Trimethyl orthobenzoate

clear colorless liquid

Trimethyl Orthobenzoate is a reagent used in the synthesis of quinazolines. Also used in the prepaaration of nintedanib (N478290), used in the treatment of idiopathic pulmonary fibrosis. Also inhibits the process blood vessel formation which may be used to assist in cancer therapy.

Journal of the American Chemical Society, 72, p. 1661, 1950 DOI: 10.1021/ja01160a067

Trimethyl orthobenzoate reacts with P-dimethylaminophosphonic acid bis(1-methylhydrazide) to yield 1,2,5,6-tetrahydro-1,5-dimethyl-6-(N,N-dimethylamino)-6-phenyl-1,2,4,5,6-tetrazaphosphorine-6-oxide.

The phenylbenzamide derivative (44.3 mmol) and methyl trifluoromethanesulfonate (5.93 mL, 52.5 mmol) were dissolved in dry dichloromethane (20 mL) and the reaction solution was stirred for 18 hours. Anhydrous ether (70 mL) was added to the reaction mixture to obtain benzimidazolium trifluoromethanesulfonate; the salt was separated by decantation. The salt was washed with anhydrous ether (10 mL) and redissolved in dichloromethane (20 mL). The mixture was cooled to 0??C and the reaction mixture was treated with sodium methanol solution. The reaction mixture was stirred at room temperature for 10 minutes; the solvent was evaporated to give the crude aniline acetal mixed with the trifluoromethanesulfonate. The mixture was dissolved in hexane (150-200 mL) and filtered to remove the salt and the solvent was removed under vacuum. The acetal dissolved in anhydrous methanol (35 mL) was treated with glacial acetic acid (3.4 mL), the reaction mixture was treated with sodium methanol solution, the reaction mixture was stirred at room temperature for 15 minutes, and the reaction mixture was treated with K2CO3 (3 g). The solvent was evaporated and ether and water were added to the reaction mixture to separate the organic layer. The solvent was removed under vacuum to obtain the crude protic acid ester. The crude product was purified by fractional distillation at 0.1 mmHg to afford N-methylaniline at 25-30 ??C and trimethyl orthobenzoate at 90-100 ??C.