Method for preparing gamma, delta-unsaturated ketone by using oxalic acid and mixed acid catalyst thereof

Abstract

The invention discloses a method for preparing gamma, delta-unsaturated ketone by using oxalic acid and a mixed acid catalyst thereof. The invention provides a preparation method of a compound as shown in a formula I. The preparation method comprises the following steps: a compound as shown in a formula II and a compound as shown in a formula III are subjected to ketonization reaction at 90-120 DEG C in the presence of a catalyst to generate the compound as shown in the formula I. R1 is C1-C3 alkyl, R2 is C1-C16 alkyl or C2-C16 alkenyl; the catalyst is oxalic acid or mixed acid of oxalic acid and acid A; the acid A is selected from one or more of phosphorous acid, phosphoric acid, alkyl sulfonic acid or aryl sulfonic acid; in the mixed acid, the molar percentage content of the oxalic acid is greater than 50%. According to the preparation method, the reaction selectivity can be improved, and side reactions and high-boiling raffinate are reduced; the catalyst is low in cost, and the reaction system is high in yield. The preparation method disclosed by the invention is simple and convenient to operate, low in cost, green and environment-friendly.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing γ,δ-unsaturated ketones using oxalic acid and its mixed acid catalysts. Background Technology

[0002] The γ,δ-unsaturated ketones prepared by the Saucy-Marbet reaction of allyl alcohol and 2-methoxypropylene are key intermediates of isophytol: methyl heptenone, geranylacetone (pseudoionone), and farnesylacetone. Their preparation process is characterized by high selectivity and few side reactions, and they are widely used in the development of intermediate processes for vitamins A and E, as well as fragrances and flavorings.

[0003] CN102197014A discloses a method for preparing methylheptenone, geranylacetone, and farnesylacetone by using ammonium chloride, ammonium bromide, and diammonium hydrogen phosphate as catalysts and reacting methylbutenol, linalool, and nerolidol with 2-methoxypropene, respectively. This method avoids the use of strong acid conditions and allows the catalysts to catalyze the reaction for a long time. The disadvantages of this reaction are that the reaction time is long, the catalyst is an inorganic salt solid, which is inconvenient to feed, and the ammonium salt decomposes during the reaction, which increases the difficulty of post-processing.

[0004] CN116829528A discloses a method for producing γ,δ-unsaturated ketones from vinyl tertiary methanol using organic tertiary ammonium salts or quaternary ammonium salts as catalysts, respectively, with vinyl ethers and ketals. Specifically, the catalysts are a series of tertiary and quaternary ammonium salts obtained by reacting organic bases such as triethylammonium, pyridinium, and tetrabutylammonium with phosphoric acid and sulfuric acid, respectively. Using this series of catalysts to catalyze allyl alcohol and 2-methoxypropylene, respectively, yields the corresponding intermediates methylheptenone and geranylacetone, with reaction times generally exceeding 16 hours and yields reaching up to approximately 92%.

[0005] CN1228757A discloses a method for preparing γ,δ-unsaturated ketones using organophosphate esters as catalysts. The reaction is carried out in a high-pressure reactor at 130-160°C for 7-9 hours, with a yield of 82%-93%. However, most of the organophosphate ester catalysts used in this method are relatively expensive.

[0006] Numerous literature and patent reports describe Saucy-Marbet ketation reactions using alkynols and allyl ethers as raw materials to prepare unsaturated ketones, generally exhibiting good selectivity and high yields. However, enols readily undergo dehydration under acid catalysts, forming more stable conjugated diene structures. Therefore, acid catalysts are required to promote the reaction while minimizing side reactions. There is an urgent need to screen and optimize catalytic systems that offer high selectivity, low cost, and ease of operation. Summary of the Invention

[0007] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing γ,δ-unsaturated ketones using oxalic acid and its mixed acid catalysts. This method improves reaction selectivity, reduces side reactions and the generation of high-boiling residues; the catalyst is low-cost, the reaction system yield is high, and it is a simple, low-cost, and environmentally friendly preparation method. This invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a method for preparing a compound of formula I, comprising the following steps: at 90-120°C, in the presence of a catalyst, a compound of formula II and a compound of formula III undergo a ketation reaction to generate a compound of formula I.

