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With hydrogenchloride; LiOH; triethylamine; In 1,4-dioxane; methanol; water; ethyl acetate;
EXAMPLE 23 Synthesis of N-Boc-(R)-Nipecotic Acid (25) A solution of ethyl N-Boc-(R)-nipecotate-L-tartrate (24) (10.00 g, 32.5 mol) in 50 mL of dioxane and 50 mL of H2O was cooled in ice-water bath and NEt3 (9 mL) was added with stirring. Stirring and cooling were continued while di-tert-butyl dicarbonate (7.44 g, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred for 4 h. 100 mL of Ethyl acetate and 20 mL of H2O were added to mixture. The aqueous layer was extracted with ethyl acetate (2*100 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 2*50 mL), aqueous HCl (5%, 2*50 mL), brine (50 mL), and dried over anhydrous sodium sulfate, filtered and evaporated to give ethyl N-Boc-(R)-nipecotate as a colorless oil 8.37 g (100%). To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H2O dropwise at 4 C. The reaction mixture was stirred overnight at 4 C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10% w/w). The aqueous layer was extracted with ethyl acetate (3*100 mL). The extracts were combined and washed with aqueous NH4Cl (sat., 2*50 mL), brine (50 mL), and dried over anhydrous Na2SO4, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).
6.25 g (92%)
With hydrogenchloride; LiOH; triethylamine; In 1,4-dioxane; methanol; water; ethyl acetate;
EXAMPLE 23 Synthesis of N-Boc-(R)-nipecotic acid (25) A solution of ethyl N-Boc-(R)-nipecotate-L-tartrate (24) (10.00 g, 32.5 mol) in 50 mL of dioxane and 50 mL of H2O was cooled in ice-water bath and NEt3 (9 mL) was added with stirring. Stirring and cooling were continued while di-tert-butyl dicarbonate (7.44 g, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred for 4 h. 100 mL of Ethyl acetate and 20 mL of H2O were added to mixture. The aqueous layer was extracted with ethyl acetate (2*100 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 2*50 mL), aqueous HCl (5%, 2*50 mL), brine (50 mL), and dried over anhydrous sodium sulfate, filtered and evaporated to give ethyl N-Boc-(R)-nipecotate as a colorless oil 8.37 g (100%). To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H2O dropwise at 4 C. The reaction mixture was stirred overnight at 4 C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10% w/w). The aqueous layer was extracted with ethyl acetate (3*100 mL). The extracts were combined and washed with aqueous NH4Cl (sat., 2*50 mL), brine (50 mL), and dried over anhydrous NaSO4, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).
o a solution of (R)-N-Boc-piperidine-3-carboxylic acid (1 kg. 4.36 mol) in N,N- dimethylacetamide (3 L) was charged potassium carbonate (0.664 kg, 4.80 mol) under mechanical stirring and the resulting suspension was stirred for 30 minutes at room temperature. To the reaction mass, ethyl iodide (0.75 kg, 4.80 mol) was charged via addition funnel and the reaction mass was stirred for 15 minutes at room temperature followed by at 50C for 1 hour. The reaction was monitored using TLC (ethyl acetate: hexane 1:1). After the reaction was complete, the reaction mass was allowed to cool to room temperature and diluted with ethyl acetate (5 L). The suspension was filtered under suction and the wet cake was washed with ethyl acetate (5 L). The filtrate was stirred with 5% w/v sodium thio sulfate (15 L) and layers were separated. The aqueous layer was re-extracted with additional ethyl acetate (5 L). The combined organic layer was washed with water (5 L) and dried over sodium sulfate. The organic layer was evaporated under vacuum to provide semi-solid which solidifies upon standing as (R)-ethyl-N-Boc-piperidine-3-carboxylate in 1.1 kg quantity in 99.5% yield.
99.5%
Step-1: Preparation of (R)-Ethyl-N-Boc-piperidine-3-carboxylate (VIII).To a solution of (R)-N-Boc-piperidine-3-carboxylic acid (1 kg. 4.36 mol) in N,N-dimethylacetamide (3 L) was charged potassium carbonate (0.664 kg, 4.80 mol) under mechanical stirring and the resulting suspension was stirred for 30 minutes at room temperature.To the reaction mass, ethyl iodide (0.75 kg, 4.80 mol) was charged via addition funnel and the reaction mass was stirred for 15 minutes at room temperature followed by at 50 C. for 1 hour.The reaction was monitored using TLC (ethyl acetate:hexane 1:1). After the reaction was complete, the reaction mass was allowed to cool to room temperature and diluted with ethyl acetate (5 L).The suspension was filtered under suction and the wet cake was washed with ethyl acetate (5 L). The filtrate was stirred with 5% w/v sodium thio sulfate (15 L) and layers were separated. The aqueous layer was re-extracted with additional ethyl acetate (5 L). The combined organic layer was washed with water (5 L) and dried over sodium sulfate.The organic layer was evaporated under vacuum to provide semi-solid which solidifies upon standing as (R)-ethyl-N-Boc-piperidine-3-carboxylate in 1.1 kg quantity in 99.5% yield. Analysis: NMR: (CDCl3): 4.63 (q, 2H), 3.90 (d, 1H), 2.87-2.95 (m, 2H), 2.73 (td, 1H), 2.32-2.39 (m, 1H), 1.66-2.01 (m, 2H), 1.52-1.68 (m, 2H), 1.39 (s, 9H), 1.19 (t, 3H). Mass: (M+1): 258.1 for C13H23NO4
(R)-tert-butyl 3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (6.61 g, 28.8 mmol) in 70 mL of dichloromethane at 0° C. was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (3.70 g, 27.7 mmol). The mixture was stirred at room temperature for 30 minutes and a solution of Example 1A (4.6 g, 22.17 mmol) and pyridine (2.24 mL, 27.7 mmol) in tetrahydrofuran (70 mL) was added. The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography on silica (Analogix 280), eluting with a gradient of 10-90percent ethyl acetate/hexane afforded the title compound. MS (ESI) m/e 420 (M+H)+.
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