Boron-containing compounds
Described herein are boron-containing compounds, compositions, and methods for their preparation.
1. A continuous flow process for making a compound of Formula (III):
wherein
P 1 is a hydroxyl protecting group; and
P 2 is a carboxyl protecting group;
the process comprising:
(a) providing a first continuous flow of a compound of Formula (II) and dichloromethane:
(b) providing a second continuous flow of a base selected from lithium diisopropylamide and 2,2,6,6-tetramethylpiperidinylmagnesium chloride:lithium chloride;
(c) mixing the first continuous flow and the second continuous flow in a mixing chamber to yield a third continuous flow comprising a first reactive intermediate;
(d) collecting the first reactive intermediate into a collection vessel at the output of the third continuous flow;
(e) treating the first reactive intermediate with a Lewis acid; and
(f) warming the collection vessel to provide the compound of Formula (III).
2. The process of claim 1 , wherein the first continuous flow further comprises a coordinating ethereal solvent and the second continuous flow further comprises a coordinating ethereal solvent.
3. The process of claim 1 , wherein the second continuous flow further comprises heptane, ethyl benzene, or a combination thereof.
4. The process of claim 1 , wherein the Lewis acid is provided as a fourth continuous flow further comprising a coordinating ethereal solvent.
5. The process of claim 1 , wherein the water content of the coordinating ethereal solvent is less than about 0.08% (w/w), less than about 0.05% (w/w), or the coordinating ethereal solvent is substantially free of water.
6. The process of claim 1 , wherein the dichloromethane is substantially free of water.
7. The process of claim 1 , wherein the base is substantially free of water.
8. The process of claim 3 , wherein the heptane, ethyl benzene, or a combination thereof is substantially free of water.
9. The process of claim 1 , comprising pre-cooling the first continuous flow to a temperature in the range of about −40° C. to about −10° C. and pre-cooling the second continuous flow to a temperature in the range of about −40° C. to about −10° C.
10. The process of claim 1 , wherein the third continuous flow has a temperature in the range of about −20° C. to about +10° C.
11. The process of claim 1 , comprising maintaining the collection vessel at the output of the third continuous flow at a temperature in the range of about −10° C. to about +10° C.
12. The process of claim 1 , wherein the collection vessel is warmed to room temperature in step (f).
13. The process of claim 1 , wherein the molar ratio of the base to a compound of Formula (II) is in the range of about 1:1 to about 1.5:1, the molar ratio of the dichloromethane to a compound of Formula (II) is in the range of about 5:1 and 7:1, and the molar ratio of the Lewis acid to a compound of Formula (II) is in the range of about 1:1 and 3:1.
14. The process of claim 1 , wherein the base is lithium diisopropylamide and the Lewis acid is ZnCl 2 .
15. The process of claim 1 , wherein P 1 is methyl and P 2 is tert-butyl.