A green synthetic process of alkynol double grignard reagent

Abstract

The method discloses a green synthesis process of acetylene alcohol double Grignard reagent, and the synthesis process comprises the following steps: dissolving benzyl chloride in an organic solvent to prepare solution A, adding metal magnesium to solution A to initiate a reaction, and preparing an initiation reaction solution; (2) dissolving benzyl chloride and acetylene alcohol substances in an organic solvent to prepare solution B; (2) adding solution B in step (2) to the initiation reaction solution in step (1) dropwise to perform a reaction, and preparing acetylene alcohol double Grignard reagent. The application provides a new synthesis method for synthesizing acetylene alcohol double Grignard reagent by using benzyl magnesium chloride, which can avoid a coupling side reaction between benzyl Grignard reagent and benzyl chloride, and does not need excessive metal magnesium.

Description

Technical Field

[0001] This invention relates to the preparation of Grignard reagents, specifically to the preparation of benzyl Grignard reagents and alkynyl alcohol Grignard reagents. Background Technology

[0002] 3-Methyl-4-penten-1-yn-3-ol and 3-methyl-2-penten-4-yn-1-ol are important intermediates in the synthesis of astaxanthin and vitamin A, respectively. Currently, industrial synthesis methods involve converting these two enynols into their corresponding digris reagents.

[0003] (1)

[0004] (2)

[0005] They are then condensed with aldehydes or ketones respectively to obtain the target intermediate products.

[0006] Patent CN109761867A discloses a method for reacting 3-methyl-4-penten-1-yn-3-ol (I) (isoC6 alcohol) with ethyl magnesium bromide in an ether solvent to obtain the above-mentioned bis-Grignard reagent of formula (2). However, the Grignard reagent used in this reaction is mainly ethyl magnesium bromide obtained by reacting bromoethane with magnesium. Therefore, this preparation method generates a large amount of ethane gas (C2H6), which cannot be recovered and reused, resulting in a large amount of waste gas generated during the production process. This not only poses safety and environmental protection problems but also reduces the atom utilization rate.

[0007] The Grignard reagents generated during the preparation of Grignard reagents from benzyl halides are highly reactive and often readily undergo further coupling reactions with unreacted halides, as shown below:

[0008] C6H5CH2Cl + Mg → C6H5CH2MgCl

[0009] C6H5CH2MgCl + C6H5CH2Cl →C6H5CH2CH2C6H5 + MgCl2

[0010] Therefore, the yield of benzyl Grignard reagent preparation is generally lower than that of bromoethane Grignard reagent preparation, and the high-boiling-point diphenylethane impurity generated by coupling side reactions limits the application of this Grignard reagent in the preparation of some products.

[0011] Patent CN109836442A discloses a batch-continuous reaction method with localized magnesium excess for the preparation of benzyl magnesium chloride Grignard reagent. This method reduces coupling side reactions through localized magnesium excess and low-temperature reaction. However, the reaction yield and specific applications are not provided in the patent. According to the disclosed content, THF is required as the reaction solvent, and a relatively low reaction temperature is used. Our research found that this method produces a relatively low concentration of benzyl magnesium chloride Grignard reagent, inevitably leading to further dilution of the benzyl magnesium chloride in subsequent reactions, thus affecting reaction efficiency. While maintaining a constant excess of magnesium during the preparation of benzyl magnesium chloride can suppress coupling reactions to some extent, the excess magnesium poses safety hazards in actual production, making large-scale industrial production difficult.

[0012] Therefore, a novel synthetic method for synthesizing acetylsyl bis-Grignard reagents using benzyl magnesium chloride is needed. This method avoids the coupling side reaction between benzyl chloride and benzyl chloride and does not require an excess of metallic magnesium, which is a key issue that urgently needs to be addressed in the existing technology. Summary of the Invention

[0013] To address the aforementioned problems in the prior art, the present invention provides a green synthesis process for alkynyl alcohol bis-Grignard reagents, the synthesis process comprising the following steps:

[0014] (1) Dissolve benzyl chloride in an organic solvent to prepare solution A, add metallic magnesium to solution A to initiate the reaction, and obtain the initiating reaction solution;

[0015] (2) Dissolve benzyl chloride and alkynols in an organic solvent to prepare solution B;

[0016] (3) Add solution B from step (2) to the initiating reaction solution from step (1) to prepare acetylsol digris reagent.

[0017] Furthermore, the organic solvent is one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and toluene.

[0018] Furthermore, in step (1), the molar concentration of benzyl chloride in solution A is 0.05~1.58 mol / L, preferably 0.39~1.58 mol / L.

[0019] Furthermore, in step (1), the magnesium metal is in the form of flakes, filaments, powder, or spheres.

[0020] Furthermore, in step (1), the molar ratio of the metallic magnesium to benzyl chloride is (5~100):1, preferably (6~15):1.

