A kind of synthetic method of pharmaceutical intermediate 4-(4-chlorophenyl)cyclohexyl-1-carboxylic acid
A synthesis method and chlorophenyl technology, applied in the preparation of carboxylate/lactone, organic chemistry, etc., can solve the problems of disorderly reaction, high corrosion, poor chlorobenzene activity, etc., and achieve the advantages of industrial production and high utilization rate. , the effect of high total yield
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Embodiment 1
[0033] 4-(4-Methylbenzenesulfonate group)-methylcyclohexylcarboxylate (II) (with R 1 is methyl, R 2 For the synthesis of p-tolyl as an example), the method is as follows: in a 500ml there-necked flask, dissolve methyl 4-hydroxycyclohexylcarboxylate (I) (0.1mol, 15.8g) in 80ml of pyridine, cool to below 0°C, Slowly add 21.1g (0.11mol) of p-toluenesulfonyl chloride dichloromethane solution (100ml) dropwise, the dropwise addition is completed within 30min, react at room temperature for 4h, add 200ml water to quench, and use dichloromethane to extract three times (each consumption is 100ml), the combined organic phase was washed three times with 3N HCl (each consumption 80ml), and then washed with 80ml, 10wt% NaHCO 3 After washing once, the organic phase was dried with anhydrous magnesium sulfate, and the solvent was distilled off to obtain 27.2 g of methyl 4-(4-methylbenzenesulfonate)-cyclohexylcarboxylate (II), with a yield of 87%.
Embodiment 2
[0035] Methyl 4-chlorophenylcyclohexylcarboxylate (III) (with R 1 For the synthesis of methyl as an example), the method is as follows: Weigh Cul (0.57g, 0.003mol) and 4-(4-methylbenzenesulfonate group)-cyclohexyl carboxylate (II) (0.03mol, 9.40 g) Add to 250ml reaction bottle. The reaction vial was evacuated, and then nitrogen gas was introduced, and the operation was repeated 3 times. Under the protection of nitrogen, a solution of 4-chlorophenylmagnesium bromide in tetrahydrofuran (90ml, 0.5mol / L, 0.045mol) was added dropwise at 0°C. The reaction solution was continued to stir at 0°C for 24h. After the reaction was completed, it was quenched with 100 ml of saturated aqueous ammonium chloride solution, extracted three times with dichloromethane (100 ml each time), dried the organic phase with anhydrous magnesium sulfate, and evaporated the solvent to obtain methyl 4-chlorophenylcyclohexylcarboxylate (III) 6.20g, yield 81%.
Embodiment 3
[0037] 4-(4-Chlorophenyl)cyclohexyl-1-carboxylic acid (IV) (with R 1 For the synthesis of methyl as an example), the method is as follows: 10.08g (0.04mol) of methyl 4-chlorophenylcyclohexylcarboxylate (III) is added to a 250ml three-necked flask, and 80ml of methanol, 20ml of water and lithium hydroxide ( 3.60g, 0.15mol), stirred at room temperature for 5h, adjusted the pH to 1 with 1N hydrochloric acid, stirred for 30min, the precipitated solid was suction filtered, and the filter cake was washed with water until the pH was 5 to obtain the crude product, which was recrystallized with 60ml ethanol to obtain a white The solid product is 8.50g, the yield is 89%, and the content is 99.17% (HPLC).
[0038] figure 1 Be the infrared spectrogram of present embodiment product, figure 2 It is the mass spectrogram of the product of this example, wherein, GC-MS (EI, 70eV): m / z (%)=238;
[0039] IR(KBr):2939,2862,2669,2615(w),1898,1836(w),1697(s),1489,1415,1300,1265,1214,1088,1007,953,...
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