Preparation method of tritylvalsartan_Kain Industrial Additive

Background and overview^[1]

Tritylvalsartan is the precursor of valsartan and can be used to prepare valsartan. Valsartan is a widely used antihypertensive drug in clinical practice. It has the advantages of low side effects and good tolerance. It can also be used to treat hypertension in patients with diabetes and kidney disease. Valsartan is a new generation of angiotensin II receptor antagonist with high selectivity and special direct effect, and can effectively antagonize AT1 receptors.

Preparation method^[1]

In the presence of commercially available Pd(PPh₃)₄, formula III(S)-3-methyl-2-{valeryl-[2 Preparation of ‘-(1-trityl-1H-tetrazolyl-5-)biphenyl-4-methyl]amino}butyric acid methyl ester

Purge toluene (20ml) with nitrogen for 0.5 hours to degas, then add Pd(PPh₃)₄ (150mg, 0.00013 mol, 0.02 equivalent) and 2 -(1-Trityl-1H-tetrazolyl-5-)phenylboronic acid (II) (3.5 g, 0.0068 mol, 1.05 equiv). The mixture was degassed for a further 0.25 hours, then water (0.3 g, 0.0163 mol, 2.5 equiv) was added and the slurry was stirred for an additional 20 minutes. Powdered KCO (2.25 g, 0.0163 mol, 2.5 equiv) and I (2.5 g, 0.0065 mol) were added to the reaction mixture, followed by further degassing for 0.25 h. Next, the mixture was heated to reflux under a nitrogen atmosphere and maintained at reflux until I disappeared (1.5-2 hours). When the reaction is complete, the mixture is cooled to room temperature and washed with 50 ml of water. Separate the organic and aqueous phases. After separation, the aqueous phase was washed with 25 ml of toluene, and the combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. 5.5 g of product III was obtained as a yellow oil with a purity of 72.5% peak area determined by HPLC.

Mix the compound of formula III with a base to obtain (S)-3-methyl-2-{pentanoyl-[2′-(1-trityl-1H-tetrazolyl-5-) of formula IV )Biphenyl-4-methyl]amino}butyric acid (i.e., tritylvalsartan). Mixing tritylvalsartan with acid gives valsartan.

Main reference materials

[1] CN200680024006.6 Method for preparing valsartan