4-amino-1-methylcyclohexan-1-ol

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

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

Procedure: 4-(Benzylamino)-1-methylcyclohexanol (335 mg, 1.53 mmol) was dissolved in EtOH (7.95 ml), followed by addition of Pd (10 wt % on activated carbon, 35 mg), and then the resulting liquid was stirred at room temperature under hydrogen stream for 31 hours. The resulting reaction liquid was filtered, concentrated under reduced pressure, and dried under vacuum, to obtain 164 mg of white solid (83%). The resulting reaction liquid was filtered concentrated under reduced pressure dried under vacuum

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

Procedure: 4-(Benzylamino)-1-methylcyclohexanol (335 mg, 1.53 mmol) was dissolved in EtOH (7.95 ml), followed by addition of Pd (10 wt % on activated carbon, 35 mg), and then the resulting liquid was stirred at room temperature under hydrogen stream for 31 hours. The resulting reaction liquid was filtered, concentrated under reduced pressure, and dried under vacuum, to obtain 164 mg of white solid (83%). The resulting reaction liquid was filtered concentrated under reduced pressure dried under vacuum

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(Dibenzylamino)cyclohexanone. A solution of dimethyl sulfoxide (5.77 mL, 81 mmol) in methylene chloride (20 mL) was added dropwise, to a solution of oxalyl chloride (3.26 mL, 37.2 mmol) in methylene chloride (150 mL) stirring at −78° C. After stirring for 15 min at −78° C., a solution of trans-4-(dibenzylamino)cyclohexanol (10.0 g, 33.9 mmol) in methylene chloride (100 mL) was added dropwise. After stirring at −78° C. for another 15 min, triethylamine (23.59 mL, 169 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture appeared as a suspension and was washed with brine (100 mL). The organic layer was separated, dried over magnesium sulfate and concentrated to give a colorless oil that was purified using silica gel flash column chromatography (5-100% ethyl acetate in hexanes) to give the title compound as a colorless oil (8.11 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.35-7.39 (m, 4H), 7.28-7.33 (m, 4H), 7.18-7.24 (m, 2H), 3.61 (s, 4H), 2.89-2.99 (m, 1H), 2.26-2.38 (m, 2H), 2.14-2.24 (m, 2H), 2.06 (td, J=2.81, 6.43 Hz, 2H), 1.81 (qd, J=4.27, 12.49 Hz, 2H). Rf=0.36 (TLC, 20% ethyl acetate in hexane); MS (ESI) m/z 294.4 [M+1]+. After stirring for 15 min at −78° C. After stirring at −78° C. for another 15 min to warm to room temperature stirred for 16 h was washed with brine (100 mL) The organic layer was separated dried over magnesium sulfate concentrated to give a colorless oil that was purified

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

Procedure: The compound obtained in Step 1 of this Reference Example was dissolved in ethanol (12 mL). To the solution, 10% palladium-carbon catalyst (hydrated, 400 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was concentrated under reduced pressure to obtain a crude product of 4-amino-1-methylcyclohexanol. This crude product and ethyl 3-(dimethylamino)-2-isocyanoacrylate (450 mg) were mixed and stirred at 75° C. for 8 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-ethyl acetate) to obtain a diastereomeric mixture of the title compound (462 mg, trans:cis=1:3). After filtration through celite the filtrate was concentrated under reduced pressure

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

Procedure: The major isomer from Step A in Example 50 (45.1 mg, 0.197 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane (492 μL, 1.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and was concentrated to afford 4-amino-1-methylcyclohexanol (major isomer). The 4-amino-1-methylcyclohexanol was reacted with (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C) according to the procedure outlined in Example 1 to provide the title product as a white solid (10.7 mg, 38% yield). MS (apci) m/z=456.1 (M+H).

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

Procedure: The minor isomer from Step A (45.1 mg, 0.197 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane (492 μL, 1.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and was concentrated to afford 4-amino-1-methylcyclohexanol (minor isomer). The 4-amino-1-methylcyclohexanol was reacted with (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C) according to the procedure outlined in Example 1 to provide the title product as a white solid (14 mg, 48% yield). MS (apci) m/z=456.1 (M+H).

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

Procedure: A solution of 4-(benzylamino)-1-methylcyclohexanol (4.9 g, 22.3 mmol) in MeOH (150 mL) was stirred with 7% Pd/C (700 mg) under H2 atmosphere at RT overnight. The resulting mixture was filtered to remove Pd/C and the filtrate was concentrated in vacuo to afford a white solid (2.9 g, quantitative yield) which was used in the next step directly. The resulting mixture was filtered to remove Pd/C the filtrate was concentrated in vacuo

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

Procedure: 4-(Benzylamino)-1-methylcyclohexanol (335 mg, 1.53 mmol) was dissolved in EtOH (7.95 ml), followed by addition of Pd (10 wt % on activated carbon, 35 mg), and then the resulting liquid was stirred at room temperature under hydrogen stream for 31 hours. The resulting reaction liquid was filtered, concentrated under reduced pressure, and dried under vacuum, to obtain 164 mg of white solid (83%). The resulting reaction liquid was filtered concentrated under reduced pressure dried under vacuum

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