Phenoxypropionyl chloride

Phenoxypropionic acid (249.0 g, 1.50 mol) is dissolved in four equivalents of thionyl chloride (438.0 ml, 6.0 mol) and heated to reflux until the HCI evolution has ceased. The solution is then cooled to room temperature and concentrated under reduced pressure to give 281.0 g (100% yield) of phenoxypropionyl chloride as a brown oil which solidifies on cooling. 

Phenoxypropionyl chloride (9.23 g, 0.05 mol) is dissolved in 100 ml acetone and cooled with an ice bath as sodium azide (3.6 g, 0.055 mol) in 10 ml water is added dropwise. After addition is completed, the reaction mixture is warmed to room temperature and stirred for 30 minutes. The solution is decanted and concentrated. The residue is dissolved in 100 ml ether and washed with saturated sodium bicarbonate and brine. The organic phase is separated, dried (MgS04) and concentrated to give 6.52 g (68.0% yield) of phenoxypropionyl azide as a yellow oil which solidifies on cooling... 

The preparation of IVF involved the condensation of substimted phenox)tpro-pionyl chlorides M20 and 2-(l-hydroxyethyl)-5,5-dimethyl-l,3,2-dioxaphosph-inane-2-one IVB-11 in the presence of triethylamine as a base. The substituted phenoxypropionyl chlorides M20 could be easily obtained by the reaction of substituted phenoxypropionic acids M19 and thionyl chloride in high yields. Substituted phenoxypropionic acids M19 could be synthesized starting from... 

Substituted phenoxypropionyl chlorides M20 could be obtained by the reaction of substituted phenoxypropionic acids M19 and thionyl chloride (Scheme 9.25). 

An appropriate substituted phenoxypropionic acid (0.1 mol) and thionyl chloride (50 mL) were refluxed for 2- h at 70 °C and then the unreacted thionyl chloride was removed under reduced pressure (50-52 °C/1.5 h/11.3 kPa) to give the corresponding substituted phenoxypropionyl chloride M20 as a yellow liquid. Several M20 were obtained by this procedure in 85-96 % yields, which could be used for the next reaction without purification. 

Cyclic alkylphosphonates IVC-IVF could be conveniently prepared by the condensation of cyclic 1-hydroxyalkylphosphonates IVB with substituted phenoxy-acetyl chlorides MS or phenoxypropionyl chlorides M20 in the presence of triethylamine as a base (Scheme 9.26). 

General procedure A solution of substituted phenoxyacetyl chlorides M5 or phenoxypropionyl chlorides M20 (0.01 mol) in dichloromethane (15 mL) was added dropwise to the stirred mixture of appropriate 2-(hydroxy(substituted) methyl)-5,5-dimethyl-l,3,2-dioxaphosphinan-2-one IVB (0.01 mol) and triethylamine (0.011 mol) in dichloromethane (20 mL) under 5 °C, the reaction solution was stirred at room temperature for 2—4 h, and then at 40 °C for another 1-2 h. The resultant mixture was washed with 0.1 M hydrochloric acid solution, saturated sodium bicarbonate solution and brine separately, dried and evaporated. The residue was chromatographed on silica with ethyl acetate/petroleum ether (1/3) as eluent to give the corresponding cyclic alkylphosphonate as a white or yellowish solid. AU IVC-IVF series could be obtained by this procedure. 

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