[0009] ,

[0010] Wherein, R1 is a C1-C3 alkyl group, and R2 is a C1-C3 alkyl group. 16 Alkyl or C2-C 16 alkenyl groups;

[0011] The catalyst is oxalic acid, or a mixture of oxalic acid and acid A; acid A is selected from one or more of phosphorous acid, phosphoric acid, alkyl sulfonic acid, and aryl sulfonic acid, and the molar percentage of oxalic acid in the mixed acid is greater than 50%. The inventors found in their research that most common catalysts for Saucy-Marbet ketation reactions tend to produce large amounts of byproducts and exhibit poor selectivity in ordinary reactors. Through extensive screening and research, this invention has discovered that when the catalytic system is predominantly oxalic acid, at a certain temperature, allyl ethers can undergo Saucy-Marbet ketation reactions with high conversion and high selectivity under conventional reaction equipment.

[0012] In one embodiment, the C1-C3 alkyl groups are straight-chain or branched alkyl groups, for example, straight-chain alkyl groups of C1-C3.

[0013] In one scheme, the C1-C 16 The alkyl group is a straight-chain or branched alkyl group, such as C1-C1. 12 Straight-chain or branched alkyl groups, for example, C6 or C6 alkyl groups. 11 Branched alkyl groups.

[0014] In one scheme, the C2-C 16 The alkenyl group can be a straight-chain or branched alkenyl group, such as C6-C. 12 Straight-chain or branched alkenyl groups, for example, C6 or C6. 11 Branched alkenyl groups.

[0015] In one scheme, the C2-C 16The alkenyl group contains 1 to 3 double bonds, for example, the double bonds are selected from one or more positions between the 3rd and 4th carbons, between the 7th and 8th carbons, and between the 11th and 12th carbons.

[0016] In one particular scheme, R1 is a methyl group.

[0017] In one particular scheme, R2 is methyl, , , , or .

[0018] In one embodiment, the compound of formula I is any of the following compounds: methylbutenol, linalool, dihydrolinalool, nerolidol, dihydronerolidol, or tetrahydronerolidol.

[0019] In one embodiment, the alkyl sulfonic acid may be methanesulfonic acid.

[0020] In one embodiment, the aryl sulfonic acid may be a substituted or unsubstituted aryl sulfonic acid, such as a substituted or unsubstituted benzenesulfonic acid, or an alkyl-substituted benzenesulfonic acid, and more preferably p-toluenesulfonic acid.

[0021] In one embodiment, the catalyst is soluble in an organic solvent selected from one or more of alcohol solvents, ketone solvents, and 2,2-dimethoxypropane.

[0022] In one embodiment, the alcohol solvent may be methanol.

[0023] In one embodiment, the ketone solvent may be acetone.

[0024] The catalyst of the present invention can be dissolved in conventional solvents, and more preferably, another product generated in the reaction is used as the solvent, which reduces the possibility of introducing impurities in the reaction and is more environmentally friendly.

[0025] In one embodiment, the mass ratio of the catalyst to the organic solvent may be 1:(30-200), for example, 1:50 or 1:100.

[0026] In one embodiment, when the catalyst is oxalic acid, the catalyst can be added over a period of 9-12 hours.

[0027] In one embodiment, when the catalyst is a mixture of oxalic acid and acid A, the catalyst can be added over a period of 5-9 hours.

[0028] This invention achieves a balance between reaction efficiency, yield, and selectivity by controlling the drop rate of the catalyst.

[0029] In one embodiment, when the catalyst is oxalic acid, the catalyst addition rate can be 0.5-3.0 mmol / h, for example 0.75 mmol / h, 1.18 mmol / h, or 2.3 mmol / h.

[0030] In one embodiment, when the catalyst is a mixture of oxalic acid and acid A, the catalyst addition rate can be 0.3-2.0 mmol / h, for example 0.55 mmol / h, 0.78 mmol / h or 1.59 mmol / h.

