A preparation method of 6-methyl-5-octen-2-one

Abstract

The invention discloses a preparation method of 6-methyl-5-octen-2-one, and belongs to the technical field of organic synthesis. 5-chloro-2-pentanone is used as a starting material, trimethyl orthoformate is used to protect the carbonyl group under acid catalysis, and then a Grignard reagent is prepared, condensed and dehydrated with 2-butanone, and then deprotected under acidic conditions to prepare 6-methyl-5-octen-2-one with high yield. The method has easy-to-obtain raw materials, low price, and can catalyze the reaction using a conventional catalyst.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 6-methyl-5-octen-2-one. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Ethyl linalool, chemical name 3,7-dimethyl-1,6-nonadien-3-ol, is a colorless or light yellow liquid at room temperature with a very fresh floral scent. It has a similar floral scent to linalool, but is more persistent and gentle than linalool. It is favored by perfumers. At present, the usage rate and consumption of daily chemical products are increasing year by year, and it is becoming more and more popular. Ethyl linalool can be used to prepare rose, lily of the valley, tuberose, lilac, vanilla, acacia, orange blossom and other fragrances. Its application is not limited by the type of fragrance, especially suitable for soap or head wax fragrance. Since ethyl linalool has a higher boiling point than linalool, its fragrance retention effect is also better than linalool, and its application will be further expanded in the future. In the production process of ethyl linalool, 6-methyl-5-octen-2-one is a key intermediate, but the synthesis method of this intermediate is currently reported very little, which limits the efficient synthesis of ethyl linalool.

[0004] In the prior art, the most commonly used method for synthesizing 6-methyl-5-octen-2-one is the rearrangement reaction of 3-methyl-1-pentene-3-ol. For example, patents WO2018091623A1 and EP3323802A1 use 3-methyl-1-pentene-3-ol and 2-methoxypropylene to undergo Saucy-Marbet rearrangement, remove one molecule of methanol, and obtain 6-methyl-5-octen-2-one. It uses phosphate as a catalyst and obtains a yield of 93%. However, the phosphate catalyst used is complex in structure, expensive, and has a high actual application cost. In addition, the method has a long reaction time (more than 10 hours), cumbersome and time-consuming operation, and is not suitable for industrial scale-up production. Patent WO2017097884A1 also uses 3-methyl-1-pentene-3-ol and 2-methoxy as raw materials, and uses triethanolamine phosphate as a catalyst, but only obtains a reaction yield of 25%.

[0005] In addition to the Saucy-Marbet reaction to synthesize 6-methyl-5-octen-2-one, there are also some reports on the use of the Carroll rearrangement reaction to synthesize 6-methyl-5-octen-2-one. For example, Pogrebnoi et al. reported using an organic aluminum salt as a catalyst and acetoacetate as a rearrangement reagent to undergo a rearrangement reaction with 3-methyl-1-penten-3-ol, removing a molecule of methanol and carbon dioxide, and finally obtaining 6-methyl-5-octen-2-one. The reaction yield was moderate, 78%, but an equivalent amount of methanol and carbon dioxide were also produced as by-products, and the atom economy was average. (Tetrahedron Letters, 1987, 28, 4893-6).

[0006] In addition to synthesizing 6-methyl-5-octen-2-one by rearrangement reaction, the patent CN113979847A of Wanhua Chemical Group Co., Ltd. discloses a method for synthesizing 6-methyl-5-octen-2-one by condensation hydrogenation, which uses its homemade 3-methyl-2-pentenal as raw material, first condenses with 2-methoxypropylene or acetone to obtain unsaturated conjugated ketone, and then selectively hydrogenates to obtain 6-methyl-5-heptene-2-one. The raw materials 3-methyl-2-pentenal and 2-methoxypropylene used in this method are active in nature, have strict requirements for storage and use, and are relatively high in price, with high cost, especially 3-methyl-2-pentenal market is not easy to purchase. Asymmetric hydrogenation reduction is used in its synthesis reaction, involving hydrogen and pressure, and the selectivity requirements for the catalyst are also high, and the versatility is not strong.

