Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances

Abstract

Preparation of 3, 3', 5, 5'-tetrakis(1-methyl)biphenyl-4,4'-diol ( 4) Propofol (1) (5 g, 28 mmol) was charged into water (150 mL) followed by addition of FeCl 3 (5.6 g, 30.3 mmol) and the reaction mixture was heated at 90 o C for 1 h. Reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate (2 × 75 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated to give the crude product which was used as such for the next step. To a solution of crude residue in THF (45 mL) and MeOH (5 mL), was added sodium borohydride (3.2 g, 84 mmol) and reaction mixture was stirred

Zinc Dialkylhydroxybenzoates with Unusual Structures: First Example of a Discrete Three‐Blade Paddle‐Wheel and a Solvent Engulfed Coordination Polymer

“…Due to the above mentioned reasons, we envisaged that it is possible to isolate molecular tricarboxylate paddle‐wheels under kinetic control by using a sterically encumbered ligand. For this purpose, we have chosen 4‐hydroxy‐3,5‐diisopropylbenzoic acid (H 2 diphba) as the carboxylate source, which is an intermediate compound obtained during the synthesis of the most widely used general anaesthetic 2,6‐disopropylphenol (popularly known as propofol ) . The choice of this ligand is intentional to further investigate the effect of bulky isopropyl group and hydroxyl group on structural topology of the resulting supramolecular arrays in combination with π‐rich N‐donor ligands.…”

Continuous Flow Synthesis of Propofol

“…Although isopropanol has been proposed to replace the gaseous propylene, these harsh conditions all led to the production of several impurities (2,4-diisopropyl and 2,4,6-triisopropyl phenol, along with the product ( Scheme 2 , path a)). These side products need to be removed from the final API (<0.05%) for medical use [ 23 ]. To address the formation of these undesired products in the synthesis of Propofol, another approach was designed using the 4-hydroxybenzoic acid ( 1 ) as the starting material to hamper the undesired alkylation at the para position.…”

“…To address the formation of these undesired products in the synthesis of Propofol, another approach was designed using the 4-hydroxybenzoic acid ( 1 ) as the starting material to hamper the undesired alkylation at the para position. [ 23 ] Thus, the alkylation of 1 using isopropyl alcohol (IPA) and H 2 SO 4 followed by a decarboxylation step under alkaline conditions (NaOH) at high temperature, afforded Propofol with a higher purity, matching with the API synthesis standard. However, this procedure suffers from acid–base neutralization at each step, resulting in exothermic quench, a serious drawback for an industrial implementation of the process.…”

“…However, this procedure suffers from acid–base neutralization at each step, resulting in exothermic quench, a serious drawback for an industrial implementation of the process. This issue was further tackled by Pramanik, who simplifies the isolation and purification steps by getting rid of the acid–base neutralization, using a toluene/water mixture ( Scheme 2 b) [ 23 ].…”

“… Path ( a ): Seminal synthesis of propofol. Path ( b ) Modified synthesis of Propofol according to Pramanik [ 23 ]. …”