[0031] In one embodiment, when the compound of formula II is methylbutenol and the catalyst is oxalic acid, the catalyst addition rate can be 1.5-3 mmol / h, for example 2.3 mmol / h.

[0032] In one embodiment, when the compound of formula II is dihydrolinalool and the catalyst is oxalic acid, the catalyst addition rate can be 0.5-2 mmol / h, for example 1.18 mmol / h.

[0033] In one embodiment, when the compound of formula II is dihydronerol and the catalyst is oxalic acid, the catalyst addition rate can be 0.5-1.5 mmol / h, for example, 0.75 mmol / h.

[0034] In one embodiment, when the compound of formula II is methylbutenol and the catalyst is a mixed acid, the catalyst addition rate can be 1-2 mmol / h, for example 1.59 mmol / h.

[0035] In one embodiment, when the compound of formula II is dihydrolinalool and the catalyst is a mixed acid, the catalyst addition rate can be 0.3-1.5 mmol / h, for example 0.78 mmol / h.

[0036] In one embodiment, when the compound of formula II is dihydroneryl tertrol and the catalyst is a mixed acid, the catalyst addition rate can be 0.3-1.0 mmol / h, for example 0.55 mmol / h.

[0037] In one embodiment, in a mixture of oxalic acid and acid A, the molar ratio of oxalic acid to acid A can be (5-20):1, for example, 10:1.

[0038] In one embodiment, when the catalyst is oxalic acid, the molar ratio of the catalyst to the compound of formula II is (0.015-0.025):1, for example, 0.02:1.

[0039] In one embodiment, when the catalyst is a mixed acid, the molar ratio of the catalyst to the compound of formula II is (0.01-0.012):1, for example, 0.011:1.

[0040] In one embodiment, the molar ratio of the compound of formula II to the compound of formula III may be 1:(2-5), preferably 1:(2.5-3), for example 1:3.

[0041] In one embodiment, the reaction temperature of the ketation reaction can be 100-110°C.

[0042] In one embodiment, the catalyst may be added by dripping; the dripping may be done using a pressure pump, such as a medium-pressure pump.

[0043] In one embodiment, the ketation reaction may be replaced with an inert gas, such as nitrogen.

[0044] In one embodiment, the post-treatment of the ketation reaction includes the following steps: lowering the temperature to 20-35°C (e.g., 25-30°C), followed by atmospheric distillation at 35-50°C (e.g., 40-55°C) to recover unreacted 2-methoxypropylene, and then continuing vacuum distillation (e.g., at 50-70 kPa) to recover the organic solvent.

[0045] In one embodiment, the compound of formula I can be obtained by vacuum distillation, which can be distillation at 0.5-3 kPa, for example at 0.6-0.8 kPa, 1-1.2 kPa or 2-3 kPa.

[0046] The positive and progressive effects of this invention are as follows:

[0047] (1) This invention improves the selectivity of Saucy-Marbet ketation reaction of enols and allyl ethers. By using oxalic acid and its mixed acid catalysts, the high-boiling residual liquid caused by the dimerization or dehydration of enol raw materials due to high temperature, strong acid or long reaction time is reduced. The product has high selectivity, high yield and high purity.

[0048] (2) The oxalic acid and its mixed acid catalysts used in this invention are low in cost and have controllable acidity. Using mixed acids can increase the reaction rate, shorten the reaction time, and improve the reaction conversion rate.

[0049] (3) The continuous pumping of acidic catalyst solution used in this invention can realize both single-reactor intermittent operation and pipeline reaction as well as continuous operation of multi-reactor series reaction.

[0050] (4) By controlling the time of continuous pumping of acidic catalyst, the present invention achieves high reaction efficiency while minimizing side reactions. Detailed Implementation

[0051] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0052] General instructions:

[0053] The medium-pressure pump has a pressure range of 0-20MPa, model CP1020, and was purchased from Shanghai Sanwei Scientific Instruments Co., Ltd.