[0021] Furthermore, in step (1), the initiation reaction temperature is 0~100℃ and the initiation reaction time is 10~100min, preferably the initiation reaction temperature is 30~90℃ and the initiation reaction time is 30~100min.

[0022] Furthermore, in step (2), the alkynol is 3-methyl-4-penten-1-yn-3-ol or 3-methyl-2-penten-4-yn-1-ol.

[0023] Furthermore, the molar ratio of benzyl chloride to alkynols added in step (2) is 1:(0.4~0.6).

[0024] Furthermore, the molar ratio of benzyl chloride added in step (2) to magnesium in step (1) is (0.9~1.2):1.

[0025] Furthermore, the mass-volume ratio of benzyl chloride to organic solvent added in step (2) is 1:(3~10), preferably 1:(4~6.5).

[0026] Furthermore, in step (3), the reaction temperature is 0~100℃ and the drop reaction time is 1~10h; preferably, the reaction temperature is 30℃~90℃ and the drop reaction time is 2.5~5h.

[0027] This invention provides a green synthesis process for alkynyl alcohol di Grignard reagents. The process involves simultaneously adding the majority of benzyl chloride and the alkynyl alcohol compound dropwise. The generated benzyl chloride single Grignard reagent is immediately consumed after further reaction with the alkynyl alcohol, ensuring that the benzyl chloride single Grignard reagent remains at a low concentration. This avoids the coupling side reaction between benzyl chloride and benzyl chloride, which is common in the preparation of high-concentration benzyl chloride Grignard reagents. Simultaneously, it increases the alkynyl alcohol concentration in the reaction system during the preparation of alkynyl alcohol di Grignard reagents, thus achieving a higher yield and concentration of the alkynyl alcohol di Grignard reagent. This process not only solves the ethane waste gas emission problem in traditional alkynyl alcohol di Grignard reagent processes but also allows the toluene byproduct to be recovered and used as an organic solvent, reducing environmental and safety issues. It is a green synthesis process. Furthermore, in this invention, magnesium does not need to be maintained in excess and can be completely reacted, avoiding solid-liquid separation and improving production safety. Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0029] Magnesium molecular weight is 24, and benzyl chloride molecular weight is 126.6.

[0030] Formula for calculating the yield of magnesium metal with alkynyl di-Graffine reagent:

[0031] Molar concentration of acetylinyl di Grignard reagent × Volume of acetylinyl di Grignard reagent solution × 2 / (Mass of magnesium feed / 24).

[0032] Example 1

[0033] (1) Benzyl chloride was dissolved in tetrahydrofuran to prepare solution A, and the molar concentration of benzyl chloride in solution A was 0.39 mol / L; 12.7 g of magnesium shavings were put into a 1000 ml four-necked flask equipped with a stirrer and a thermometer, 100 mL of solution A was added, and the mixture was heated to 60~70 °C and refluxed for 30 min to initiate the reaction, thus obtaining the initiating reaction solution;

[0034] (2) Weigh 65g of benzyl chloride and 25g of 3-methyl-4-penten-1-yn-3-ol and dissolve them in 300mL of tetrahydrofuran to prepare solution B;

[0035] (3) The solution B from step (2) was added dropwise to the initiating reaction solution from step (1) to carry out the reaction. The reaction temperature was maintained at 60~70℃ and the dropwise reaction time was 2.5h. After the reaction was completed, 501mL of alkynyl alcohol di-Gräger's reagent solution was obtained. The concentration of alkynyl alcohol di-Gräger's reagent was 0.52mol / L, and the yield of alkynyl alcohol di-Gräger's reagent for metallic magnesium was 98.46%.

[0036] Example 2

[0037] (1) Benzyl chloride was dissolved in diethyl ether to prepare solution A, the molar concentration of benzyl chloride in solution A was 0.78 mol / L; 12.6 g of magnesium wire was put into a 1000 ml four-necked flask equipped with a stirrer and a thermometer, 60 mL of solution A was added, and the mixture was heated to 30~40℃ and refluxed for 50 min to initiate the reaction, thus obtaining the initiating reaction solution;

[0038] (2) Weigh 75g of benzyl chloride and 25g of 3-methyl-4-penten-1-yn-3-ol and dissolve them in 300mL of diethyl ether to prepare solution B;

[0039] (3) The solution B from step (2) was added dropwise to the initiating reaction solution from step (1) to carry out the reaction. The reaction temperature was maintained at 30~40℃ and the dropwise reaction time was 4h. After the reaction was completed, 441mL of alkynyl alcohol digris reagent solution was obtained. The concentration of alkynyl alcohol digris reagent was 0.59mol / L and the yield of alkynyl alcohol digris reagent for metallic magnesium was 99.12%.

[0040] Example 3

[0041] (1) Benzyl chloride was dissolved in toluene to prepare solution A, and the molar concentration of benzyl chloride in solution A was 1.17 mol / L; 12.8 g of magnesium powder was added to a 1000 ml four-necked flask equipped with a stirrer and a thermometer, 50 mL of solution A was added, and the mixture was heated to 80~90℃ for 60 min to initiate the reaction and obtain the initiating reaction solution.

