Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group
A synthetic method and a technology of protecting groups, which are applied in the field of synthesis of 3-aza-bicyclo[4.1.0]heptane-6-carboxylic acid, can solve the problems of short synthetic route and overall yield, and achieve short reaction time and high yield. High efficiency and mild reaction conditions
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Embodiment 1
[0018] 1. Mix 100g of ethyl isonicotinate (0.66mol) and 115g of benzyl bromide (13.2mol) in 1L of methanol, stir and heat to reflux at 65°C for 12 hours, remove the solvent and dissolve the white solid obtained in 1L of ethanol, cool Add 100mL aqueous solution of 25g sodium borohydride (6.5mol) dropwise at 0°C, stir at room temperature for 1 hour after dropping, evaporate the solvent ethanol, add 2L dichloromethane and 1L water to the residue, stir and separate, and use 1L dichloromethane Washed twice with water, washed once with 250mL saturated saline, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain light yellow liquid ethyl N-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (compound 10, R=Bn). Yield 98%.
[0019] 28 g of sodium hydrogen (0.7 mol) was suspended in 1.3 L of DMSO, and 153 g (0.7 mol) of trimethylsulfoxide iodide was added in portions with stirring under nitrogen protection, and the resulting mixture was stirred at room temperature for...
Embodiment 2
[0022] Dissolve ethyl N-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10g, 59mmol) in 100mL ether, add 0.2g palladium acetate, cool to 0°C, add freshly prepared About 0.5mol / L dry diazomethane ether solution (250mL), the temperature is controlled at 0-2°C. After the dropwise completion, the mixture was stirred at 25° C. for 12 hours. The excess diazomethane was quenched with acetic acid, the reaction solution was mixed with diatomaceous earth and filtered, the filtrate was concentrated to dryness, and purified by silica gel column chromatography to obtain 500 mg of the desired N-methyl-3-aza-bicyclo[4.1.0] Ethyl heptane-6-carboxylate (compound 11, R=Me), yield 4.9%
Embodiment 3
[0024] 1. 4.5g of ethyl N-benzyl-3-aza-bicyclo[4.1.0]heptane-6-carboxylate (compound 11, R=Bn, 17.4mmol) was dissolved in 100ml of ethanol, and 3.9g of Boc was added 2 O (17.8mmol) and 0.5g 10% Pd(OH) 2 / C, the mixture was hydrogenated under 45 psi hydrogen gas at room temperature for 5 hours with stirring, and TLC (n-hexane:ethyl acetate volume percentage=4:1) detected that the reaction was complete. The reaction solution was filtered and concentrated to obtain 4.3 g of ethyl N-Boc-3-aza-bicyclo[4.1.0]heptane-6-carboxylate (compound 11, R=Boc) as a white solid, with a yield of 92%.
[0025] 4.3g of ethyl N-Boc-3-aza-bicyclo[4.1.0]heptane-6-carboxylate (compound 11, R=Boc, 16mmol) was dissolved in 50mL of methanol, and 6.8g of lithium hydroxide monohydrate was added dropwise (160 mmol) in 50 mL aqueous solution, stirred and heated to reflux for 3 hours after dropping, cooled to room temperature, removed most of the methanol under reduced pressure, and washed with ether to rem...
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