Background and overview[1][2]
At present, statin cholesterol-lowering drugs (statins) used to treat cardiovascular diseases can reduce the incidence of coronary heart disease by reducing LDL-cholesterol, but they have little effect on increasing HDL-cholesterol. CEPT inhibitors can not only increase HDL-cholesterol, but also effectively reduce the occurrence of coronary heart disease (CHD) and atherosclerosis. 2,6-Difluoro-α-methylbenzyl alcohol compound is an important intermediate for CEPT inhibitor drugs and has significant application in the preparation method of a new type of CEPT inhibitor drugs reported in the patent CN101212966A of Merck of Germany.
2,6-Difluoro-α-methylbenzyl alcohol
Preparation[2]
Preparation of methyl 2,6-difluoro-α-phthalate
Mix 10g of anhydrous potassium fluoride powder, 100mL of sulfolane, 8.75g of 2,6-difluoro-α-phthaloyl chloride, and 1g of calixarene catalyst into the reactor, and raise the temperature to 220°C. After reacting for 2 hours, the temperature was lowered to below 20°C, 100 mL of anhydrous methanol was added, and the reaction was carried out at 60°C for 6 hours. Filter the esterification product with suction to remove potassium fluoride and inorganic salts. After removing the solvent from the filtrate, add about 50 mL of water to precipitate, filter, wash with water, and dry to obtain 6.43 g of product with a yield of 93.87%. The melting point of the product: 72°C ~ 74°C, and the purity of the product analyzed by liquid chromatography is 97.01%.
Preparation of 2,6-difluoro-α-benzyl alcohol
Dissolve 1.90g sodium borohydride in 30mL diethylene glycol dimethyl ether, and slowly add 5.00g of the obtained 2,6-difluoro-α-dissolved in 10mL diethylene glycol dimethyl ether. For dimethyl phthalate, keep the temperature below 10°C and react for 12 hours. Extract with dichloromethane, lower the temperature to 0°C, wash with acid and alkali, and recover the solvent to obtain 2.76g of product with a melting point of 122°C to 124°C and a yield of 70.0%. The product was identified by gas-mass spectrometry.
Preparation of 2,6-difluoro-α-bromomethylbenzyl alcohol
1g (4.8mmol) of the obtained 2,6-difluoro-α-dibenzyl alcohol was added to 5mL, 10g (47mmol) of 48% HBr acid and 10mL of benzene were added. The reaction mixture was heated and stirred at 65°C to 70°C for 2 hours. After the reaction mixture was cooled, the upper toluene layer was separated. The toluene was dried with anhydrous magnesium sulfate and then rotary evaporated to recover the toluene to obtain 0.7g of light yellow solid, with a yield of 54%. Identified by gas-mass spectrometry, the purity of liquid phase analysis was 94%.
The aqueous layer after separating toluene was extracted with diethyl ether (2×10mL). After the diethyl ether was evaporated, 0.5g of raw material was obtained, which was recycled and reused. The total yield calculated based on raw material consumption is close to 100%. Example 4
Preparation of 2,6-difluoro-α-methylbenzyl alcohol
Dissolve 1.4g of 2,6-difluoro-α-bromomethylbenzyl alcohol obtained in Example 3 in 40mL of methanol, cool it in an external ice bath, add 2.8g of magnesium powder (51.3mmol), and stir for 2 hours at room temperature. Stir for 14h. Pour into 20 mL of water, add hydrochloric acid to acidify, and then extract with diethyl ether. The diethyl ether is evaporated to obtain 0.7g of solid product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 70%. Liquid phase analysis showed purity of 97%.
Main reference materials
[1] Yuan Qiliang, Shi Zhengjun, Qian Jie, Zhang Jiabing, & Chen Haifeng. (2013). Research on the synthesis of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl alcohol. Chemical Production and Technology , 20(006), 11-14.
[2] Li Linsha, She Yuanbin, Zhao Wenbo, Wang Pan, & Zhang Yanhui. (2012). 4-ethyl-α-methylbenzyl alcohol and α,α. Chemical Reagents (05), 15-16+26.
[3] Li Liangchun, Yuan Xiaohong, Zhang Youguo, Li Qiang, Huang Yi, & Zheng Renlin. (0). A method for preparing 2,4-difluoro-α,α-bis(1hydro-1,2, Synthesis method of 4-triazol-1-ylmethyl)benzyl alcohol dibenzyl phosphate.
