Tiopronin
From The Cure For The Needy
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Tiopronin (Thiola)
Effective Against
Tiopronin helps keep cystine dissolved in the urine, which makes cystine kidney stones less likely to form.
Cost
From Sigma-Aldrich: 67.30 USD (100mg)
From Universal Drug Store: 114 USD for 100 100mg tablets
Reported Route of Synthesis
S-Benzylation of 2-mercaptopropionic acid (I) with PhCH2Cl or PnbBr affords corresponding benzylated 2-(mercapto)propionic acids (IIa) and (IIb), which upon chlorination with SOCl2 yields corresponding acid chlorides (IIIa) and (IIIb). Coupling of acid chlorides (IIIa) or (IIIb) with glycine (IV) in the presence of NaOH gives N-acyl glycines (Va) and (Vb) correspondingly, which then undergoes debenzylation by means of Na in the presence of NH3 at -50°C affords the title compound (1). Alternative route for the preparation of Tiopronin: Thioesterification of 2-mercaptopropionic acid (I) with PhCOCl or p-O2NPhCOCl affords corresponding esters (VIa) and (VIb), which upon chlorination by means of SOCl2 provides propanoyl chlorides (VIIa) and (VIIb) correspondingly. Coupling of intermediates (VIIa) or (VIIb) with glycine (IV) in the presence of NaOH in H2O generates glycinamides (VIIIa) and (VIIIb). Finally, hydrolysis of (VIIIa) or (VIIIb) by means of Ba(OH)2 in H2O furnishes the title compound (1).
Santen Pharmaceutical Co., Ltd. Mercaptopropionic acid derivatives. US 3246025
Substitution of [(2-bromopropionyl)amino]acetic acid (I) with PhCOSH in the presence of K2CO3 in H2O yields 2-[2-(benzoylsulfanyl)propionamido]acetic acid (II), which is then treated with NH3 in the presence of NaHCO3 in H2O furnishing (III). Finally, hydrolysis of glycinamide derivative (III) by means of HCl provides the title compound. Tiopronin can be prepared by two other alternative routes: 1.Condensation of [(2-bromopropionyl)amino]acetic acid (I) with CH3COSH in the presence of KOH in EtOH yields 2-[2-(acetylsulfanyl)propionamido]acetic acid (VII), which undergoes hydrolysis in the presence of NaOH to afford the title compound. 2.Substitution of [(2-bromopropionyl)amino]acetic acid (I) with potassium xanthogenate (VIII) in the presence of NaHCO3 in H2O yields alpha-ethylxanthogenpropionylglycine (IX), which upon treatment with NH3 gives corresponding glycinamide (X). Finally, hydrolysis of amide (X) by means of HCl yields the title compound. Preparation of intermediate (III): Condensation of [(2-bromopropionyl)amino]acetate (V) with PhCOSH in the presence of KOH in EtOH yields [[2-(benzoylthio)propionyl]amino]acetate (VI), which upon treatment with NH3 in H2O furnishes the desired intermediate (III) (can also be prepared by the condensation of N-(2- carbamoylmethyl)-2-bromopropionamide (IV) with PhCOSH in the presence of KOH in EtOH ) (1).
Santen Pharmaceutical Co., Ltd. Mercaptopropionic acid derivatives. US 3246025