tert-butyl N-(3-hydroxyphenyl)carbamate

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

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

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

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl azodicarboxylate (3 ml) was added over 15 minutes to a stirred mixture of 1-(4-pyridyl)piperidin-4-ol (3.39 g), 3-(N-tert-butoxycarbonylamino)phenol (Chemical Abstracts, vol. 119, abstract 139113; PCT Patent Application WO 9306085; 3.98 g), triphenylphosphine (4.99 g) and THF (150 ml) which had been cooled to 4° C. The resultant mixture was stirred for 48 hours at ambient temperature. The solvent was evaporated and the residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The resultant foam was crystallised from diethyl ether to give tert-butyl N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (4.65 g), m.p. 165-166° C. The solvent was evaporated the residue was purified by column chromatography a 9:1 mixture of methylene chloride and methanol as eluent The resultant foam was crystallised from diethyl ether

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

Procedure: To a solution of t-butyloxycarbonylamino-3-hydroxybenzene (418.5 mg; 2 mmol; from step (i) above), triphenylphosphine (629.5 mg; 2.4 mmol) and 2-(4-cyanophenyl)ethanol (353.2 mg; 2.4 mmol) in THF (50 mL), under an atmosphere of nitrogen, was added diethylazodicarboxylate (518 mg; 3 mmol) and the mixture was stirred for one week. Ice cold water was added and the THF was removed by evaporation. The remaining water phase was extracted three times with EtOAc. The combined organic phase was washed twice with 0.2 M NaOH, once with brine, and then dried (Na2SO4). Evaporation followed by flash chromatography using a stepwise gradient of toluene:EtOAc (100:0, 90:10, 80:20 and 60:40) gave 300 mg (44%) of the sub-title compound. Ice cold water was added the THF was removed by evaporation The remaining water phase was extracted three times with EtOAc The combined organic phase was washed twice with 0.2 M NaOH, once with brine dried (Na2SO4) Evaporation

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

Procedure: To a solution of tert-butyl (3-hydroxyphenyl)carbamate (1 g, 4.79 mmol) in DMF (15 mL) was added NaH (0.126 g, 5.26 mmol) at 0° C. After stirring for 30 min, 2-(bromomethyl)oxirane (0.716 g, 5.26 mmol) was added and the mixture stirred at 0° C. for 1 h before quenching with the addition of MeOH. After evaporation of this mixture, the resulting residue was dissolved in ethyl acetate and washed with water, dried and with sodium sulfate and concentrated with the resulting crude product used for next step without further purification. the mixture stirred at 0° C. for 1 h before quenching with the addition of MeOH After evaporation of this mixture the resulting residue was dissolved in ethyl acetate washed with water dried and with sodium sulfate concentrated with the resulting crude product used for next step without further purification

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

Procedure: A solution of tert-butyl 3-hydroxyphenylcarbamate (12-2, 6.40 g, 30.6 mmol, 1 equiv), t-butyldimethylsilyl chloride (4.61 g, 30.6 mmol, 1.00 equiv), and imidazole (2.71 g, 39.8 mmol, 1.30 equiv) in DMF (50 mL) was stirred at 23° C. for 16 h. The reaction mixture was partitioned between half-saturated sodium bicarbonate solution and ethyl acetate (200 mL). The organic layer was washed successively with half-saturated ammonium chloride solution (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL), then dried over sodium sulfate and concentrated to give tert-butyl 3-{[tert-butyl(dimethyl)silyl]oxy}phenylcarbamate (12-3) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.92 (t, 1H, J=7.8 Hz), 6.73 (m, 2H), 6.31 (ddd, 1H, J=7.8, 1.9, 0.7 Hz), 6.20 br s, 1H), 1.32 (s, 9H), 0.78 (s, 9H), −0.02 (s, 6H). The reaction mixture was partitioned between half-saturated sodium bicarbonate solution and ethyl acetate (200 mL) The organic layer was washed successively with half-saturated ammonium chloride solution (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL) dried over sodium sulfate concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of N-(3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (1.9 g, 9.0 mmol) in anhydrous toluene (60 mL) was added N-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (2.36 g, 5.3 mmol). Polymer bound triphenylphosphine (2.8 g, 8.4 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.28 mL, 6.5 mmol) was added in a dropwise fashion. After stirring at room temperature for 60 hours, the crude reaction mixture was filtered and the resulting solid was washed with toluene. The filtrate was concentrated and the crude product was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min; B: 10% for 10 min; B: 10% to 30% over 30 min; detection at 214 nm) to give 2.0 g (3.1 mmol, 59% yield) of the title compound as a white foam. MS (ESI) 639.4 was then added After stirring at room temperature for 60 hours the crude reaction mixture was filtered the resulting solid was washed with toluene The filtrate was concentrated the crude product was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 Å, 35 mL/min A: hexanes, B: EtOAc, B: 0% for 5 min B: 0% to 10% over 10 min B: 10% for 10 min B: 10% to 30% over 30 min

