Henkel Confidential

Acrylate Platform – December 2011 Synthesis of BCHTU Page 1 Synthesis of Benzoyl cyclohexylthiourea (BCHTU)

Method: To a 5-Liter 4-neck round bottom flask equipped with a water condenser, thermo-probe, thermalcontroller, React-IR probe, dry nitrogen purge (with desiccant), overhead stirring and pressureequilibrated addition funnel is added ammonium thiocyanate (366.20 g, 4.6904 mol) followed by dry ethyl acetate (2000 mL). This solution/suspension is cooled near 5-10° C in an ice-water bath. To the cooled solution/suspension is added slowly over approx. 60 minutes a solution of benzoyl chloride (605.5 g, 500.0 mL, 4.2640 mol) in dry ethyl acetate (2000 mL). The resulting mild exotherm is controlled with cooling and the temperature of the reaction is maintained below 20° C during the addition. After the complete addition of the benzoyl chloride solution, the reaction is warmed to reflux (77° C) and held at reflux minimally 2 hours. Note: Reaction progress toward the intermediate is monitored and confirmed by FT-IR.The reaction becomes reddish with white insoluble solids present. External heating is removed from the reaction and the mixture is cooled again near 5-10° C. To the cooled solution is added slowly over approx. 60 minutes a solution of cyclohexylamine (453.1 g, 4.4772 mol) in ethyl acetate (2000 mL). The resulting mild exotherm is controlled with cooling and the temperature of the reaction is maintained below 20° C during the addition. After the complete addition of the cyclohexylamine solution, the reaction is allowed to warm to ambient temperature and stirred overnight Note: Alternatively the solution can be warmed to reflux for 2 hours and then cooled to ambient temperature. Reaction progress toward the target is monitored by FT-IR.Upon confirmation of the target, the reaction mixture is washed twice with 10% HCl (2 x 4000 mL) and then deionized water (4000 mL). The organic portion is separated, dried over anhydrous MgSO4, gravity filtered through fluted filter paper, and then concentrated in vacuo at 40° C to a pale yellow to dark orange oil. Note: The oil may solidify overnight. Crude yield is 89.4%.Henkel Confidential

Acrylate Platform – December 2011 Synthesis of BCHTU Page 2 Purification: The dried crude solid is hot-filtered dual-solvent recrystallized in the following proportions; 1 part solid: 5 parts ethanol: 1 part water. Note: These proportions are critical to the proper crystallization of the solid. The solid (1000 g) is dissolved in ethanol (5000 mL) at reflux. The hot solution is gravity filtered through fluted filter paper (to remove any insoluble material). With gentle mixing, deionized water (1000 mL) is added to facilitate precipitation. Note: Scratching of the glass will promote slow and uniform recrystallization. The flask is allowed to cool to ambient temperature, prior to cooling in the refrigerator overnight. In the morning the crystals are collected cold by vacuum filtration through a glass-fritted funnel. The solid is washed with a minimal amount of cold deionized water, suctioned to near dryness and then dried in vacuo at 40° C at <1 Torr. Additional recrystallizations may be necessary to assure a high level of purity. Ultimately this provides a pale yellow to slightly off-white solid that is analytically consistent with the target structure. The overall reaction yield of BCHTU (mw 262.37 g mol -1 ) (after recrystallization) is approx. 71.5%. Recrystallization yields are 60 to 80 %. Note: The filtrates can be combined and concentrated to provide additional ‘crude’ solids (which can be combined with subsequent batches) and then recrystallized in a separate manner to supplement the overall yield.

Analysis: Appearance: Visual inspection, pale yellow to off-white crystalline solid.

1 H NMR: Solvent DMSOd6
, į11.25 ppm (s, HN-C=O), 10.95 ppm (d, (HN) 2 -C=S), 7.98 & 7.95 ppm (s, aromatic C-H), 7.6 (m, aromatic C-H), 7.45 ppm (m, aromatic C-H), 4.2 ppm (m, -CH=), 3.35 ppm (solvent exchange, water in DMSOd6), 2.50 ppm (solvent DMSO protons), 1.9 ppm (s, ring -CH 2 -), 1.6 ppm (s, ring –CH 2 -), 1.5 ppm (s, ring –CH 2 -), 1.3 ppm (m, ring –CH 2 -).

13C NMR: Solvent DMSOd6
, į179.5 ppm (C=S), 169.0 (C=O), 134.0 (aromatic C), 133.5 (aromatic C-H), 129.0 (aromatic C), 53.5 (ring -CH=), 40.0 (DMSOd6 solvent), 31.5 (ring -CH 2 -), 26.0 (ring -CH 2 -), 24.5 (ring -CH 2 -).
FT-IR: ATR Accessory, 3168 cm -1 (-NH), 3047 (aromatic C-H), 2940 & 2854 (alkyl C-H), 1668 (C=O), 1600 (aromatic C-H), 1525 (C=S), 1260 (-C=O-NH-), 1167 (-(NH) 2 -C=S), 705 (-CH 2 -), 688 (aromatic C-H). Melting point: DSC, Sharp at 67° C
Chemical Name: Benzamide, N -[(cyclohexylamino)thioxomethyl]-
Common Name: Benzoyl cyclohexylthiourea (BCHTU) CAS Registry Number: 4921-92-0

Materials: Ammonium thiocyanate (reagent ACS 97.5 %), CAS 1762-95-4, mw 76.12, mp 145.9° C (lit) Benzoyl chloride (99+ %), CAS 98-88-4, mw 140.57, mp -1° C (lit), bp 197-199° C (lit) Cyclohexylamine (98+ %), CAS 108-91-8, mw 99.17, mp -17° C (lit), bp 134° C (lit) Ethyl acetate (reagent grade), CAS 14-78-6, bp 77° C (lit), d 0.897 g mL -1 Hydrochloric acid (concentrated), CAS 7647-01-0, 36-38 % Ethanol (reagent grade), bp 78.4 C (lit), d 0.789 g mL -1Henkel Confidential

Acrylate Platform – December 2011 Synthesis of BCHTU Page 3 Mass Balance Flow Chart - Reaction, Work-up and Purification of BCHTU

Reaction

Work-upHenkel Confidential

Acrylate Platform – December 2011 Synthesis of BCHTU Page 4 Purification