Background and overview of preparation and application of 3-chlorophenylboronic acid
3-Chlorophenylboronic acid is an important intermediate in the synthesis of prolyl hydroxylase inhibitors. Prolyl hydroxylase inhibitors are a method of preventing and treating, inter alia, peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia and anemia.
Preparation and application of 3-chlorophenylboronic acid
Using m-dichlorobenzene as the starting material, iodine particles and 1,2-dibromoethane as initiators, react with magnesium in an organic solvent to prepare 3-chlorophenylmagnesium chloride; then react with boric acid in an organic solvent The trimethyl ester reaction is used to prepare 3-chlorophenylboronic acid dimethyl ester; then hydrolysis, extraction, and crystallization are performed to obtain 3-chlorophenylboronic acid. The specific steps are as follows:
Preparation and application of 3-chlorophenylboronic acid (1) Preparation of 3-chlorophenylmagnesium chloride reaction solution:
Selection of raw materials (specific raw material selection and dosage can be selected arbitrarily according to the scope of the claims and does not affect the implementation of the present invention, the same below): 44.1g m-dichlorobenzene, 10.94g magnesium shavings, 0.3g iodine granules, 1, 2-dibromoethane 1.95g, tetrahydrofuran 90mL, toluene 90mL;
Reaction steps: Use a 500mL four-neck bottle as the reaction vessel, replace the reaction vessel with nitrogen, put in 10.94g magnesium chips and organic solvents 90mL tetrahydrofuran and 90mL toluene under nitrogen protection, add 0.3g iodine particles and 1.95g 1,2 – Dibromoethane, raise the temperature to initiate the reaction; add 44.1g of m-dichlorobenzene dropwise at 62 to 74°C, and complete the addition in about 3 to 4 hours. After the dropwise addition is completed, keep stirring for 3 to 4 hours to obtain 3-chlorobenzene. Magnesium chloride reaction solution, set aside.
Preparation and application of 3-chlorophenylboronic acid (2) Preparation of 3-chlorophenylboronic acid dimethyl ester:
Raw material selection: 46.76g trimethyl borate, 180mL toluene;
Reaction steps: Use a 1L four-neck bottle as the reaction vessel, replace the reaction vessel with nitrogen, put in 46.76g trimethyl borate and 180mL toluene under nitrogen protection, cool to -90~-50℃, and add 3-chlorine dropwise For the phenylmagnesium chloride reaction solution, control the dropping time to about 2 to 3 hours to complete the addition. After the dropwise addition is completed, keep stirring for 2.5 hours to prepare the 3-chlorophenylborate dimethyl ester reaction solution.
Preparation and application of 3-chlorophenylboronic acid (3) Preparation of 3-chlorophenylboronic acid:
Raw material selection: 300mL of 10% hydrochloric acid aqueous solution, extraction organic solvent toluene (regular dosage, the same below); 30mL of crystallization organic solvent methanol, 150mL of water;
Reaction steps: In the 1L four-neck bottle of the 3-chlorophenyl dimethyl borate reaction solution prepared in the above step (2), dropwise add 300mL of 10% hydrochloric acid aqueous solution, control the internal temperature to 0~10°C, and control the dripping The addition time is about 1 to 2 hours. After the dropwise addition, keep the temperature for another 3 hours. Then raise the temperature to 3 boric acid 0 to 40°C and separate the liquids. Use 100 mL of toluene (conventional dosage, the same below) to back-extract the water phase twice, and combine the organic compounds. phase, wash the organic phase twice with 100 mL water (conventional dosage, the same below), distill the organic phase under reduced pressure to remove toluene, and concentrate the organic phase to a constant weight; add 30 mL methanol and 150 mL water, and raise the temperature to 70~80°C, and the material dissolves Clear, keep warm and stir for 0.5h, cool to -5~5℃, keep warm and stir for 2h, filter with suction, wash the filter cake with 50mL water (regular amount, not included in the amount of raw materials stated above, the same below), and blast dry at 70℃ , 24.9g of 3-chlorophenylboronic acid was obtained, the yield was 53.1%, and the HPLC purity was 98.8%.
Preparation and application of 3-chlorophenylboronic acid
Preparation and application of 3-chlorophenylboronic acid Application 1.
CN201610206230.2 discloses a synthesis method of Vadadustat. In this method, 3,5-dichloro-2-pyridinecarboxylic acid and glycine methyl ester hydrochloride are subjected to a condensation reaction; the obtained N-(3,5-dichloropyridine-2-carbonyl)glycine methyl ester and 3-chlorobenzene are Boric acid was used to perform a catalytic coupling reaction; the obtained N-[5-(3-chlorophenyl)-3-chloropyridine-2-carbonyl]glycine methyl ester was subjected to a methoxy substitution reaction with sodium methoxide; the obtained N- [5-(3-Chlorophenyl)-3-methoxypyridine-2-carbonyl]glycine undergoes hydrolysis reaction to obtain the finished product Vadadustat. The synthesis method has shorter route steps, simplified operations and lower cost. It is a green and environmentally friendly method and is suitable for industrial production.
Preparation and application of 3-chlorophenylboronic acid 2.
CN201811249120. 8-12 parts of flame retardant, 5-8 parts of auxiliary film-forming additives, 12-16 parts of calcium carbonate whiskers, 15-20 parts of mica powder, 22-30 parts of modified nanometer plant fiber, 3-chlorine 6-12 parts of phenylboric acid, 12-18 parts of pentaerythritol, 8-14 parts of dimethyl carbonate; this flame retardant coating has very good fire retardant properties, and can also inhibit the formation of smoke during the combustion process.
References
[1] [Chinese invention] CN201810933448.7 Synthesis method of 3-chlorophenylboronic acid
[2] CN201610206230.2 A synthesis method of methyltetrahydrofuran Vadadustat
[3] CN201811249120.X Flame retardant coating and preparation method thereof