[0007] Therefore, it is necessary to develop a new synthetic route for 6-methyl-5-octen-2-one, starting from low-cost raw materials and efficiently synthesizing 6-methyl-5-octen-2-one. Summary of the invention

[0008] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing 6-methyl-5-octen-2-one. The synthetic route of 6-methyl-5-octen-2-one provided by the present invention has the advantages of easy availability of raw materials, low cost and high yield.

[0009] In order to achieve the above object, the technical solution of the present invention is:

[0010] In a first aspect of the present invention, a method for preparing 6-methyl-5-octen-2-one is provided, comprising:

[0011] 5-chloro-2-pentanone was carbonyl protected to obtain an intermediate;

[0012] converting the intermediate into a Grignard reagent;

[0013] The Grignard reagent reacts with 2-butanone and undergoes deprotection to obtain 6-methyl-5-octen-2-one.

[0014] In some embodiments of the present invention, the preparation method comprises: adding a carbonyl protecting agent, 5-chloro-2-pentanone and a catalyst into an organic solvent, heating and refluxing to react, and obtaining an intermediate.

[0015] In some embodiments of the present invention, the carbonyl protecting agent includes one of trimethyl orthoformate, ethylene glycol, propylene glycol, 1,3-propanedithiol, 1,2-ethanedithiol or 1,2-trimethylsiloxyethane;

[0016] The catalyst is one of p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid or camphorsulfonic acid;

[0017] The molar ratio of the carbonyl protecting agent, 5-chloro-2-pentanone and the catalyst is (1.1-1.3):1:0.1;

[0018] The organic solvent includes one of methanol or ethanol.

[0019] In some embodiments of the present invention, trimethyl orthoformate, 5-chloro-2-pentanone and p-toluenesulfonic acid are added to methanol, and the mixture is heated under reflux to react to obtain an intermediate.

[0020] In some embodiments of the present invention, the preparation method comprises: adding magnesium, an intermediate and an initiator to a Grignard solvent, heating to initiate a Grignard reaction, cooling, dropwise adding a mixture of the intermediate and the Grignard solvent, and cooling to room temperature after the dropwise addition to obtain a Grignard reagent.

[0021] In some embodiments of the present invention, the Grignard solvent is selected from one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether;

[0022] The initiator is iodine.

[0023] In some embodiments of the present invention, the Grignard reaction is initiated by heating to 60-62°C, and the temperature is lowered after the reaction is initiated to control the temperature at 50-55°C, and a mixture of the intermediate and the Grignard solvent is added dropwise. After the addition is completed, the temperature is lowered to room temperature to obtain the Grignard reagent.

[0024] In some embodiments of the present invention, the preparation method comprises: adding 2-butanone to an organic solvent under nitrogen protection, controlling the temperature at 10-13°C, adding a Grignard reagent dropwise, and stirring at this temperature for 1.5-2.5 hours. Then, heating the mixture to 35-40°C, stirring at this temperature for 1.5-2.5 hours, quenching with acid, filtering, stirring the filtrate at this temperature for 3-6 hours, removing the organic solvent, extracting with dichloromethane, combining the organic phases, washing with an aqueous sodium bicarbonate solution, desolventizing the organic phases, and distilling the mixture to obtain 6-methyl-5-octen-2-one.

[0025] In some embodiments of the present invention, the organic solvent is selected from one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether;

[0026] The acid is dilute sulfuric acid.

[0027] In some embodiments of the present invention, the usage ratio of 2-butanone to Grignard reagent is 1.1:1.