[0054] The chromatographic conditions used to determine the purity of methylheptenone in the following examples are as follows:

[0055] Injector temperature 200°C, detector temperature 260°C, detector type: FID, column temperature: initial temperature 60°C, hold for 2 min, increase to 240°C at a rate of 10°C / min, hold for 15 min.

[0056] Split ratio 50:1, flow rate 2.0 ml / min. Injection volume 0.2 μL, column dimensions 30 m * 0.32 mm * 1.0 μm, column model: DB-WAX

[0057] Sample preparation: Take 1 ml of sample and add 3-4 drops of triethylamine.

[0058] The chromatographic conditions used to determine the purity of dihydrogeranylacetone and dihydrofarnesylacetone in the following examples are as follows:

[0059] Injector temperature 200°C, detector temperature 260°C, detector type: FID, column temperature: initial temperature 60°C, hold for 2 min, increase to 240°C at a rate of 20°C / min, hold for 15 min.

[0060] Split ratio 50:1, flow rate 2.0 ml / min. Injection volume 0.2 μL, column dimensions 30 m * 0.32 mm * 1.0 μm, column model: DB-WAX

[0061] Example 1 Synthesis of methylheptenone

[0062]

[0063] Preparation of oxalic acid solution: At a temperature of 20-30℃, dissolve oxalic acid (2.1g, 0.023mol, 0.02eq) in 50 times the volume of 2,2-dimethoxypropane (105g, 50wt / wt) solution to obtain a 2%wt / wt oxalic acid 2,2-dimethoxypropane solution.

[0064] In a 1L autoclave, after purging with nitrogen, methylbutenol (100.0 g, 1.163 mol, 1.0 eq) and 2-methoxypropene (251.5 g, 3.488 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 2% wt / wt oxalic acid solution in 2,2-dimethoxypropane was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 10 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered under normal pressure at 40-50℃. A small amount of acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70 kPa). Finally, the temperature was raised to 80-90℃, and vacuum distillation (2-3 kPa) was performed to obtain methylheptenone.

[0065] The reaction conversion rate was 99.0%, the selectivity was 97.5%, and the yield was 93.6%.

[0066] 1 H NMR (400 MHz, CDCl3) δ 5.05 (t, J = 8.4 Hz, 1H), 2.44 (t, J = 7.4Hz, 2H), 2.24 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H).

[0067] Example 2 Synthesis of methylheptenone

[0068] Preparation of oxalic acid-phosphorous acid mixed acid solution: At a temperature of 20-30℃, dissolve oxalic acid (1.05g, 0.0115mol, 0.01eq) and phosphorous acid (0.09g, 0.0012mol, 0.001eq) in 100 times the amount of acetone (114g, 100wt / wt) to obtain a 1%wt / wt mixed acid solution.

[0069] In a 1L autoclave, after purging with nitrogen, methylbutenol (100.0g, 1.163mol, 1.0eq) and 2-methoxypropene (251.5g, 3.488mol, 3.0eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt mixed acid solution was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 8 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃) for later reuse. Acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70kPa), and finally, the temperature was raised to 80-90℃, and vacuum distillation (2-3kPa) was performed to obtain methylheptenone.

[0070] The reaction conversion rate was 99.5%, the selectivity was 96.9%, and the yield was 92.7%.

[0071] 1 H NMR (400 MHz, CDCl3) δ 5.05 (t, J = 8.4 Hz, 1H), 2.44 (t, J = 7.4Hz, 2H), 2.24 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H).

[0072] The amount of methylbutenol and 2-methoxypropylene fed, the experimental conditions and the operating steps in Examples 3-5 were the same as in Example 2 (only the type, quality and dropping time of the acid catalyst were different).

[0073] Data from Examples 1-5 are shown in Table 1:

[0074] Table 1

[0075]

[0076] Note: Total acid molar ratio = (number of moles of acid catalyst / number of moles of methylbutenol) * 100%

[0077] Example 6 Synthesis of dihydrogeranylacetone

[0078]

[0079] Preparation of oxalic acid solution: At 20-30℃, dissolve oxalic acid (1.15g, 0.013mol, 0.02eq) in 100 times its volume of 2,2-dimethoxypropane (115g, 100wt / wt) solution to obtain a 1%wt / wt oxalic acid 2,2-dimethoxypropane solution.

