Yield:1018450-35-5 94%

Reaction Conditions:

Stage #1: 1,1-dimethylethyl (4-chloro-3-fluorophenyl)carbamatewith n-butyllithium in tetrahydrofuran at -80 - 75; for 2.66667 h;
Stage #2: with iodine in tetrahydrofuran at -80 - 35; for 17 h;

Steps:

7

Compound 103[00321]; Compound 102 (80.2g, 0.326mol) was added to a 3L four-neck round bottom flask equipped with overhead stirrer, an internal temperature probe, 500ml addition funnel and an argon inlet. Anhydrous tetrahydrofuran (640ml) was charged to the flask and cooled using a dry ice bath plus liquid nitrogen, ensuring an internal temperature of -8O⁰C < T < - 75⁰C at all times during the reaction. ?-Butyl lithium (405ml, 1.01 lmol) was transferred via canula to the argon filled funnel and added dropwise to the solution with minimal splashing over 2h. After aging for 40min, a solution of iodine (289.9g, 1.142mol) in anhydrous tetrahydrofuran (430ml + 100ml rinse) was added dropwise to the cold reaction mixture, ensuring an internal temperature of -8O⁰C < T < -75⁰C over 3h.The reaction mixture was allowed to warm slowly to -3O⁰C over 14h after which time analysis by ΗPLC method Test 20 (sample quenched with NaHSO₃ aq, diluted with MeCN then MeCN layer diluted with MeOH) indicated nearly complete conversion of starting material (Rt 6.17min, 1.6% (at) 254nm) to one product (Rt 6.73min).[00322] A solution OfNH₄Cl (41.6g in 160ml water) was added gradually, followed by a solution OfNaHSO₃ (184.8g in 560ml water) ensuring T < -1O⁰C. The quenching mixture was allowed to warm to 1O⁰C whilst stirring for 1.5h.[00323] After transferring the mixture to a one-neck flask, 1370ml of THF distillate was removed and water (500ml) was added. The mixture was stirred vigorously at 4⁰C for 15h and filtered. After washing with water (400ml) a beige solid was obtained with a colorless filtrate which contained no product by HPLC. [00324] The solid was dissolved in hot (65⁰C) ethanol (700ml) and filtered whilst hot to remove insoluble material (3.5g, no product by HPLC). The filtrate obtained was concentrated at 45⁰C under vacuum to 150ml at which point solids began to precipitate. Water (32ml) was added dropwise to the mixture which was then cooled slowly to 4⁰C over 1.5h. Filtration under vacuum, washing with 4⁰C ethanol:water 2:1 (250ml) and drying under vacuum at 4O⁰C gave Compound 103 as a pale yellow solid (114. Ig, 94% yield). Compound 103: C iH₁₂CIFINO₂ 371.57gmol^"'. HPLC analysis (Test 20, MeOH): R_t 6.73min; 99% purity (at) 272nm. m.p.: 66-67⁰C. ¹H NMR δ_H (400 MHz, CDCl₃): 1.45 (9H, s, 3 x CH₃), 7.27 (1Η, dd, Ar-H), 7.55 (1Η, t, Ar-H), 8.70 (1Η, s, CON-H). ¹³C NMR δ_c (100 MHz, CDCl₃): 28.04 (C(CH₃)₃), 79.73 (C(CH₃)₃), 86.23, 86.49 (C-I), 1 15.11, 1 15.32 (C-Cl), 122.35, 122.38 (C-N), 129.89 (C-H), 140.99, 141.02 (C-H), 152.94 (C=O), 155.47, 157.87 (C-F).

References:

WO2008/42240,2008,A2 Location in patent:Page/Page column 112-114