[0028] The beneficial effects of the present invention are:

[0029] The invention provides a novel preparation method of 6-methyl-5-octen-2-one, which uses 5-chloro-2-pentanone as a starting material, firstly performs carbonyl protection with trimethyl orthoformate under acid catalysis, then prepares a Grignard reagent, performs condensation dehydration with 2-butanone, and then performs deprotection under acidic conditions to prepare 6-methyl-5-octen-2-one with high yield. The raw materials used in the preparation method are easy to obtain and cheap, and the production cost is reduced. Conventional catalysts can be used for catalytic reaction, the reaction conditions are mild, the yield is high and can reach 80%, and the method is suitable for industrial large-scale production of 6-methyl-5-octen-2-one. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0031] Figure 1 This is the H NMR spectrum of 6-methyl-5-octen-2-one prepared in Example 1 of the present invention;

[0032] Figure 2 This is the mass spectrum of 6-methyl-5-octen-2-one prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] The first typical embodiment of the present invention provides a method for preparing 6-methyl-5-octen-2-one, comprising:

[0035] 5-chloro-2-pentanone was carbonyl protected to obtain an intermediate;

[0036] converting the intermediate into a Grignard reagent;

[0037] The Grignard reagent reacts with 2-butanone and undergoes deprotection to obtain 6-methyl-5-octen-2-one.

[0038] The invention provides a new 6-methyl-5-octen-2-one synthesis route, which uses 5-chloro-2-pentanone and 2-butanone as raw materials to synthesize 6-methyl-5-octen-2-one. The raw materials are easily available and low in price, and no complex and expensive catalyst is required. The reaction conditions are mild and the yield is high.

[0039] In some examples of this embodiment, the preparation method comprises: adding a carbonyl protecting agent, 5-chloro-2-pentanone and a catalyst into an organic solvent, heating and refluxing to react, and obtaining an intermediate.

[0040] In some examples of this embodiment, the carbonyl protecting agent includes one of trimethyl orthoformate, ethylene glycol, propylene glycol, 1,3-propanedithiol, 1,2-ethanedithiol or 1,2-trimethylsiloxyethane, preferably trimethyl orthoformate. Trimethyl orthoformate has a high protection yield, is easy to deprotect, and has the best comprehensiveness.

[0041] In some examples of this embodiment, the catalyst is one of p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid or camphorsulfonic acid; p-toluenesulfonic acid is preferred.

[0042] In some examples of this embodiment, the molar ratio of the carbonyl protecting agent, 5-chloro-2-pentanone and the catalyst is (1.1-1.3):1:0.1, specifically 1.1:1:0.1, 1.2:1:0.1, 1.3:1:0.1 and the like.

[0043] In some examples of this embodiment, the organic solvent includes but is not limited to one of methanol or ethanol, preferably methanol.

[0044] In some examples of this embodiment, trimethyl orthoformate, 5-chloro-2-pentanone and p-toluenesulfonic acid are added to methanol, and the mixture is heated under reflux to react to obtain an intermediate.

[0045] In some examples of this embodiment, after the heating reflux reaction is completed, the solvent is removed and the excess trimethyl orthoformate is recovered, the concentrate is dissolved in dichloromethane, washed once with clean water, and washed once with sodium bicarbonate until the pH of the aqueous phase is ≥7, the layers are separated, the lower organic phase is separated, the solvent is removed to obtain a crude intermediate, and distillation is performed to collect the fraction at 73-76°C under 15 mmHg to obtain an intermediate.

[0046] In some examples of this embodiment, the preparation method includes: adding magnesium, an intermediate and an initiator to a Grignard solvent, heating to initiate a Grignard reaction, cooling, dripping a mixture of the intermediate and the Grignard solvent, and cooling the temperature to room temperature to obtain a Grignard reagent.

[0047] In some examples of this embodiment, the Grignard solvent is selected from one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether; preferably tetrahydrofuran.

[0048] In some examples of this embodiment, the initiator is iodine.

[0049] In some examples of this embodiment, the Grignard reaction is initiated by heating to 60-62°C, and the temperature is lowered after the reaction is initiated to control the temperature at 50-55°C, and a mixture of the intermediate and the Grignard solvent is added dropwise. After the addition is completed, the temperature is lowered to room temperature to obtain the Grignard reagent.

