tert-butyl N-[4-(hydroxymethyl)phenyl]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:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H). The resulting reaction mixture quenched with water (25 mL) The aqueous layer was extracted with dichloromethane (50 mL) the organic layer was dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H). The resulting reaction mixture quenched with water (25 mL) The aqueous layer was extracted with dichloromethane (50 mL) the organic layer was dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (51 mg, 0.111 mmol) was mixed with tert-butyl N-(4-(hydroxymethyl)phenyl)carbamate (119 mg, 0.533) in pyridine (0.8 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 4-aminobenzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate (9 mg, 0.015 mmol). 1H NMR (CDCl-d) δ 1.52(s, 1H), 2.08(m, 4H), 3.65(m, 2H), 3.90(s, 3H), 4.14(m, 2H), 4.97(m, 1H), 5.17(s, 2H), 5.37(bs, 1H), 6.55(s, 1H), 6.95(s, 1H), 7.03(s, 1H), 7.06(m, 1H), 7.31(s, 1H), 7.38(m, 3H), 8.16(bs, 1H), 8.30(s, 1H). LC/MS: MH+589. The solvent was removed the residue was purified by preparative reverse phase LC/MS

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (51 mg, 0.111 mmol) was mixed with tert-butyl N-(4-(hydroxymethyl)phenyl)carbamate (119 mg, 0.533) in pyridine (0.8 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 4-aminobenzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate (9 mg, 0.015 mmol). 1H NMR (CDCl-d) δ 1.52(s, 1H), 2.08(m, 4H), 3.65(m, 2H), 3.90(s, 3H), 4.14(m, 2H), 4.97(m, 1H), 5.17(s, 2H), 5.37(bs, 1H), 6.55(s, 1H), 6.95(s, 1H), 7.03(s, 1H), 7.06(m, 1H), 7.31(s, 1H), 7.38(m, 3H), 8.16(bs, 1H), 8.30(s, 1H). LC/MS: MH+589. The solvent was removed the residue was purified by preparative reverse phase LC/MS

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

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

Procedure: To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)-phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H). The resulting reaction mixture quenched with water (25 mL) The aqueous layer was extracted with dichloromethane (50 mL) the organic layer was dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 4-aminobenzyl alcohol (2.00 g, 16.2 mmol) in 10 mL of dioxane was added a solution of sodium hydroxide (0.65 g, 16 mmol) in 40 mL of water at room temperature. After addition of di-tert-butyl carbonate (4.95 g, 22.7 mmol), the reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-(tert-butoxycarbonylamino)benzyl alcohol. the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine dried over MgSO4 After filtration the filtrate was concentrated in vacuo

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

Procedure: The title B compound, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (98 mg, 0.34 mmol) and (4-hydroxymethylphenyl)carbamic acid t-butyl ester (153 mg, 0.68 mmol) and triphenylphosphine (180 mg, 0.68 mmol) are dissolved in THF (10 mL) with stirring under argon atmosphere. The reaction is cooled in an ice/water bath and diethyl azodicarboxylate (0.107 mL, 0.68 mmol) dissolved in THF (0.107 mL) is added dropwise. After 16 h, the solvent is evaporated and the residue is taken up in a minimal amount of CH2Cl2 and chromatographed on silica gel with a gradient from 1 to 5% EtOAc in CH2Cl2 over 15 min to give {4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-carbamic acid t-butyl ester as an oil: [M+NH4]+=509. The reaction is cooled in an ice/water bath is added dropwise the solvent is evaporated chromatographed on silica gel with a gradient from 1 to 5% EtOAc in CH2Cl2 over 15 min