154212-61-0

Light Yellow Oil

An intermediate in the synthesis of Ritonavir.

N-[[N-Methyl-N-[(2-isopropyl]-4-thiazolyl)methyl)amino]carbonyl-L-valine Carboxylic Acid (Ritonavir EP Impurity A) is an intermediate in the synthesis of Ritonavir.

The general procedure for the synthesis of (S)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-3-methylbutanoic acid from N-((N-methyl-N-((2-isopropylthiazol-4-yl)methyl)amino)formyl)-L-valine methyl ester was as follows: compound 28 was prepared by reference to the method used for the preparation of compound 6 in Scheme 4, except that compound 9 was substituted for compound 4 as the starting material. Compound 28 (0.757 g, 2.31 mmol) was dissolved in THF (9 mL), and a freshly prepared aqueous 1M LiOH solution (4.6 mL, 4.6 mmol) was slowly added at room temperature. After 1.5 h of reaction, 1M HCl aqueous solution (7 mL, 7 mmol) was added to neutralize the reaction solution. Subsequently, the reaction mixture was extracted several times with EtOAc (5 × 15 mL). All organic layers were combined and dried with anhydrous sodium sulfate.

[1] Patent: WO2008/10921, 2008, A2. Location in patent: Page/Page column 199-200
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 4, p. 602 - 617
[3] Patent: WO2006/90270, 2006, A1. Location in patent: Page/Page column 10
[4] Patent: US5484801, 1996, A
[5] Patent: US5559158, 1996, A