[0050] In some examples of this implementation mode, the preparation method includes: adding 2-butanone to an organic solvent under nitrogen protection, controlling the temperature at 10-13°C, adding a Grignard reagent dropwise, and stirring at this temperature for 1.5-2.5 hours. Then, the temperature is raised to 35-40°C, and the temperature is kept warm and stirred for 1.5-2.5 hours. The mixture is quenched with acid, filtered, and the filtrate is kept warm and stirred for 3-6 hours. After removing the organic solvent, the mixture is extracted with dichloromethane, the organic phases are combined, washed with a sodium bicarbonate aqueous solution, the organic phases are desolventized, and distilled to obtain 6-methyl-5-octen-2-one.

[0051] In some examples of this embodiment, the organic solvent is selected from one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether.

[0052] In some examples of this embodiment, the acid is dilute sulfuric acid.

[0053] In some examples of this embodiment, the usage ratio of 2-butanone to Grignard reagent is 1.1:1. The usage of 2-butanone is slightly more than that of Grignard reagent, which can ensure that the Grignard reagent is converted as much as possible.

[0054] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0055] Example 1

[0056] A method for preparing 6-methyl-5-octen-2-one, the synthetic route is as follows:

[0057]

[0058]

[0059] The specific method includes the following steps:

[0060] (1) Preparation of 5-chloro-2-pentanone diketal

[0061] Add 300 g methanol, 127 g (1.2 mol) trimethyl orthoformate, 120.5 g (1 mol) 5-chloro-2-pentanone, and 17.2 g (0.1 mol) p-toluenesulfonic acid into a flask, heat to reflux for reaction for 3 h, cool to room temperature, add 10.5 g triethylamine for neutralization, filter, remove the solvent from the filtrate under negative pressure to obtain a crude 5-chloro-2-pentanone diketal intermediate, and distill to collect the fraction at 73-76°C under 15 mmHg to obtain 152.8 g of 5-chloro-2-pentanone diketal with a yield of 92%.

[0062] 1 HNMR (200MHz, CDCl3): δ=1.28 (s, 3H), 1.71-1.89 (m, 4H), 3.18 (s, 6H), 3.56 (t, 2H, J=6.2Hz).

[0063] (2) Preparation of Grignard reagent

[0064] In a three-necked flask equipped with a reflux condenser and a thermometer, add 100 g of tetrahydrofuran, 24 g (1.08 mol) of magnesium chips, 25 g (0.15 mol) of 5-chloro-2-pentanone diketal, and 2 g of iodine particles. Heat to 60-62°C to initiate the Grignard reaction, then control the temperature at 50-55°C, and dropwise add a mixture of 95 g (0.57 mol) of 5-chloro-2-pentanone diketal and 50 g of tetrahydrofuran. After the dropwise addition, cool to room temperature and set aside.

[0065] (3) Condensation and deprotection

[0066] Under nitrogen protection, 100 g of tetrahydrofuran and 54.5 g (0.76 mol) of 2-butanone were added to a three-necked flask, the temperature was controlled at 10-13°C, and the Grignard reagent prepared in step (2) was added dropwise (all added). After the addition was completed, stirring was continued for 2 h, and the temperature was raised to 35-40°C and stirred for 2 h. 117 g of 30% dilute sulfuric acid was added dropwise to quench the mixture, and the mixture was filtered. The filtrate was continued to be temperature-controlled at 35-38°C and stirred for 3 h. The temperature was lowered and an aqueous sodium carbonate solution was added to adjust the pH of the system to 7-8. The tetrahydrofuran was removed under negative pressure, and dichloromethane was added for extraction three times. The organic phases were combined and desolventized to obtain a crude product, which was then distilled under negative pressure. The fraction at 70-71°C under 15 mmHg was collected to obtain 86.3 g of 6-methyl-5-octen-2-one with a yield of 95.1%.

[0067] 1 H NMR (400 MHz, CDCl3): δ=0.66 (t, 3H), 0.96 (t, 2H), 1.67 (m, 2H), 1.81 (s, 3H), 1.94 (s, 3H), 2.15 (m, 2H), 3.86 (m, 1H).

