CN-112375091-B - Green synthesis process of alkynol double Grignard reagent

Abstract

The invention discloses a green synthesis process of an alkynol double Grignard reagent, which comprises the following steps of dissolving benzyl chloride in an organic solvent to prepare a solution A, adding metal magnesium into the solution A to perform an initiating reaction to prepare an initiating reaction solution, dissolving benzyl chloride and alkynol substances in the organic solvent to prepare a solution B, and dripping the solution B in the step (2) into the initiating reaction solution in the step (1) to perform a reaction to prepare the alkynol double Grignard reagent. The invention provides a novel synthesis method for synthesizing alkynol double Grignard reagent by adopting benzyl magnesium chloride, which can avoid coupling side reaction between the benzyl chloride Grignard reagent and benzyl chloride and does not need excessive magnesium metal.

Inventors

• ZHENG ZHAOXIANG
• WANG XUBIN
• GU WENJING
• SHAN GUOHONG
• LIANG DONG
• REN GUANGMING
• SUN LIN

Assignees

• 上虞新和成生物化工有限公司

Dates

Publication Date

20260512

Application Date

20201208

Claims (5)

1. 1. The synthesis process of the alkynol double Grignard reagent is characterized by comprising the following steps of: (1) Dissolving benzyl chloride in an organic solvent to prepare a solution A, adding metal magnesium into the solution A for initiating reaction to obtain an initiating reaction solution, wherein the molar concentration of the benzyl chloride in the solution A is 0.05-1.58 mol/L, the molar ratio of the metal magnesium to the benzyl chloride is (5-100): 1, the initiating reaction temperature is 0-100 ℃, and the initiating reaction time is 10-100 min; (2) Dissolving benzyl chloride and alkynol substances into an organic solvent to prepare a solution B, wherein the molar ratio of the added benzyl chloride to the metal magnesium in the step (1) is (0.9-1.2): 1, the molar ratio of the benzyl chloride to the alkynol substances is (0.4-0.6), the mass volume ratio of the benzyl chloride to the organic solvent is (1) (3-10), and the alkynol substances are 3-methyl-4-pentene-1-alkyne-3-ol or 3-methyl-2-pentene-4-alkyne-1-ol; (3) And (3) dropwise adding the solution B in the step (2) into the initiation reaction liquid in the step (1) for reaction, wherein the reaction temperature is 0-100 ℃, and the dropwise adding reaction time is 1-10 h, so as to prepare the alkynol double Grignard reagent.
2. 2. The synthesis process according to claim 1, wherein in the step (1), the molar concentration of benzyl chloride in the solution A is 0.39-1.58 mol/L, the molar ratio of magnesium metal to benzyl chloride is (6-15): 1, the initiation reaction temperature is 30-90 ℃, and the initiation reaction time is 30-100 min.
3. 3. The synthesis process according to claim 1, wherein in the step (2), the mass-volume ratio of benzyl chloride to the organic solvent is 1 (4-6.5).
4. 4. The synthesis process according to claim 1, wherein in the step (3), the reaction temperature is 30 ℃ to 90 ℃ and the dropwise addition reaction time is 2.5 to 5 hours.
5. 5. The synthesis process according to any one of claims 1 to 4, wherein the organic solvent is one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and toluene.

Description

Green synthesis process of alkynol double Grignard reagent Technical Field The invention relates to preparation of Grignard reagent, in particular to preparation of benzyl Grignard reagent and alkynol Grignard reagent. Background 3-Methyl-4-penten-1-yn-3-ol and 3-methyl-2-penten-4-yn-1-ol are important intermediates for the synthesis of astaxanthin and vitamin A, respectively. At present, in the industrialized synthesis method, the two alkynols are respectively converted into corresponding double Grignard reagents: (1) (2) then respectively carrying out condensation reaction on the two components and aldehyde or ketone to obtain the target intermediate product. Patent CN109761867a discloses a process for obtaining the double grignard reagent of formula (2) above by reacting 3-methyl-4-penten-1-yn-3-ol (I) (iso-C6 alcohol) with ethylmagnesium bromide in an ether solvent. However, the Grignard reagent used in the reaction process is mainly ethyl magnesium bromide obtained by reacting bromoethane with magnesium. Therefore, a large amount of ethane gas (C 2H6) can be generated in the preparation method, and cannot be recycled, so that a large amount of waste gas can be generated in the production process, and the preparation method has the advantages of safety and environmental protection and reduces the atom utilization rate. The grignard reagent generated in the process of preparing the grignard reagent by the benzyl halohydrocarbon is easy to further carry out coupling reaction with unreacted halohydrocarbon due to high activity, and the grignard reagent is shown as follows: C6H5CH2Cl + Mg → C6H5CH2MgCl C6H5CH2MgCl + C6H5CH2Cl →C6H5CH2CH2C6H5 + MgCl2 Thus, the yield of benzyl grignard reagent preparation is generally lower than that of bromoethane grignard reagent preparation, and the use of the grignard reagent in the preparation of some products is limited due to the high boiling point of diphenylethane impurities generated by coupling side reactions. Patent CN109836442a discloses a method for preparing benzyl magnesium chloride grignard reagent by batch-continuous reaction-local excess of magnesium metal, the coupling side reaction is reduced by local magnesium metal excess and low temperature reaction, the reaction yield and specific application are not shown in the patent. According to the disclosure in this document, THF is required as a reaction solvent, and a lower reaction temperature is adopted, and according to our studies, it was found that the concentration of the grignard reagent of benzyl magnesium chloride prepared by this method is relatively low, which inevitably results in further dilution of benzyl magnesium chloride when the next reaction is carried out, thereby affecting the reaction efficiency. The excessive metal magnesium is always kept in the process of preparing the benzyl magnesium chloride, and the coupling reaction can be inhibited to a certain extent, but the excessive metal magnesium is easy to generate potential safety hazard in actual production, so that the large-scale industrial production is difficult to realize. In view of the above, the novel synthesis method for synthesizing the alkynol double grignard reagent by adopting benzyl magnesium chloride is provided, so that the coupling side reaction between the benzyl chloride grignard reagent and benzyl chloride can be avoided, excessive metal magnesium is not needed, and the key to be solved in the prior art is urgent. Disclosure of Invention In order to solve the problems in the prior art, the invention adopts the technical scheme that the invention provides a green synthesis process of alkynol double Grignard reagent, which comprises the following steps: (1) Dissolving benzyl chloride in an organic solvent to prepare a solution A, and adding magnesium metal into the solution A to perform an initiation reaction to prepare an initiation reaction solution; (2) Dissolving benzyl chloride and alkynols into an organic solvent to prepare a solution B; (3) And (3) dropwise adding the solution B in the step (2) into the initiation reaction liquid in the step (1) to react to prepare the alkynol double Grignard reagent. Further, the organic solvent is one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and toluene. Further, in the step (1), the molar concentration of benzyl chloride in the solution A is 0.05 to 1.58mol/L, preferably 0.39 to 1.58mol/L. Further, in the step (1), the metal magnesium is in a flake, wire, powder or sphere shape. In the step (1), the molar ratio of the magnesium metal to the benzyl chloride is (5-100): 1, preferably (6-15): 1. Further, in the step (1), the initiation reaction temperature is 0-100 ℃, the initiation reaction time is 10-100 min, preferably the initiation reaction temperature is 30-90 ℃, and the initiation reaction time is 30-100 min. Further, in the step (2), the alkynol substance is 3-methyl-4-pentene-1-alkyne-3-ol or 3-methyl-2-pentene-4-alkyne-1-ol. Further, the molar