Yield:-

Reaction Conditions:

in 2-MeTHF at 5 - 20;

Steps:

64.8
Intermediate 64-8: Methyl 2-fn r.4rWU4-f4A5.5-tetramethyl-T .3.2-rtioxahorolan-2- vDnhenylkvclohexyDacetateTrimethylphosphonoacetate (1.05X-1.06X) was added dropwise to a suspended solution of t-BuOK (0.70X-0.71X) in 2-MeTHF (10 vol) at 5-1O⁰C. The resulting solution was stirred at 15-2O⁰C for 3.5-4.0 hours. The reaction mixture was cooled to 5-1O⁰C and DIPEA (0.81-0.82X) was added to the reaction at 10-15⁰C. 4-(4-Hydroxyphenyl)cyclohexanone (1.0 X) was added in portions to the above reaction mixture at 10-15⁰C and the resulting solution was stirred at 15-2O⁰C for 3-6 hours and then sampled for HPLC analysis. NH4C1- sol (5.0X-6.0X) was added to the reaction mixture at 0-15⁰C, and the reaction was quenched. The organic layer was separated and the aqueous layer was extracted with 2- MeTHF (2.5X-3.0X). The two organic extracts were combined and washed with NaHSO₃ aq. and then NaCl-solution (2.5X-3.0X) twice. The organic layer was concentrated to 2~3 vol and n-heptane was added to give a suspended solution, and the above mixture was concentrated to below 3% of 2-MeTHF residue to give a suspended solution. The mixture was cooled to 0-5 ⁰C, stirred for 1.0-2.0 h, filtered and the cake washed with n-heptane (2 vol X2). Dry in vacuum at below 45⁰C to give the desired phenoxyacrylate product.

References:

ASTRAZENECA AB;ASTRAZENECA UK LIMITED WO2009/81195, 2009, A1 Location in patent:Page/Page column 29; 161-162