[0068] Example 2

[0069] A method for preparing 6-methyl-5-octen-2-one, the specific method comprising the following steps:

[0070] Add 200 g toluene, 186 g (3 mol) ethylene glycol, 120.5 g (1 mol) 5-chloro-2-pentanone, and 17.2 g (0.1 mol) p-toluenesulfonic acid into a flask, heat to reflux, and separate water with a water separator. React for 8 h, cool, add 10.5 g triethylamine to neutralize, filter, and remove the solvent from the filtrate under negative pressure to obtain a crude 5-chloro-2-pentanone diketal intermediate. Distill and collect the fraction at 73-76°C at 15 mmHg to obtain 143.2 g of 5-chloro-2-pentanone diketal with a yield of 86.1%.

[0071] The two steps of "preparation of Grignard reagent" and "condensation and deprotection" were the same as those in Example 1. 75.4 g of 6-methyl-5-octen-2-one was obtained with a yield of 82.9%.

[0072] Example 3

[0073] A method for preparing 6-methyl-5-octen-2-one, the specific method comprising the following steps:

[0074] Add 200 g toluene, 228 g (3 mol) propylene glycol, 120.5 g (1 mol) 5-chloro-2-pentanone, and 17.2 g (0.1 mol) p-toluenesulfonic acid into a flask, heat to reflux, and separate water with a water separator. React for 8 h, cool, add 10.5 g triethylamine to neutralize, filter, and remove the solvent from the filtrate under negative pressure to obtain a crude 5-chloro-2-pentanone diketal intermediate. Distill and collect the fraction at 73-76°C at 15 mmHg to obtain 145.5 g of 5-chloro-2-pentanone diketal with a yield of 80.6%.

[0075] The steps of "preparation of Grignard reagent" and "condensation and deprotection" were the same as those in Example 1. 73.3 g of 6-methyl-5-octen-2-one was obtained with a yield of 80.6%.

[0076] Example 4

[0077] A method for industrial production of 6-methyl-5-octen-2-one comprises the following steps:

[0078] (1) Preparation of 5-chloro-2-pentanone diketal

[0079] In a 500 L enamel reactor, 150 kg methanol, 63.5 kg trimethyl orthoformate, 60.25 kg 5-chloro-2-pentanone and 8.5 kg p-toluenesulfonic acid were added. The mixture was stirred and the temperature was controlled at 60-65 °C. The mixture was heated under reflux for 3 h. The mixture was cooled to room temperature, 5.3 kg triethylamine was added dropwise to adjust the acidity, the solid was filtered out, and the filtrate was concentrated to obtain 84 kg of a crude intermediate of 5-chloro-2-pentanone diketal. After negative pressure distillation, 5 batches of crude products were combined and added to a 500 L distillation reactor. The qualified fractions at 73-75 °C under a vacuum of 15 mmHg were collected to obtain 387.4 kg of 5-chloro-2-pentanone diketal with a yield of 93.3%.

[0080] (2) Preparation of Grignard reagent

[0081] In a 500 L high-position enamel kettle, 100 kg of tetrahydrofuran, 24 kg of new metal magnesium chips, and 25 kg of 5-chloro-2-pentanone diketal were added, stirring was started, circulating water was turned on for cooling, and the condenser was kept in a normal state. 1 kg of ketal Grignard solution prepared according to the pilot process (i.e., "(2) Preparation of Grignard Reagent" in Example 1) was added by drip irrigation. After the initiation was completed, the temperature was controlled at 50-55° C., and a mixed solution of 50 kg of tetrahydrofuran and 95 kg of 5-chloro-2-pentanone diketal was continuously added dropwise. After the dripping was completed, the reaction was stirred for 2 h, and the temperature was lowered to room temperature for standby use.

[0082] It should be noted that the ketal Grignard solution used for initiation is the Grignard solution of 5-chloro-2,2-dimethoxy-pentane.

[0083] (3) Condensation and deprotection

[0084] In a 1000 L low-position enamel kettle, 100 kg of tetrahydrofuran and 54.5 kg of 2-butanone were added, and the mixture was cooled by freezing and kept at 10-13°C. The Grignard reaction solution in the high-position enamel kettle was added dropwise. After all the additions were completed, the mixture was kept warm and stirred for 2 h, and then the temperature was raised to 35-40°C, kept warm for 2 h, and then cooled. The temperature of the low-position enamel kettle was controlled to be ≤40°C. 117 kg of 30% dilute sulfuric acid was added dropwise to quench the mixture, and the pH of the system was adjusted to acidic. The mixture was filtered and the filtrate was transferred to a heat-insulating kettle. The mixture was heated and kept at 35-38°C. The reaction was continued for 3 h, and then cooled. The pH of the system was adjusted to 7-8 with an aqueous sodium carbonate solution. The solvent was removed under negative pressure. The mixture was extracted three times with 200 kg of dichloromethane, and the lower organic phase was combined and the solvent was removed to obtain 98 kg of a crude product of 6-methyl-5-octen-2-one. Four batches of the crude product were transferred to 500 In the L distillation kettle, negative pressure distillation was carried out by Roots pump, and the qualified fraction 6-methyl-5-octen-2-one at 70-71°C under 15 mmHg was collected, 342.6 kg / batch, with a yield of 94.3%.

[0085] In Example 1, the total yield of 6-methyl-5-octen-2-one reached 87%, and in the scaled-up production of Example 4, the total yield of 6-methyl-5-octen-2-one still reached 87%. It can be seen that the synthetic route of 6-methyl-5-octen-2-one provided by the present invention has the advantages of easy availability of raw materials, low cost and high yield.

[0086] Compared with the synthesis routes disclosed in patents WO2018091623A1, EP3323802A1 and CN113979847A, the synthesis route of the present invention has obvious cost advantages.

[0087] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 6-methyl-5-octen-2-one, characterized in that: include: In an organic solvent, a carbonyl protecting agent, 5-chloro-2-pentanone and a catalyst are added, and the mixture is heated under reflux to react to obtain an intermediate; the carbonyl protecting agent comprises one of trimethyl orthoformate, ethylene glycol, propylene glycol, 1,3-propanedithiol, 1,2-ethanedithiol or 1,2-trimethylsiloxyethane; the catalyst is one of p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid or camphorsulfonic acid; Add magnesium, an intermediate and an initiator to a Grignard solvent, heat to initiate a Grignard reaction, and after cooling, dropwise add a mixed solution of the intermediate and the Grignard solvent, and after the dropwise addition, cool to room temperature to obtain a Grignard reagent; the Grignard solvent is selected from one of tetrahydrofuran, ether, methyl tert-butyl ether or isopropyl ether; and the initiator is iodine; Under nitrogen protection, add 2-butanone to the organic solvent, control the temperature at 10-13°C, add the Grignard reagent dropwise, and after the addition, keep warm and stir for 1.5-2.5 h, then raise the temperature to 35-40°C, keep warm and stir for 1.5-2.5 h, quench with acid, filter, keep the filtrate warm and stir for 3-6 h, remove the organic solvent, extract with dichloromethane, combine the organic phases, wash with sodium bicarbonate aqueous solution, desolventize the organic phase, and distill to obtain 6-methyl-5-octen-2-one.

2. The preparation method according to claim 1, characterized in that The molar ratio of the carbonyl protecting agent, 5-chloro-2-pentanone and the catalyst is (1.1-1.3):1:0.1; In the intermediate preparation process, the organic solvent includes one of methanol or ethanol.

3. The preparation method according to claim 1, characterized in that: Trimethyl orthoformate, 5-chloro-2-pentanone and p-toluenesulfonic acid are added to methanol, and the mixture is heated under reflux to react to obtain an intermediate.

4. The preparation method according to claim 1, characterized in that: The reaction is heated to 60-62°C to initiate the Grignard reaction. After the reaction is initiated, the temperature is lowered to 50-55°C, and a mixed solution of the intermediate and the Grignard solvent is added dropwise. After the addition is completed, the temperature is lowered to room temperature to obtain the Grignard reagent.

5. The preparation method according to claim 1, characterized in that: The step of adding 2-butanone to an organic solvent, wherein the organic solvent is selected from one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether; The acid is dilute sulfuric acid.

6. The preparation method according to claim 1, characterized in that: The usage ratio of the 2-butanone to the Grignard reagent is 1.1:1.

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