BOC-(+/-)-CIS-3-AMINOCYCLOHEXANE-1-CARBOXYLIC ACID

Step 1 : 3-(|[(1 , 1-dimethylethyl)oxylcarbonyl}amino)cvclohexanecarboxylic acid; To a suspension of 3-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol) in 1 , 4- Dioxane (100.0 ml.) was added 1 N NaOH (41.9 ml, 105 mmol). After stirring for 10 minutes, the mixture turned to a clear solution and bis(1 , 1-dimethylethyl) dicarbonate (21.08 ml, 91 mmol) was added to the reaction. The reaction was stirred at room temperature overnight. The resulting solids were vacuum filtered and then redissolved in water (150 ml_). The aqueous material was made acidic (pH 4) with 3N HCI, and then extracted (2 x100 ml_) with DCM. The organics were dried over Na2SU4 and evacuated to yield the title compound as a white powder (17.0 g, 100percent).3-(tert-Butoxycarbonyl)cyclohexanecarboxylic acid. A mixture of 3- aminocyclohexanecarboxylic acid (25 g, 175 mmol), di-tert-butyl dicarbonate (49.5 g, 227 mmol), diisopropylethylamine (34 ml, 193 mmol), THF (100 ml), and water (100 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to about one half of the initial volume and 35 ml of 6 M hydrochloric acid was added. The resulting mixture was extracted with 300 ml of MTBE. The organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuum and dried in high vacuum at 45sodium hydroxide (1.6 g, 40.00 mmol, 2.00 eq.) and Boc2O (5.232 g, 24.00 mmol, 1.20 eq.) were added to a solution of 3-aminocyclohexane-1-carboxylic acid (2.86 g, 19.97 mmol, 1.00 eq.) in water (50 mL) and the mixture was stirred for 3 hours at room temperature. The solids were collectedby filtration to give 4.048 g (83percent) of 3-[[(tert-butoxy)carbonyl]amino]cyclohexane-1- carboxylic acid as a white solid. LC-MS (ES, m/z): [M+H] = 244.1.sodium hydroxide (1.6 g, 40.00 mmol, 2.00 eq.) and BocTo a stirred solution of 3-aminocyclohexanecarboxylic acid (5 g, 34.92 mmol), in 1, 4-dioxane (50 mL) was added sodium hydroxide and stirred the reaction mixture at room temperature for 24h. The progress of the reaction was monitored by TLC. Reaction mixture was cooled to 0°C then added iN HC1 to adjustthe p” to 4, the solid precipitates were filtered and washed with water (100 mL) dried under vacuum togive 3-(tert-butoxycarbonylamino) cyclohexane carboxylic acid (7.0 g, 82percent) as white coloursolid. ‘HNIVIR (400 MHz, DMSO-d6) ö 0.985-1.3(m, 4H), 1.39 (s, 9H), 1.6-1.8 (m, 3H), 1.9-2.0 (m, 1H), 2.2-2.4(m, 1H), 3.15-3.3 (m, 1H), 6.73-6.75(d, J=8.0 Hz, 1H), 12.04(s, 1H).LC-MSm/z(M+H): 144.05A. A solution of 3-aminocyclohexanecarboxylic acid (1.005 g, 7.02 mmol) in a mixture of a 2N-aqueous sodium hydroxide solution (14 ml, 28 mmol) and 1, 4-dioxane (15 ml) was cooled on a water bath, and di-tert-butyl dicarbonate (3.25 ml, 14.1 mmol) was added thereto and stirred overnight. The resulting solution was diluted with water and washed with diethyl ether, and the aqueous layer was adjusted to pH 6 to 7 with 1N-hydrochloric acid and then to pH 2 to 3 with a 5percent-aqueous potassium hydrogensulfate solution. The aqueous layer was extracted three times with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (1.587 g, 93percent).Step 1 : 3-(|[(1 , 1-dimethylethyl)oxylcarbonyl}amino)cvclohexanecarboxylic acid; To a suspension of 3-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol) in 1 , 4- Dioxane (100.0 ml.) was added 1 N NaOH (41.9 ml, 105 mmol). After stirring for 10 minutes, the mixture turned to a clear solution and bis(1 , 1-dimethylethyl) dicarbonate (21.08 ml, 91 mmol) was added to the reaction. The reaction was stirred at room temperature overnight. The resulting solids were vacuum filtered and then redissolved in water (150 ml_). The aqueous material was made acidic (pH 4) with 3N HCI, and then extracted (2 x100 ml_) with DCM. The organics were dried over Na2SU4 and evacuated to yield the title compound as a white powder (17.0 g, 100percent).3-(tert-Butoxycarbonyl)cyclohexanecarboxylic acid. A mixture of 3- aminocyclohexanecarboxylic acid (25 g, 175 mmol), di-tert-butyl dicarbonate (49.5 g, 227 mmol), diisopropylethylamine (34 ml, 193 mmol), THF (100 ml), and water (100 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to about one half of the initial volume and 35 ml of 6 M hydrochloric acid was added. The resulting mixture was extracted with 300 ml of MTBE. The organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuum and dried in high vacuum at 45sodium hydroxide (1.6 g, 40.00 mmol, 2.00 eq.) and Boc2O (5.232 g, 24.00 mmol, 1.20 eq.) were added to a solution of 3-aminocyclohexane-1-carboxylic acid (2.86 g, 19.97 mmol, 1.00 eq.) in water (50 mL) and the mixture was stirred for 3 hours at room temperature. The solids were collectedby filtration to give 4.048 g (83percent) of 3-[[(tert-butoxy)carbonyl]amino]cyclohexane-1- carboxylic acid as a white solid. LC-MS (ES, m/z): [M+H] = 244.1.sodium hydroxide (1.6 g, 40.00 mmol, 2.00 eq.) and BocTo a stirred solution of 3-aminocyclohexanecarboxylic acid (5 g, 34.92 mmol), in 1, 4-dioxane (50 mL) was added sodium hydroxide and stirred the reaction mixture at room temperature for 24h. The progress of the reaction was monitored by TLC. Reaction mixture was cooled to 0°C then added iN HC1 to adjustthe p” to 4, the solid precipitates were filtered and washed with water (100 mL) dried under vacuum togive 3-(tert-butoxycarbonylamino) cyclohexane carboxylic acid (7.0 g, 82percent) as white coloursolid. ‘HNIVIR (400 MHz, DMSO-d6) ö 0.985-1.3(m, 4H), 1.39 (s, 9H), 1.6-1.8 (m, 3H), 1.9-2.0 (m, 1H), 2.2-2.4(m, 1H), 3.15-3.3 (m, 1H), 6.73-6.75(d, J=8.0 Hz, 1H), 12.04(s, 1H).LC-MSm/z(M+H): 144.05A. A solution of 3-aminocyclohexanecarboxylic acid (1.005 g, 7.02 mmol) in a mixture of a 2N-aqueous sodium hydroxide solution (14 ml, 28 mmol) and 1, 4-dioxane (15 ml) was cooled on a water bath, and di-tert-butyl dicarbonate (3.25 ml, 14.1 mmol) was added thereto and stirred overnight. The resulting solution was diluted with water and washed with diethyl ether, and the aqueous layer was adjusted to pH 6 to 7 with 1N-hydrochloric acid and then to pH 2 to 3 with a 5percent-aqueous potassium hydrogensulfate solution. The aqueous layer was extracted three times with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (1.587 g, 93percent).

Molecular Weight:243.30
XLogP3:1.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:243.14705815
Monoisotopic Mass:243.14705815
Topological Polar Surface Area:75.6
Heavy Atom Count:17
Complexity:295
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes