Yield:355391-05-8 93%

Reaction Conditions:

Stage #1: Ethyl 4-hydroxybenzoate;cyclopropylcarbinyl bromidewith sodium ethanolate in ethanol; for 3 h;Reflux;Large scale;
Stage #2: with sodium hydroxide in ethanol;water; for 2 h;Reflux;Large scale;

Steps:

5 4.5 Synthesis of N-(3-amino-2-methylphenyl)-4-(cyclopropylmethoxy)benzamide (3b)

To a solution of ethyl 4-hydroxybenzoate (24.6kg, 148mol) in 20% NaOEt/ EtOH (55.3kg, 163mol) was added (bromomethyl)cyclopropane (30kg, 222mol). The mixture was refluxed 3h and then refluxed with 3N aq NaOH (73.9kg, 222mol) for 2h. After acidified with concd HCl (59kg), the mixture was cooled to room temperature. The resultant precipitate was collected by filtration, washed with water/EtOH (2:1, 46kg), and dried in vacuo to give 4-(cyclopropylmethoxy)-benzoic acid (26.6kg, 138mol, 93% yield) as white crystals. Mp180°C; ¹H NMR (300MHz, CDCl₃) δ 0.35-0.40 (m, 2H), 0.64-0.70 (m, 2H), 1.27-1.31 (m, 1H), 3.88 (d, J=6.9Hz, 2H), 6.91-6.96 (m, 2H), 8.03-8.08 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ 3.23, 10.08, 72.96, 114.27, 121.48, 132.34, 163.54, 171.67; IR (KBr) ν 3084, 1675cm^-1; MS (FAB) m/z 193 (MH)⁺. Anal. Calcd for C₁₁H₁₂O₃: C, 68.74; H, 6.29. Found: C, 68.48; H, 6.20.

References:

Sawai, Yasuhiro;Mizuno, Masahiro;Ito, Tatsuya;Yamano, Mitsuhisa [Tetrahedron,2014,vol. 70,# 14,p. 2370 - 2377]