The synthesis of Linzagolix Choline is accomplished via an efficient two-component polymerization, as shown in Figures 1 and 2. The synthesis of the first component, intermediate 35.6, begins with the reaction of dimethyl maleate 35.1 and methyl thioacetate 35.2 under alkaline conditions (Figure 1). After treatment under mild acidic conditions, a crystalline solid cyclic thiol compound 35.3 is obtained. This cyclic thiol is then converted to the corresponding thiophene by aromatization. The ketone 35.3 is converted to the corresponding oxime by treatment with hydroxylamine hydrochloride in warm pyridine, and the resulting oxime is then treated under strongly acidic conditions to afford the aminothiophene 35.5, a sequence known as the Semmler–Wolff aromatization reaction. Finally, 35.5 is reacted with phenyl chloroformate to afford the carbamate intermediate 35.6 in 92% yield.
The synthesis of the second component, intermediate 35.11, begins with sodium borohydride reduction of the aldehyde 35.7 to the corresponding alcohol, which is subsequently chlorinated using concentrated hydrochloric acid (Figure 2). The bromide is then generated in situ and tetrabutylammonium bromide is added to achieve this. Under alkaline conditions, the ether is formed by adding phenol 35.8 to obtain ether 35.9, and the total yield of the three-step reaction is 89%. Conventional nitration conditions are then used to obtain compound 39.10. Raney nickel reduction is used to obtain the corresponding amine, thereby synthesizing the key aniline intermediate 35.11. At this point, the two higher intermediates 35.6 and 35.11 are condensed under alkaline conditions to produce a high-yield urea 35.12. 35.12 is exposed to the carboxyl group under the action of lithium hydroxide, and the intramolecular cyclization reaction is promoted by acidic conditions. It is then treated with choline carbonate to precipitate Linzagolix Choline, which is finally isolated as a choline salt.
