, the mass of compound 1 charged per 1 L of reaction medium is 144-281.5 g, in some specific embodiments of the first aspect, the mass of compound 1 charged per 1 L of reaction medium is optionally 150 g, 170 g, 190 g, 210 g, 230 g, 250 g, 270 g.

[0024] In some embodiments, the mass of compound 2 charged per 1 L of reaction medium is 356.5-1230 g, in some specific embodiments of the first aspect, the mass of compound 2 charged per 1 L of reaction medium is optionally 360 g, 460 g, 560 g, 660 g, 760 g, 860 g, 960 g, 1060 g, 1160 g.

[0025] In some embodiments, the reaction temperature is 0-110 °C, in some embodiments, the reaction temperature is optionally 50-100 °C, or 10 °C, 30 °C, 50 °C, 70 °C, 90 °C.

[0026] Amberlyst® 15 is purchased from Merck Sharp & Dohme under the model number Amberlyst® 15; Nanda Synthetic A35 is purchased from Jiangyin Nanda Synthetic Chemical Co., Ltd. under the model number A35; Nanda Synthetic A45 is purchased from Jiangyin Nanda Synthetic Chemical Co., Ltd. under the model number A45; Dowex® 50WX4 is purchased from Shanghai Anpu Experimental Science and Technology Co., Ltd. and the model is Dowex® 50WX4; The reagents used in the present application are all purchased from open and legal markets and are not further purified.

[0027] In some embodiments, the room temperature is 5-45℃, in some embodiments, the room temperature is 10-40℃, in some embodiments, the room temperature is 15-35℃, in some embodiments, the room temperature is 20-30℃, and in some embodiments, the room temperature is 25℃.

[0028] The beneficial effects of the present application are: 1. The raw material 1,3-dihydroxyacetone of the present application is a bio-based raw material, which is abundant in source, simple in reaction operation, high in yield, low in cost, and suitable for small batch preparation in laboratory and industrial production.

[0029] 2. The present application uses water as the reaction solvent, and the homogeneous catalyst is simple to handle and has little pollution. If a heterogeneous catalyst is used, it can be repeatedly used after simple filtration. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 The gas chromatogram of the reaction distillation crude product of Example 1 of the present application is shown in the figure, with ethyl acetate as the dilution solvent; Figure 2 The gas chromatogram of the reaction distillation crude product of Example 2 of the present application is shown in the figure, with ethyl acetate as the dilution solvent; Figure 3 The nuclear magnetic resonance spectrum of the main product of Example 3 of the present application is shown in the figure, with CDCl3 as the detection solvent; Figure 4 The nuclear magnetic resonance spectrum of the main product of Example 3 of the present application is shown in the figure, with CDCl3 as the detection solvent; Figure 5 The gas chromatogram of the reaction distillation crude product of Example 3 of the present application is shown in the figure, with ethyl acetate as the dilution solvent; Figure 6 The infrared spectrum of the main product of Example 3 of the present application is shown in the figure. DETAILED DESCRIPTION

[0031] The further features, advantages and effects of the present application will be more clearly and thoroughly understood by those skilled in the art through the further detailed description of the embodiments of the present application in conjunction with the accompanying drawings and specific embodiments.

[0032] Example 1:

[0033] Into the reaction flask, 1,3-dihydroxyacetone 50 g, water 230 g, 47% hydroxyacetone aqueous solution 261 g, Amberlyst® 15 resin 20 g, start stirring, gradually warming, after the internal temperature reaches 100°C, reaction for 16 h, stop the reaction, cooling, suction filtration, recover the catalyst, the mother liquor is extracted with ethyl acetate (5 x 250 mL). Concentrate the organic matter, get crude product 150 g, diaphragm pump vacuum, recover hydroxyacetone 60 g, content 92%, switch to oil pump distillation, get crude product 58.4 g (sum of the threo and erythro isomers), content 82.8%, using ethyl acetate recrystallization, get pure product 31 g, the total yield is 59.6%.

[0034] According to the same experimental procedure as described above, several other experiments were carried out using heterogeneous catalyst. The results are summarized in Table 1.

[0035] Table 1 Summary of the results of the condensation reaction of 1,3-dihydroxyacetone with hydroxyacetone in the presence of heterogeneous catalyst

[0036] Example 2:

[0037] Into the reaction flask, 1,3-dihydroxyacetone 50 g, water 177.6 g, 47% hydroxyacetone 261 g, 47% sulfuric acid 22 g, start stirring, gradually warming, after the internal temperature reaches 100°C, HPLC monitoring reaction progress, after the content reaches the highest peak, stop the reaction, start cooling, gradually add 40% sodium hydroxide solution to the reaction liquid, adjust the pH to 7, ethyl acetate extraction (5 x 250 mL). Concentrate the organic matter, get crude product 141 g, diaphragm pump vacuum, recover hydroxyacetone 59 g, content 91.1%, switch to oil pump distillation, get crude product 58 g, content 78.3% (threo + erythro), using ethyl acetate recrystallization, get pure product 30 g, the total yield is 56%.