[0080] In a 1L autoclave, after purging with nitrogen, dihydrolinalool (100.0 g, 0.641 mol, 1.0 eq) and 2-methoxypropene (139 g, 1.928 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt oxalic acid solution of 2,2-dimethoxypropane was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 11 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃). Further vacuum distillation (50-70 kPa) was performed to recover small amounts of acetone and 2,2-dimethoxypropane. Finally, the temperature was raised to 100-110℃, and vacuum distillation (1-1.2 kPa) was performed to obtain dihydrogeranylacetone.

[0081] The reaction conversion rate was 98.8%, the selectivity was 97.0%, and the yield was 93.3%.

[0082] 1 H NMR (400 MHz, CDCl3) δ 5.06 (td, J = 7.1, 1.2 Hz, 1H), 2.47 – 2.42(m, 2H), 2.30 – 2.21 (m, 2H), 2.13 (s, 3H), 2.02 – 1.90 (m, 2H), 1.66 – 1.60(d, J = 1.2 Hz, 3H), 1.57 – 1.47 (m, 1H), 1.42 – 1.31 (m, 2H), 1.19 – 1.08(m, 2H), 0.87 (d, J = 6.6 Hz, 3H), 0.87 – 0.84 (d, J = 6.6 Hz, 3H).

[0083] Example 7 Synthesis of dihydrogeranylacetone

[0084] Preparation of oxalic acid-phosphorous acid mixed acid solution: At a temperature of 20-30℃, dissolve oxalic acid (0.58g, 0.0064mol, 0.01eq) and phosphorous acid (0.053g, 0.00064mol, 0.001eq) in 100 times the amount of acetone (63.3g, 100wt / wt) to obtain a 1%wt / wt mixed acid solution.

[0085] In a 1L autoclave, after purging with nitrogen, dihydrolinalool (100.0 g, 0.641 mol, 1.0 eq) and 2-methoxypropene (139 g, 1.928 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt mixed acid solution was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 9 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃) for later reuse. Acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70 kPa). Finally, the temperature was raised to 100-110℃, and vacuum distillation (1-1.2 kPa) was performed to obtain dihydrogeranylacetone.

[0086] The reaction conversion rate was 99.5%, the selectivity was 96.9%, and the yield was 92.7%.

[0087] 1H NMR (400 MHz, CDCl3) δ 5.06 (td, J = 7.1, 1.2 Hz, 1H), 2.47 – 2.42(m, 2H), 2.30 – 2.21 (m, 2H), 2.13 (s, 3H), 2.02 – 1.90 (m, 2H), 1.66 – 1.60(d, J = 1.2 Hz, 3H), 1.57 – 1.47 (m, 1H), 1.42 – 1.31 (m, 2H), 1.19 – 1.08(m, 2H), 0.87 (d, J = 6.6 Hz, 3H), 0.87 – 0.84 (d, J = 6.6 Hz, 3H).

[0088] The amount of dihydrolinalool and 2-methoxypropylene fed in Examples 8-10, the experimental conditions and operating procedures are the same as in Example 7 (only the type, quality and dropping time of the acid catalyst are different).

[0089] Data from Examples 6-10 are shown in Table 2:

[0090] Table 2

[0091]

[0092] Note: Total acid molar ratio = (number of moles of acid catalyst / number of moles of dihydrolinalool) * 100%

[0093] Example 11 Synthesis of dihydrofarnesylacetone

[0094]

[0095] Preparation of oxalic acid solution: At 20-30℃, dissolve oxalic acid (0.80g, 0.009mol, 0.02eq) in 100 times its volume of 2,2-dimethoxypropane (80g, 100wt / wt) solution to obtain a 1%wt / wt oxalic acid 2,2-dimethoxypropane solution.

