Background and Overview
2-Hydroxy-4-methylbenzaldehyde is a chemical intermediate.
Preparation[1]
Synthesis of 2-hydroxy-4-methyl-benzaldehyde
M-cresol and polyformaldehyde are mixed in solvent A, and carbonylation reaction is carried out under alkaline conditions and catalyzed by Lewis acid catalyst. The reaction temperature is controlled at 60-120°C, preferably 100°C, and the time is 8h. Finally, we get 2-Hydroxy-4-methyl-benzaldehyde, the schematic diagram of the reaction process is shown in Figure 5; wherein, the solvent A is an aprotic solvent such as benzene, toluene, xylene, decalin, acetonitrile, cyclohexane, etc. One or more mixtures, preferably toluene; the Lewis acid catalyst is one of tin tetrachloride, tin dichloride, ferric chloride or aluminum trichloride, preferably tin tetrachloride; The base is one of organic bases such as triethylamine, tributylamine, trihexylamine or trioctylamine, preferably tributylamine; the m-cresol, polyformaldehyde and Lewis acid catalyst used in the reaction process The molar ratio, that is, m-cresol:polyformaldehyde:Lewis acid catalyst is 1:1.2~5:0.05~0.2, preferably 1:1.8~2.2:0.08~0.1; more preferably 1:2.2:0.1; used in the reaction process The molar ratio of the base to the Lewis acid catalyst, that is, the Lewis acid catalyst:base is 1:2 to 5, preferably 1:3 to 4; more preferably 1:3. Specific examples are as follows:
Dissolve 108g m-cresol in 200ml toluene, add 26g tin tetrachloride (0.1mol) and 54g tributylamine (0.3mol) under nitrogen protection, and stir the mixture at room temperature for 20 minutes. Then add 66g polyformaldehyde (2.2mol), heat to 100°C and react for 8 hours, then cool to room temperature, pour into 500ml cold water, acidify with dilute hydrochloric acid, extract with ether, wash the organic phase with brine, dry over anhydrous magnesium sulfate, and recover the solvent , to obtain 119g of 2-hydroxy-4-methyl-benzaldehyde (GC content>98%), yield 86%, m.p.60-61℃;
Apply [2]
Compound 4-((2-(aminomethyl)-5-methylphenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester and related derivatives have wide applications in medicinal chemistry and organic synthesis. application. At present, the synthesis of tert-butyl 4-((2-(aminomethyl)-5-methylphenoxy)methyl)piperidine-1-carboxylate is difficult. Therefore, it is necessary to develop a synthesis method with easily available raw materials, convenient operation, easy control of the reaction, and suitable overall yield. CN201611074598.4 discloses a preparation method of piperidine derivative 4-((2-(aminomethyl)-5-methylphenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester, using 2- Hydroxy-4-methylbenzaldehyde is used as the starting material. After oximation, elimination, etherification, and catalytic hydrogenation, the target product 5 is obtained. The synthesis steps are as follows: (1) Using 2-hydroxy-4-methylbenzaldehyde as The starting material is subjected to oximation reaction to obtain 2; (2) 2 is subjected to elimination reaction to obtain 3; (3) 3 is subjected to etherification reaction to obtain 4; (4) 4 is subjected to catalytic hydrogenation reaction to obtain 5. There is currently no preparation method for the preparation method of a piperidine derivative 4-((2-(aminomethyl)-5-methylphenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester involved in the invention. Other relevant patent literature reports.
Main reference materials
[1] CN201110191857.2 A synthesis method of 2-methoxy-4-methylbenzylamine
[2] CN201611074598.4 Preparation method of piperidine derivatives
