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Stage #1: With sodium hydroxide In 1,4-dioxane; water at 20℃; Stage #2: With hydrogenchloride; water In 1,4-dioxane
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).
97%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; water at 20℃; for 3 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran
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 450C to provide the desired product was as a white solid (41.4 g, 97percent).
83%
With sodium hydroxide In water at 20℃; for 3 h;
sodium 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.
83%
With sodium hydroxide In water at 20℃; for 3 h;
sodium hydroxide (1.6 g, 40.00 mmol, 2.00 eq.) and Boc20 (5.232 g, 24.00 mmol, 1.20 eq.) were added to a solution of 3-aminocyclohexane-l-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 collected by filtration to give 4.048 g (83percent) of 3-[[(tert-butoxy)carbonyl]amino]cyclohexane-l- carboxylic acid as a white solid. LC-MS (ES, m/z): [M+H]+ = 244.1.
82%
With sodium hydroxide In 1,4-dioxane at 20℃; for 24 h; Inert atmosphere
To 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) ? 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): 144.05
76%
With sodium hydroxide In dioxane-H2O
A. 3-[(tert-Butoxycarbonyl)amino]cyclohexanecarboxylic acid To a suspension of 3-aminocyclohexanecarboxylic acid (0.72 g, 5.0 mmol) in dioxane-H2O (10 mL-5 mL) were added 1N aqueous NaOH (5.0 mL, 5.0 mmol) and di-tert-butyl dicarbonate (1.2g, 5.3 mmol) at 0° C. The mixture was stirred for 1 day at room temperature, and concentrated in vacuo. The residue was diluted with H2O, acidified with 10percent aqueous citric acid, and extracted with AcOEt. The extract was dried over MgSO4, and filtered. Removal of solvent gave a product (0.97g, 76percent) as a white solid. 1H-NMR (CDCl3) 67: 4.55-4.40 (1H, m), 3.55-3.35 (1H, m), 2.50-2.20 (2H, m), 2.03-1.80 (3H, m), 1.44 (9H, s), 1.40-0.95 (4H, m).
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).
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