[0042] (2) Weigh 65g of benzyl chloride and 25g of 3-methyl-4-penten-1-yn-3-ol and dissolve them in 300mL of toluene to prepare solution B;

[0043] (3) The solution B from step (2) was added dropwise to the initiating reaction solution from step (1) to carry out the reaction. The reaction temperature was maintained at 80~90℃ and the dropwise reaction time was 5h. After the reaction was completed, 439mL of alkynyl alcohol digris reagent solution was obtained. The concentration of alkynyl alcohol digris reagent was 0.55mol / L and the yield of alkynyl alcohol digris reagent for metallic magnesium was 90.54%.

[0044] Example 4

[0045] (1) Benzyl chloride was dissolved in 2-methyltetrahydrofuran to prepare solution A, the molar concentration of benzyl chloride in solution A was 1.58 mol / L; 12.7 g of magnesium balls were added to a 1000 ml four-necked flask equipped with a stirrer and a thermometer, 50 mL of solution A was added, and the mixture was heated to 70~80 °C and refluxed for 100 min to initiate the reaction, thus obtaining the initiating reaction solution;

[0046] (2) Weigh 65g of benzyl chloride and 25g of 3-methyl-2-penten-4-yn-1-ol and dissolve them in 400mL of 2-methyltetrahydrofuran to prepare solution B;

[0047] (3) The solution B from step (2) was added dropwise to the initiating reaction solution from step (2) to carry out the reaction. The reaction temperature was maintained at 70~80℃ and the dropwise reaction time was 4h. After the reaction was completed, 479mL of alkynyl alcohol digris reagent solution was obtained. The concentration of alkynyl alcohol digris reagent was 0.53mol / L and the yield of alkynyl alcohol digris reagent for metallic magnesium was 95.95%.

[0048] Example 5

[0049] (1) Benzyl chloride was dissolved in diethyl ether to prepare solution A, the molar concentration of benzyl chloride in solution A was 1.17 mol / L; 12.8 g of magnesium sheet was added to a 1000 ml four-necked flask equipped with a stirrer and thermometer, 50 mL of solution A was added, and the mixture was heated to 30~40℃ and refluxed for 30 min to initiate the reaction, thus obtaining the initiating reaction solution;

[0050] (2) Weigh 65g of benzyl chloride and 25g of 3-methyl-2-penten-4-yn-1-ol and dissolve them in 400mL of diethyl ether to prepare solution B;

[0051] (3) The solution from step (2) was added dropwise to the initiating reaction solution from step (1) to carry out the reaction. The reaction temperature was maintained at 30~40℃ and the dropwise reaction time was 5h. After the reaction was completed, 481mL of alkynyl alcohol digris reagent solution was obtained. The concentration of alkynyl alcohol digris reagent was 0.55mol / L and the yield of alkynyl alcohol digris reagent for metallic magnesium was 99.21%.

Claims

1. A process for synthesizing an alkynyl alcohol bis-Graffic reagent, characterized in that, Includes the following steps: (1) Benzyl chloride is dissolved in an organic solvent to prepare solution A. Magnesium metal is added to solution A to initiate the reaction and an initiating reaction solution is obtained. The molar concentration of benzyl chloride in solution A is 0.05~1.58 mol / L, the molar ratio of magnesium metal to benzyl chloride is (5~100):1, the initiation reaction temperature is 0~100℃, and the initiation reaction time is 10~100 min. (2) Dissolve benzyl chloride and alkynols in an organic solvent to prepare solution B; the molar ratio of benzyl chloride to magnesium in step (1) is (0.9~1.2):1, the molar ratio of benzyl chloride to alkynols is 1:(0.4~0.6), the mass-volume ratio of benzyl chloride to organic solvent is 1:(3~10), and the alkynols are 3-methyl-4-penten-1-alkyn-3-ol or 3-methyl-2-penten-4-alkyn-1-ol; (3) Add solution B from step (2) to the initiating reaction solution from step (1) for reaction. The reaction temperature is 0~100℃ and the reaction time is 1~10h to obtain the acetylacetonate bis-Gräger reagent.

2. The synthesis process according to claim 1, characterized in that, In step (1), the molar concentration of benzyl chloride in solution A is 0.39~1.58 mol / L, the molar ratio of magnesium to benzyl chloride is (6~15):1, the initiation reaction temperature is 30~90℃, and the initiation reaction time is 30~100 min.

3. The synthesis process according to claim 1, characterized in that, In step (2), the mass-volume ratio of benzyl chloride to organic solvent is 1:(4~6.5).

4. The synthesis process according to claim 1, characterized in that, In step (3), the reaction temperature is 30℃~90℃ and the dropwise reaction time is 2.5~5h.

5. The synthesis process according to any one of claims 1 to 4, characterized in that, The organic solvent is one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and toluene.