methyl (1R,2S)-2-aminocyclohexane-1-carboxylate

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1R,2S)-2-Amino-cyclohexanecarboxylic acid methyl ester (1 g, 6.4 mmol) was dissolved in methanol (70 mL). 4-Fluoro-benzaldehyde (0.794 g, 6.4 mmol) was added followed by acetic acid (1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (1 g, 16 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1R,2S)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.8 g, 3 mmol, 47%), as a light yellow oil. LC-MS (ESI) calcd for C15H20FNO2 265.15, found 266.2 [M+H+]. the mixture was stirred at 25° C. for 16 h The aqueous layer was extracted with ethyl acetate (2×150 mL) The organic layer was dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1R,2S)-2-Benzyloxycarbonylamino-cyclohexanecarboxylic acid methyl ester (5.78 g, 19.8 mmol) was dissolved in methanol (200 mL). 10% Palladium on charcoal (0.21 g) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 5 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford the desired product, (1R,2S)-2-amino-cyclohexanecarboxylic acid methyl ester (2.5 g, 15.9 mmol, 80%), as a clear oil. LC-MS (ESI) calcd for C8H15NO2 157.11, found 158.1 [M+H+]. The flask was degassed the filtrate was concentrated in vacuo

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

Procedure: cis-2-Amino-1-cyclohexane carboxylic acid (2500 mg, 17.5 mmol) was suspended in methanol (30 ml) at 0° C. Gaseous hydrochloric acid was bubbled through the suspension for 10 minutes. The reaction was allowed to reach room temperature then stirred under nitrogen for 1 h and the solvent removed under reduced pressure. The residue was azeotroped with diethyl ether (2×20 ml) and dried to give the title compound as a solid. Gaseous hydrochloric acid was bubbled through the suspension for 10 minutes to reach room temperature the solvent removed under reduced pressure The residue was azeotroped with diethyl ether (2×20 ml) dried

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

Procedure: cis-2-Amino-1-cyclohexane carboxylic acid (2500 mg, 17.5 mmol) was suspended in methanol (30 ml) at 0° C. Gaseous hydrochloric acid was bubbled through the suspension for 10 minutes. The reaction was allowed to reach room temperature then stirred under nitrogen for 1 h and the solvent removed under reduced pressure. The residue was azeotroped with diethyl ether (2×20 ml) and dried to give the title compound as a solid. Gaseous hydrochloric acid was bubbled through the suspension for 10 minutes to reach room temperature the solvent removed under reduced pressure The residue was azeotroped with diethyl ether (2×20 ml) dried

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

Procedure: To a solution of (1R,2S)-2-aminocyclohexanecarboxylic acid (0.13 g, 0.91 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step. at reflux overnight The reaction mixture was concentrated in vacuo to afford an oil which

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

Procedure: cis-2-Aminocyclohexanecarboxylic acid methyl ester (2.20 g, 14.0 mmol) was treated with aqueous ammonium hydroxide (40 mL) in toluene (40 mL) and stirred vigorously at room temperature for 16 h. The reaction was concentrated to dryness in vacuo and azeotroped with toluene (50 mL). The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2 H, s br), 7.67 (s, 1 H), 7.25 (s, 1 H), 1.87 (m, 2 H), 1.60 (m, 4 H), 1.41 (m, 4 H). The reaction was concentrated to dryness in vacuo azeotroped with toluene (50 mL) The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification

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

Procedure: Thionyl chloride (5.48 g, 46.1 mmol) was added dropwise to a solution of cis-2-aminocyclohexanecarboxylic acid (2.0 g, 14.0 mmol) in methanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stir for 18 h. The clear solution was then evaporated to dryness, and the residual volatiles were removed on high vacuum. The crude product, cis-2-aminocyclohexanecarboxylic acid methyl ester, was isolated in quantitative yield and used in the next reaction without purification: 1H NMR (400 MHz, CDCl3) δ 8.50 (s br, 2 H), 3.78 (s, 3 H), 3.59 (s br, 1 H), 3.18 (s br, 1 H), 2.27 (m, 1 H), 2.08 (m, 1 H), 1.88 (m, 2 H), 1.45 (m, 4 H). The clear solution was then evaporated to dryness the residual volatiles were removed on high vacuum

