The Production Process of 9,9-Dimethyl-9H-fluoren-2-yl-boronic acid

The production process of 9,9-dimethyl-9H-fluoren-2-yl-boronic acid, a key intermediate in the synthesis of the widely used antimalarial drug, artesunate, is a complex and multi-step process that involves various chemical reactions and purification steps.

The production process of 9,9-dimethyl-9H-fluoren-2-yl-boronic acid can be broken down into several stages, including the synthesis of the starting materials, the reaction steps, and the purification and isolation of the final product.

Stage 1: Synthesis of starting materials

The first step in the production process is the synthesis of the starting materials, which include 2-fluoromethyl-2H-fluoren-1-one and boric acid.

2-Fluoromethyl-2H-fluoren-1-one is synthesized by a sequence of reactions involving the reduction of 2,3-dihydrobenzofuran-1,2-diol with lithium aluminum hydride, followed by hydrolysis of the resulting lithium borate with aqueous sodium hydroxide.

Boric acid is typically produced by the neutralization of boric oxide with sulfuric acid.
The resulting boric acid can then be purified by precipitation with sodium hydroxide and filtration.

Stage 2: Reaction steps

The synthesis of 9,9-dimethyl-9H-fluoren-2-yl-boronic acid involves several chemical reactions, including the condensation of 2-fluoromethyl-2H-fluoren-1-one and boric acid to form 2-[(2-fluoromethyl-2H-fluoren-1-yl) boron]-1,3-oxazolidin-3-one, followed by acid-catalyzed hydrolysis of the resulting boronate ester.

The first step in the synthesis of 9,9-dimethyl-9H-fluoren-2-yl-boronic acid is the condensation of 2-fluoromethyl-2H-fluoren-1-one and boric acid in the presence of a condensation catalyst such as pyridine or tin(II) chloride.
The reaction conditions, such as temperature and pressure, must be carefully controlled to ensure optimal yield and purity of the product.

The resulting boronate ester is then hydrolyzed using an acid catalyst, such as hydrochloric acid or sulfuric acid, to form 9,9-dimethyl-9H-fluoren-2-yl-boronic acid.
This step requires careful monitoring of the reaction conditions to avoid unwanted side reactions or decomposition of the boronate ester.

Stage 3: Purification and isolation

The final step in the production process of 9,9-dimethyl-9H-fluoren-2-yl-boronic acid is the purification and isolation of the product.

This step typically involves a combination of chromatography techniques such as gel permeation chromatography (GPC), high-performance liquid chromatography (HPLC), and recrystallization.
These techniques are used to separate and isolate the pure boronic acid from any impurities that may have been introduced during the previous steps.

Recrystallization is often used to obtain high-purity boronic acid by dissolving the crude product in a suitable solvent, such as ethanol or acetone, and allowing the solvent to slowly evaporate.
The resulting crystals are then collected, washed with deionized water, and dried to yield the final product.

Conclusion

The production process of 9,9-dimethyl-9H-fluoren-2-yl-boronic acid is a complex and multi-step process that requires careful control of the