[0096] In a 1L autoclave, after purging with nitrogen, dihydroneratol (100.0 g, 0.446 mol, 1.0 eq) and 2-methoxypropene (96.6 g, 1.339 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt oxalic acid solution in 2,2-dimethoxypropane was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 12 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃). Small amounts of acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70 kPa). Finally, the temperature was raised to 120-130℃, and vacuum distillation (0.6-0.8 kPa) was performed to obtain dihydrofarnesylacetone.

[0097] The reaction conversion rate was 98.5%, the selectivity was 97.2%, and the yield was 93.1%.

[0098] 1 H NMR (400 MHz, CDCl3) δ 5.09 – 5.06 (m, 2H), 2.48 – 2.41 (m, 2H), 2.26 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 2.09 – 1.90 (m, 6H), 1.69 – 1.64 (m,2H), 1.59 (m, 4H), 1.52 (m, 1H), 1.41 – 1.31 (m, 2H), 1.19 – 1.08 (m, 2H), 0.88 (d, J = 6.6 Hz, 3H), 0.88 – 0.86 (d, J = 6.6 Hz, 3H).

[0099] Example 12 Synthesis of dihydrofarnesylacetone

[0100] Preparation of oxalic acid-phosphorous acid mixed acid solution: At a temperature of 20-30℃, dissolve oxalic acid (0.40 g, 0.0045 mol, 0.01 eq) and phosphorous acid (0.037 g, 0.00045 mol, 0.001 eq) in 100 times the amount of acetone (40.4 g, 100 wt / wt) to obtain a 1% wt / wt mixed acid solution.

[0101] In a 1L autoclave, after purging with nitrogen, dihydroneratol (100.0 g, 0.446 mol, 1.0 eq) and 2-methoxypropene (96.6 g, 1.339 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt mixed acid solution was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 9 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃) for later reuse. Acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70 kPa). Finally, the temperature was raised to 120-130℃, and vacuum distillation (0.6-0.8 kPa) was performed to obtain dihydrofarnesylacetone.

[0102] The amount of dihydroneryl alcohol and 2-methoxypropylene in Examples 13-15, the experimental conditions and operating procedures are the same as in Example 12 (only the type, quality and dropping time of the acid catalyst are different).

[0103] The reaction conversion rate was 98.8%, the selectivity was 96.5%, and the yield was 92.1%.

[0104] 1 H NMR (400 MHz, CDCl3) δ 5.09 – 5.06 (m, 2H), 2.48 – 2.41 (m, 2H), 2.26 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 2.09 – 1.90 (m, 6H), 1.69 – 1.64 (m,2H), 1.59 (m, 4H), 1.52 (m, 1H), 1.41 – 1.31 (m, 2H), 1.19 – 1.08 (m, 2H), 0.88 (d, J = 6.6 Hz, 3H), 0.88 – 0.86 (d, J = 6.6 Hz, 3H).

[0105] Data from Examples 11-15 are shown in Table 3:

[0106] Table 3

[0107]

[0108] Note: Total acid molar ratio = (number of moles of acid catalyst / number of moles of dihydronerol) * 100%

[0109] Comparative Example 1: Synthesis of Methylheptenone

[0110] Preparation of p-toluenesulfonic acid solution: At a temperature of 0-30℃, dissolve p-toluenesulfonic acid (1.01, 0.0058 ol, 0.005) in 100 times the amount of acetone (101 g, 100 wt / wt) to obtain a 1% wt / wt acid solution.

[0111] In a 1L autoclave, after purging with nitrogen, methylbutenol (100.0g, 1.163mol, 1.0eq) and 2-methoxypropene (251.5g, 3.488mol, 3.0eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt p-toluenesulfonic acid solution was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 4 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃) for later reuse. Acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70kPa), and finally, the temperature was raised to 80-90℃, and vacuum distillation (2-3kPa) was performed to obtain methylheptenone.

[0112] The reaction conversion rate was 100%, the selectivity was 79.5%, and the yield was 78.3%.