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

Procedure: cis-2-Aminocyclohexanecarboxylic acid methyl ester (2.20 g, 14.0 mmol) was treated with aqueous ammonium hydroxide (40 mL) in toluene (40 mL) and stirred vigorously at room temperature for 16 h. The reaction was concentrated to dryness in vacuo and azeotroped with toluene (50 mL). The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2 H, s br), 7.67 (s, 1 H), 7.25 (s, 1 H), 1.87 (m, 2 H), 1.60 (m, 4 H), 1.41 (m, 4 H). The reaction was concentrated to dryness in vacuo azeotroped with toluene (50 mL) The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification

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

Procedure: Thionyl chloride (5.48 g, 46.1 mmol) was added dropwise to a solution of cis-2-aminocyclohexanecarboxylic acid (2.0 g, 14.0 mmol) in methanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stir for 18 h. The clear solution was then evaporated to dryness, and the residual volatiles were removed on high vacuum. The crude product, cis-2-aminocyclohexanecarboxylic acid methyl ester, was isolated in quantitative yield and used in the next reaction without purification: 1H NMR (400 MHz, CDCl3) δ 8.50 (s br, 2 H), 3.78 (s, 3 H), 3.59 (s br, 1 H), 3.18 (s br, 1 H), 2.27 (m, 1 H), 2.08 (m, 1 H), 1.88 (m, 2 H), 1.45 (m, 4 H). The clear solution was then evaporated to dryness the residual volatiles were removed on high vacuum

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1R,2S)-2-Amino-cyclohexanecarboxylic acid methyl ester (1 g, 6.4 mmol) was dissolved in methanol (70 mL). 4-Fluoro-benzaldehyde (0.794 g, 6.4 mmol) was added followed by acetic acid (1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (1 g, 16 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1R,2S)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.8 g, 3 mmol, 47%), as a light yellow oil. LC-MS (ESI) calcd for C15H20FNO2 265.15, found 266.2 [M+H+]. the mixture was stirred at 25° C. for 16 h The aqueous layer was extracted with ethyl acetate (2×150 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: cis-2-Aminocyclohexanecarboxylic acid methyl ester (2.20 g, 14.0 mmol) was treated with aqueous ammonium hydroxide (40 mL) in toluene (40 mL) and stirred vigorously at room temperature for 16 h. The reaction was concentrated to dryness in vacuo and azeotroped with toluene (50 mL). The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2 H, s br), 7.67 (s, 1 H), 7.25 (s, 1 H), 1.87 (m, 2 H), 1.60 (m, 4 H), 1.41 (m, 4 H). The reaction was concentrated to dryness in vacuo azeotroped with toluene (50 mL) The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification

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

Procedure: Thionyl chloride (5.48 g, 46.1 mmol) was added dropwise to a solution of cis-2-aminocyclohexanecarboxylic acid (2.0 g, 14.0 mmol) in methanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stir for 18 h. The clear solution was then evaporated to dryness, and the residual volatiles were removed on high vacuum. The crude product, cis-2-aminocyclohexanecarboxylic acid methyl ester, was isolated in quantitative yield and used in the next reaction without purification: 1H NMR (400 MHz, CDCl3) δ 8.50 (s br, 2 H), 3.78 (s, 3 H), 3.59 (s br, 1 H), 3.18 (s br, 1 H), 2.27 (m, 1 H), 2.08 (m, 1 H), 1.88 (m, 2 H), 1.45 (m, 4 H). The clear solution was then evaporated to dryness the residual volatiles were removed on high vacuum