Difluoromethyl ethers, synthesis

Scheme 15.86 Key difluoromethyl ether synthesis for CRFl antagonists.

In a later version of the synthesis [9], the trifluoroethyl difluoromethyl ether IS made directly from tnlluoroethanol and chlorodifluoromethane (equation 2) and then chlorinated to give the final product. Again, the major problem is overchlorination, because all the hydrogens are readily replaced by chlorine. Separation of the overchlonnated by-products poses a special problem because of close boiling points. This problem can be solved by adding acetone to create a more easily separable azeotrope of acetone and isoflurane [10]. 

B.R. Langlois, Improvement of the synthesis of aryl difluoromethyl ethers and thioethers by using a solid-liquid phase-transfer technique, J. Fluorine Chem. 41 (2) (1988) 247-261. 

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