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 mg 2(2-Cyano-3,5-difluoro-phenyl)-(2-fluoro-4-iodo-phenyl)-carbamic acid tert-butyl ester (1.05 mmol, 1 eq.) and 412 mg Cs2CO3 (1.27 mmol, 1.2 eq) were dissolved in 5.5 mL DMF and treated with 265 mg (3-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.27 mmol. 1.2 eq.) dissolved in 5.5 mL DMF. The resulting mixture is stirred at 50° C. for 16 h. Extractive workup provided a crude product containing the desired target compound as a mixture of regioisomers along with a smaller fraction of the product of double substitution. This mixture was advanced without further purification.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1470 mg, 4.62 mmol) in acetonitrile (10 mL) was added tert-butyl (3-hydroxyphenyl)carbamate (966 mg, 4.62 mmol) and K2CO3 (1280 mg, 9.24 mmol) and the mixture heated at 80° C. with stirring overnight. The reaction was then cooled to rt, EtOAc (20 mL) added, washed with water (50 mL), the aqueous layer extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a light oil. Upon standing, the light oil solidified to give the title compound (2052 mg, 90% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38-9.83 (m, 1H) 7.73 (d, J=3.78 Hz, 1H) 7.41-7.46 (m, 2H) 7.51 (s, 1H) 6.97 (dt, J=5.98, 2.68 Hz, 1H) 6.58 (d, J=3.78 Hz, 1H) 5.64 (s, 2H) 3.54-3.67 (m, 2H) 1.54 (s, 9H) 0.91-0.96 (m, 2H) 0.00 (s, 9H). LCMS (ESI, pos): m/z (ESI+) for C23H31ClN4O4Si 491.20 (M+H)+. The reaction was then cooled to rt washed with water (50 mL) the aqueous layer extracted with EtOAc (three×20 mL) dried with MgSO4 filtered

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

Procedure: To an ice-cooled solution of 1,1-(azodicarbonyl) dipiperidine (18.08 g, 71.7 mmol) in anhydrous THF (200 mL) is added via syringe tributylphosphine (17.69 mL, 79.7 mmol) and allowed to stir for 2.5 hours. To this ice-cooled mixture is added a solution of (3-hydroxy-phenyl)-carbamic acid tert-butyl ester (10.0 g, 47.8 mmol) and 4-hydroxy-piperidine-1-carboxylic acid benzyl ester (7.23 mL, 47.8 mmol) in anhydrous THF (30 mL) causing a light yellow precipitate to form. The mixture is warmed to room temperature and stirred overnight. The mixture is filtered through a fritted funnel and washed solid with THF (3×15 mL). After removal of solvent, the residue is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a clear oil (11.8 g, 57.9% yield, ES+(m/z) 427.2 [M+H]). to form stirred overnight The mixture is filtered through a fritted funnel washed solid with THF (3×15 mL) After removal of solvent the residue is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a clear oil (11.8 g, 57.9% yield, ES+(m/z) 427.2 [M+H])

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl azodicarboxylate (3 ml) was added over 15 minutes to a stirred mixture of 1-(4-pyridyl)piperidin-4-ol (3.39 g), 3-(N-tert-butoxycarbonylamino)phenol (Chemical Abstracts, vol. 119, abstract 139113; PCT Patent Application WO 9306085; 3.98 g), triphenylphosphine (4.99 g) and THF (150 ml) which had been cooled to 4° C. The resultant mixture was stirred for 48 hours at ambient temperature. The solvent was evaporated and the residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The resultant foam was crystallised from diethyl ether to give tert-butyl N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (4.65 g), m.p. 165-166° C. The solvent was evaporated the residue was purified by column chromatography a 9:1 mixture of methylene chloride and methanol as eluent The resultant foam was crystallised from diethyl ether