[0113] Comparative Example 2: Synthesis of dihydrogeranylacetone

[0114] Preparation of methanesulfonic acid solution: At a temperature of 0-30℃, dissolve methanesulfonic acid (0.31, 0.0033 mol, 0.005 eq) in 100 times its volume of acetone (31 g, 100 wt / wt) to obtain a 1% wt / wt acid solution.

[0115] In a 1L autoclave, after purging with nitrogen, dihydrolinalool (100.0 g, 0.641 mol, 1.0 eq) and 2-methoxypropene (139 g, 1.928 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt methanesulfonic acid solution was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 4 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃) for later reuse. Acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70 kPa). Finally, the temperature was raised to 100-110℃, and vacuum distillation (1-1.2 kPa) was performed to obtain dihydrogeranylacetone.

[0116] The reaction conversion rate was 100%, the selectivity was 83.5%, and the yield was 81.6%.

[0117] Comparative Example 3: Synthesis of dihydrofarnesylacetone

[0118] Preparation of phosphorous acid solution: At a temperature of 0-30℃, dissolve phosphorous acid (0.73, 0.0089 mol, 0.02 eq) in 100 times its volume of acetone (73 g, 100 wt / wt) to obtain a 1% wt / wt acid solution.

[0119] In a 1L autoclave, after purging with nitrogen, dihydroneratol (100.0 g, 0.446 mol, 1.0 eq) and 2-methoxypropene (96.6 g, 1.339 mol, 3.0 eq) were added. The temperature was raised to 100-110℃, and a 1% wt / wt solution of phosphorous acid was added dropwise using a medium-pressure pump, controlling the autoclave temperature between 100-110℃ for approximately 7 hours. The temperature was then lowered to 25-30℃, and the material was transferred to a distillation flask. Unreacted 2-methoxypropene was recovered at atmospheric pressure (40-50℃) for later reuse. Acetone and 2,2-dimethoxypropane were recovered by vacuum distillation (50-70 kPa). Finally, the temperature was raised to 120-130℃, and vacuum distillation (0.6-0.8 kPa) was performed to obtain dihydrofarnesylacetone.

[0120] The reaction conversion rate was 99.7%, the selectivity was 92.2%, and the yield was 86.8%.

[0121] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that, It includes the following steps: At 90-120°C, in the presence of a catalyst, compounds of formula II and III undergo ketation to produce compound I. ， Wherein, R1 is a C1-C3 alkyl group, and R2 is a C1-C3 alkyl group. 16 Alkyl or C2-C 16 alkenyl groups; The catalyst is oxalic acid, or a mixture of oxalic acid and acid A; acid A is selected from one or more of phosphorous acid, phosphoric acid, alkyl sulfonic acid and aryl sulfonic acid; in the mixed acid, the molar percentage of oxalic acid is greater than 50%.

2. The method for preparing the compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The alkyl groups of C1-C3 are straight-chain or branched alkyl groups; (2) The C1-C 16 The alkyl group is a straight-chain or branched alkyl group; (3) The C2-C 16 The alkenyl group can be a straight-chain or branched alkenyl group; (4) The C2-C 16 The alkenyl group contains 1-3 double bonds; (5) The C2-C 16 The alkenyl double bond is selected from one or more positions between the 3rd and 4th carbons, between the 7th and 8th carbons, and between the 11th and 12th carbons; (6) The alkyl sulfonic acid is methanesulfonic acid; (7) The aryl sulfonic acid is a substituted or unsubstituted aryl sulfonic acid; (8) When the catalyst is oxalic acid, the catalyst is added at a time of 9-12 hours; (9) When the catalyst is the mixed acid, the catalyst is added over a period of 5-9 hours. (10) When the catalyst is oxalic acid, the catalyst is added at a rate of 0.5-3.0 mmol / h; (11) When the catalyst is a mixture of oxalic acid and acid A, the catalyst addition rate is 0.3-2.0 mmol / h; (12) The catalyst is added by dripping.

