N-[(4-tert-butylphenyl)methylidene]hydroxylamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-chlorosuccinimide (8.1 g, 61 mmol) was added to a solution of 4-tert-butylbenzaldehyde oxime (9 g, 50.1 mmol) in DMF (50 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being cooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethyl-4-tert-butylbenzene was obtained as a yellowish solid (10.7 g). to rise briefly to 50° C The reaction mixture was cooled in an ice bath while being cooled with ice extracted with ether (3×100 ml) The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml) dried the solvent was removed under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydroxylamine hydrochloride (4.65 g, 67.4 mmol) was slowly added to a solution of 4-tert-butylbenzaldehyde (10 g, 61.6 mmol) in water (34 ml) and EtOH (7 ml). An aqueous solution of sodium hydroxide (3.6 g, 153 mmol) was slowly added dropwise, so the temperature of the reaction mixture did not exceed 25° C. The reaction mixture was stirred overnight at RT and mixed with diethyl ether. The aqueous phase was neutralised with 0.5 M aq. hydrochloric acid solution and extracted several times with ether. The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. The desired product 4-tert-butylbenzaldehyde oxime was obtained in a yield of 84% of the theoretical amount (9.1 g) did not exceed 25° C extracted several times with ether The combined organic phases were dried over magnesium sulphate the solvent was removed under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The desired product was prepared using a procedure similar to Step 6 of example 34. Thus, 2-[(biphenyl-4-carbonyl)-amino]-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.325 g, 0.694 mmol) was reacted with Cs2Co3 (0.475 g, 1.457 mmol) and 4-tert-Butyl-benzaldehyde oxime (0.135 g, 0.763 mmol) in acetone (30 ml) to give 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.258 g, 0.457 mmol, 66%) as a viscous yellow oil. 1H NMR (DMSO-d6) δ 1.20 (s, 9H), 2.05-2.18 (m, 2H), 3.85 (s, 3H), 4.18 (t, 2H), 4.23 (t, 2H), 6.79 (d, 1H), 7.32-7.50 (m, 7H), 7.73 (d, 2H), 7.85 (d, 2H), 7.95-8.02 (m, 3H), 8.18 (s, 1H), 8.39 (s, 1H), 11.98 (s, 1H), mass spectrum [ES(+)], m/z 565 (M+H)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The desired product was prepared using a procedure similar to Step 6 of example 34. Thus, 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-(3-bromopropoxy)benzoic acid methyl ester (0.299 g, 0.605 mmol) was reacted with cesium carbonate (0.414 g, 1.271 mmol) and 4-tert-butyl-benzaldehyde oxime (0.118 g, 0.665 mmol) in acetone (30 ml) to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.148 g, 0.251 mmol, 41%) as a pale yellow solid, mp 120-122° C. 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 2.10-2.22 (m, 2H), 3.85 (s, 3H), 4.18 (t, 2H), 4.26 (t, 2H), 6.80 (dd, 1H), 6.95 (d, 1H), 7.37-7.54 (m, 7H), 7.62-7.78 (m, 5H), 7.83 (d, 2H), 7.97 (d, 1H), 8.22 (s, 1H), 8.30 (dd, 1H), 11.16 (s, 1H); mass spectrum [ES(−)], m/z 589 (M−H)−.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.40 g, 1.30 mmol), 4-tert-butyl-benzaldehyde oxime (0.24 g, 1.36 mmol) and cesium carbonate (1.69 g, 5.20 mmol) in acetone (50 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 83%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.13 (s, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.49 (d, 2H), 7.39-7.36 (m, 3H), 5.18 (s, 2H), 3.92 (s, 3H), 1.32 (s, 9H). This compound was produced The crude material was purified by flash chromatography through silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.53 g, 1.00 mmol) and 4-tert-butyl-benzaldehyde oxime (0.20 g, 1.10 mmol) in acetone (35 mL) was added cesium carbonate (1.30 g, 4.00 mmol). The mixture was heated to reflux overnight and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 5/95) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.30 g, 48%) as an off-white solid. 1H NMR (400 MHz, CDCl3); δ 12.52 (s, 1H), 8.51 (d, 1H), 8.48 (s, 2H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99 (d, 1H), 7.47-7.35 (AA′BB′, 4H), 6.67 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 3.92 (s, 3H), 2.23 (m, 2H), 1.28 (s, 9H). The mixture was heated to reflux overnight The mixture was partitioned between ethyl acetate and brine the layers were then separated The aqueous layer was extracted with two additional portions of ethyl acetate dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The crude oil was purified by flash chromatography through silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (0.117 g, 64%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and 4-tert-butyl-benzaldehyde oxime using a procedure similar to step 1 of example 6. mp=121.1-122.0° C.; mass spectrum API-ES, (M−H) m/z 541. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 11.90 (bs, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.80 (m, 3H), 7.50 (d, 2H), 7.39 (d, 2H), 6.82 (dd, 1H), 4.28 (t, 2H), 4.18 (t, 2H), 2.15 (m, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C29H29F3N2O5: C, 62.2; H, 5.39; N, 5.16, Found: C, 63.8; H, 5.26; N, 5.04.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared as a white solid (3.056 g, 76%) from 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester and 4-tert-butyl-benzaldehyde oxime using a procedure similar to that of step 1 of example 6. mp=161.4-162.7° C.; mass spectrum (+APCI, M+H) m/z 358. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 8.24 (s, 1H), 7.68 (d, 1H), 7.54 (d, 2H), 7.42 (d, 2H), 6.52 (m, 2H), 4.40 (t, 2H), 4.29 (t, 2H), 1.38 (s, 9H). Elemental analysis: Calcd. for C20H23NO5: C, 67.21; H, 6.49; N, 3.92, Found: C, 66.86; H, 6.42; N, 3.88.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared as a white solid (0.193 g, 41%) from 4-tert-butyl-benzaldehyde oxime and 4-bromomethyl-phenyl-acetic acid using a procedure similar to example 2. mp=93.3-96.2° C.; mass spectrum (−APCI, M−H) m/z 324. 1H NMR (400 MHz, DMSO-d6); δ 12.30 (bs, 1H), 8.23 (s, 1H), 7.52 (d, 2H), 7.42 (d, 2H), 7.33 (d, 2H), 7.24 (d, 2H), 5.10 (s, 2H), 3.55 (s, 2H), 1.25 (s, 9h). Elemental analysis: Calcd. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30, Found: C, 73.15; H, 7.14; N, 4.01.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The desired product was prepared using a procedure similar to Step 6 of example 34. Thus, 2-[(biphenyl-4-carbonyl)-amino]-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.325 g, 0.694 mmol) was reacted with Cs2Co3 (0.475 g, 1.457 mmol) and 4-tert-Butyl-benzaldehyde oxime (0.135 g, 0.763 mmol) in acetone (30 ml) to give 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.258 g, 0.457 mmol, 66%) as a viscous yellow oil. 1H NMR (DMSO-d6) δ 1.20 (s, 9H), 2.05-2.18 (m, 2H), 3.85 (s, 3H), 4.18 (t, 2H), 4.23 (t, 2H), 6.79 (d, 1H), 7.32-7.50 (m, 7H), 7.73 (d, 2H), 7.85 (d, 2H), 7.95-8.02 (m, 3H), 8.18 (s, 1H), 8.39 (s, 1H), 11.98 (s, 1H), mass spectrum [ES(+)], m/z 565 (M+H)+.