Continuous flow carboxylation reaction
The present invention is related to a two-step carboxylation reaction of an aryl group using continuous flow reaction conditions. This process permits large scale synthesis of useful reaction products in high yield.
1. A process of preparing a compound of Formula I:
comprising:
reacting a compound of Formula II:
with n-BuLi and tetramethylethylenediamine at −78° C. to afford a compound of Formula III:
quenching said compound of Formula III with gaseous carbon dioxide to afford a compound of Formula IV:
and
treating said compound of Formula IV with HCl to afford the compound of Formula I, wherein said method is performed using continuous flow reaction conditions, and wherein a reaction temperature is maintained at less than −65° C. during the quenching with gaseous carbon dioxide.
2. The process of claim 1 , wherein said reacting a compound of Formula II with n-BuLi and tetramethylethylenediamine at −78° C. is performed in a polar aprotic solvent.
3. The process of claim 2 , wherein said polar aprotic solvent is THF.
4. The process of claim 1 , wherein said reacting a compound of Formula IV with HCl is performed in a polar solvent.
5. The process of claim 4 , wherein said polar solvent is 1,4-dioxane.
6. The process of claim 1 , wherein said HCl is 4N HCl.
7. The process of claim 1 , wherein the compound of Formula I is an intermediate used in the synthesis of lifitegrast.
8. The process of claim 1 , wherein said process is carried out in a continuous flow batch reactor.
9. The process of claim 8 , wherein said continuous flow batch reactor comprises stainless steel reactor tubes.