3. The method for preparing the compound of formula I as described in claim 2, characterized in that, It meets one or more of the following conditions: (1) The C1-C3 alkyl group is a C1-C3 straight-chain alkyl group; (2) The C1-C 16 The alkyl group is C1-C 12 Straight-chain or branched alkyl groups; (3) The C2-C 16 The alkenyl group is C6-C 12 Straight-chain or branched alkenyl groups; (4) The aryl sulfonic acid is a substituted or unsubstituted benzenesulfonic acid; (5) When the catalyst is oxalic acid, the addition rate of the catalyst is 0.75 mmol / h, 1.18 mmol / h or 2.3 mmol / h; (6) When the catalyst is a mixture of oxalic acid and acid A, the catalyst addition rate is 0.55 mmol / h, 0.78 mmol / h or 1.59 mmol / h; (7) The dripping is done using a pressure pump.

4. The method for preparing the compound of formula I as described in claim 3, characterized in that, It meets one or more of the following conditions: (1) The alkyl group of C1-C3 is methyl; (2) The C1-C 16 The alkyl group is methyl, C6 branched alkyl, or C6 branched alkyl. 11 Branched alkyl groups; (3) The C2-C 16 The alkenyl group is a C6 branched alkenyl or C6 branched alkenyl. 11 Branched alkenyl groups; (4) The aryl sulfonic acid is an alkyl-substituted benzenesulfonic acid; (5) The dripping is done using a medium-pressure pump.

5. The method for preparing the compound of formula I as described in claim 4, characterized in that, It meets one or two of the following conditions: (1) R2 is methyl, , , , or ; (2) The aryl sulfonic acid is p-toluenesulfonic acid.

6. The method for preparing the compound of formula I as described in claim 5, characterized in that, The compound of Formula I is any one of the following compounds: methylbutenol, linalool, dihydrolinalool, nerolidol, dihydronerolidol, or tetrahydronerolidol.

7. A method for preparing the compound of formula I according to any one of claims 1-6, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of the catalyst to the compound of formula II is (0.005-0.05):1; (2) The molar ratio of the compound of formula II to the compound of formula III is 1:(2-5); (3) In the mixed acid, the molar ratio of oxalic acid to acid A is (5-20):

1.

8. The method for preparing the compound of formula I as described in claim 7, characterized in that, It meets one or more of the following conditions: (1) When the catalyst is oxalic acid, the molar ratio of the catalyst to the compound of formula II is (0.015-0.025):1; (2) When the catalyst is a mixed acid, the molar ratio of the catalyst to the compound of formula II is (0.01-0.012):1; (3) The molar ratio of the compound of formula II to the compound of formula III is 1:(2.0-5.0); (4) In the mixed acid, the molar ratio of oxalic acid to acid A is 10:1; (5) The reaction temperature of the ketation reaction is 100-110℃; (6) The compound of formula I is obtained by vacuum distillation.

9. The method for preparing the compound of formula I as described in claim 8, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of the compound of formula II to the compound of formula III is 1:(2.5-3.0); (2) The catalyst is dissolved in an organic solvent, wherein the organic solvent is selected from one or more of alcohol solvents, ketone solvents and 2,2-dimethoxypropane; (3) The ketation reaction is performed using an inert gas purging. (4) The compound of formula I was obtained by vacuum distillation at 0.5-3 kPa; (5) When the catalyst is oxalic acid, the molar ratio of the catalyst to the compound of formula II is 0.02:1; (6) When the catalyst is a mixed acid, the molar ratio of the catalyst to the compound of formula II is 0.011:

1.

10. The method for preparing the compound of formula I as described in claim 9, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of the compound of formula II to the compound of formula III is 1:3; (2) The alcohol solvent is methanol; (3) The ketone solvent is acetone; (4) The mass ratio of the catalyst to the organic solvent is 1:(30-200); (5) The compound of formula I is obtained by vacuum distillation at 0.6-0.8 kPa, 1-1.2 kPa or 2-3 kPa; (6) The ketation reaction is performed using nitrogen purging; (7) The post-treatment of the ketation reaction includes the following steps: lowering the temperature to 20-35°C, then distilling at atmospheric pressure at 35-50°C, and then continuing to distill under reduced pressure to recover the organic solvent.

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