[0038] According to the same experimental procedure as described above, several other experiments were carried out using homogeneous catalyst. The results are summarized in Table 2.

[0039] Table 2 Summary of the results of the condensation reaction of 1,3-dihydroxyacetone with hydroxyacetone in the presence of homogeneous catalyst

[0040] Example 3:

[0041] To a reaction flask, add 100 g of 1,3-dihydroxyacetone, 450 g of water, 300 g of 85% hydroxybutanone, and 42 g of Amberlyst® 15 acidic resin. Stirring was initiated and the temperature was gradually increased. Once the internal temperature reached 100°C, the reaction progress was monitored by HPLC. The reaction was stopped after 6 h, the temperature was lowered, the mixture was filtered, and the catalyst was recovered. The mother liquor was extracted with ethyl acetate (5 x 300 mL). The organic matter was concentrated to obtain 312 g of crude product. Vacuuming with a diaphragm pump recovered 158 g of hydroxybutanone with a content of 88.6%. Switching to an oil pump for distillation, 117 g of product was obtained with a content of 80.9% (threo + erythro). Recrystallization from ethyl acetate yielded 56 g of pure product (the main product), for a total yield of 53%. NMR of the main product: 1 H NMR (500 MHz, CDCl3, ppm): δ4.59 (d, J=5 Hz,1H), 4.58 (d, J=5 Hz,1H), 3.59 (brs, 2H), 2.66-2.78(m, 1H), 2.53-2.65(m, 1H), 2.36(s, 3H), 1.18(t,J=5 Hz, 3H),; 13 C NMR (125 MHz, CDCl3, ppm): δ 208.1, 205.3, 77.6, 76.8, 31.3, 25.4,7.4. IR (ATR) νmax: 3476, 2982, 2941, 2917, 2878, 1712, 1667, 1456, 1402,1364, 1265, 1224, 1153, 1114, 1093, 1063, 1033 cm-1 Example 4:

[0042] To the reaction flask, add 11.4 g of 1,3-dihydroxyacetone, 32 g of water, 33 g of 82% hydroxybutanone, and 5 g of 47% sulfuric acid. Stirring was initiated and the temperature was gradually increased. After the internal temperature reached 100°C, the reaction was allowed to proceed for 3 hours. The reaction was stopped and the temperature was lowered. 40% sodium hydroxide solution was gradually added dropwise to the reaction solution to adjust the pH to 7. Extraction was then performed with ethyl acetate (5 × 80 mL). The organic matter was concentrated to obtain 30 g of crude product. Vacuuming with a diaphragm pump recovered 20.1 g of hydroxyacetone (90% content). Switching to an oil pump for distillation yielded 10.7 g of product (68.6% content (threo + erythro), for a total yield of 36.2%).

[0043] The above merely describes preferred embodiments of the present application, and therefore cannot limit the scope of the present application, i.e. equivalent changes and modifications made according to the scope of the present application and the content of the specification should still be within the scope of the present application.

Claims

1. A process for preparing 1-alkyl-4-methyl-2,3-diol-1,4-butanedione, characterized in that: The reaction formula is as follows: ； Compound 1, compound 2, a reaction medium and an acidic catalyst are mixed to obtain a mixture, and the mixture is reacted to obtain compound 3; Said R is a substituted or unsubstituted alkyl group; The reaction medium includes water, and the mass fraction of water in the mixture is greater than 30 wt %.

2. The preparation process of compound 3 according to claim 1, characterized in that: The R is a linear or branched alkyl group; and / or, the R is a C1 to C10 alkyl group.

3. The preparation process according to any one of claims 1 or 2, characterized in that: The R is a C1 to C3 straight chain or branched alkyl group, a C4 to C6 straight chain or branched alkyl group, a C7 to C10 straight chain or branched alkyl group; and / or, the R is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, or a heptyl group; and / or, the R is a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

4. The preparation process according to any one of claims 1 to 3, characterized in that: The acidic catalyst is selected from a liquid acid or a solid acid, and the liquid acid is selected from any one of phosphoric acid, sulfuric acid, hydrochloric acid, formic acid, nitric acid or oxalic acid; and / or, the acidic catalyst is selected from a solid acid, and the solid acid is selected from any one of tartaric acid and an acidic resin; and / or, the acidic resin is Amberlyst® 15.

5. The preparation process according to claims 1 to 4, characterized in that: The reaction medium includes water or a mixture of water and an organic solvent.

6. The preparation process according to claims 1 to 5, characterized in that: The reaction occurs under acidic conditions; and / or the pH of the reaction is 0-5.

7. The preparation process according to claims 1 to 6, characterized in that: The reaction occurs in a homogeneous or heterogeneous phase.

8. The preparation process according to claims 1 to 7, characterized in that: The catalyst is fed in an amount of 8.69 to 200 g per 1 L of reaction medium.

9. The preparation process according to claims 1 to 8, characterized in that: The mass of the compound 1 in each 1 L of reaction medium is 144-281.5 g; and / or the mass of the compound 2 in each 1 L of reaction medium is 356.5-1230 g.

10. The preparation process according to claims 1 to 9, characterized in that: The reaction temperature is 50~100℃.

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