Study On The Synthetic Process Of Lorlatinib Intermediate

Lung cancer is one of the biggest problems affecting human life and health,especially non-small cell carcinoma（NSCLC）.It accounts for 85%of the total number of patients,and 3-8%of the patients carry ALK gene mutation.ALK is a key target for cancer treatment.Lorlatinib,as a third-generation ALK inhibitor,Lorlatinib has many advantages,including novel and reversible.It was approved by the FDA on November 2,2018 for the treatment of non-small cell cancer and has good market prospects.In this paper,the synthesis of（4-bromo-5-cyano-1-methyl-1H-pyrazole-3-yl）methyl metharbamate tert-butyl ester was studied,that is the key intermediate of Lorlatinib.In the basis of literature,design a synthetic process route,through laboratory research,improve and optimize the synthesis conditions and purification methods,that is to use diethyl oxalate as the raw material,and acetone through the ester-ketone condensation reaction and cyclization reaction to obtain 3-Methyl-5-pyrazole carboxylate（compound S-2）was purified by recrystallization from ethyl acetate/n-hexane,and the yield reached 86.1%;1,3-dimethyl-5-pyrazole formate（compound S-3）was obtained by methylation of S-2,and the yield was increased to 89.6%after optimization.1,3-dimethyl-5-pyrazolecarboxamide（compound S-4）was obtained by aminolysis of S-3,Then,4-bromo-1,3-dimethyl-5-pyrazolonitrile（compound S-6）was obtained by dehydration reaction of phosphorus trichloroxy and electrophilic bromination reaction,and the solid product was obtained by solvent recrystallization to avoid column chromatography separation.S-6 undergoes free radical bromination reaction under the initiation of benzoyl peroxide（BPO）to obtain 4-bromo-3-bromomethyl-1-methyl-5-pyrazolecarbonitrile（compoundS-7）,theyieldwas67.1%,theby-product4,4-dibromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carbonitrile in the reaction process was isolated;S-7 was substituted by methylamine and protected by Boc to produce（4-bromo-5-cyano-1-methyl-1H-pyrazole-3-yl）methyl metharbamate with a yield of80.9%.The chemical structure of the intermediates was confirmed by IR,¹H-NMR and¹³C-NMR.