1-Bromo-4-fluorobenzene → 4-[(4-Fluorophenyl)hydroxymethyl]-3-(hydroxymethyl)benzenecarbonitrile

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Reaction Steps

In particular, step (a), consisting of the treatment of 5-cyanophthalide with a 4-fluorophenylmagnesium halide, occurs according to a classical Grignard reaction procedure, for example under the conditions described in Example 1 of U.S. Pat. No. 4,136,193 for the 5-bromophthalide, by treating 1.05-1.35 equivalents of a Grignard solution, titred at 15-20%, said solution being prepared from p-fluorobromobenzene and magnesium turnings in an ether, for example in tetrahydrofuran, with 5-cyanophthalide and by adding said Grignard reagent in the amount capable of consuming practically the whole starting 5-cyanophthalide. In practice, the operator controls the course of the reaction by HPLC [column: Develosil C18 4.6×250 mm, 5μ; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aqueous NH4H2PO4+H3PO4 at pH=2.85/B: CH3CN/H2O=9/1 (v/v)] and stops it when 2-3% of unreacted 5-cyanophthalide remains. The product thus obtained is directly submitted to the next step (b) consinsting of a reduction with an agent reducing ketones to alcohols for example with NaBH4, or with LiAlH4 as described in Example 3 of U.S. Pat. No. 4,136,193, to obtain the corresponding 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile.

Provenance & Evidence