Preparation method of L-nicotine
A technology of nicotine and alkaline reagents, which is applied in the field of preparation of L-nicotine, can solve the problems of cumbersome process, difficult detection and quantification of residual protein, protein residue, etc., and achieve the goal of improving reaction quality, simple operation, and cheap and easy-to-obtain reaction materials Effect
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Embodiment 1
[0069] Example 1: Preparation of intermediate compound of formula II
[0070] Add 10kg ethyl acetate, 2kg formula I compound (R is tert-butoxycarbonyl, i.e. (4-oxo-4-(pyridin-3-yl)butyl) tertiary carbamate in the autoclave of 20L at 20°C Butyl ester), the system was mixed evenly; at the same time, 10g of ligand L3 and 5g of Ni(COD) were added to a 500mL three-necked flask under nitrogen protection. 2 , the system was stirred at 30 °C for 1 h and the in-situ generated catalyst was transferred to a 20L autoclave with nitrogen. The 20L autoclave was replaced with 0.2MPa nitrogen three times, and then 1.0Mpa hydrogen was injected. The system was reacted at 30-40°C for 4h, and TLC confirmed the complete conversion of the raw materials. After the system was evacuated and replaced with 0.2MPa nitrogen for 2 times, then concentrated under reduced pressure to remove 6kg of ethyl acetate and cooled to 20° C. In the concentrated solution, 5kg of n-hexane was added dropwise to separate o...
Embodiment 2
[0071] Example 2: Preparation of L-nornicotine
[0072] 15kg of dichloromethane, 3kg of intermediate 3 and 3kg of triethylamine were added to a 50L there-necked flask at 25°C, the temperature of the system was controlled at 20°C, 2.5kg of p-toluenesulfonyl chloride was added dropwise, and the system was reacted at 30°C for 2h after the dropwise addition. , TLC confirmed that the intermediate 3 was completely consumed, 2kg of 6N hydrochloric acid was added dropwise and stirred for 2h, and then 4kg of 20% aqueous sodium hydroxide solution was added. The system was reacted at 30° C. for 2 h, extracted three times with dichloromethane, each with 9 kg, and the combined organic phases were concentrated to obtain 1.42 kg of the target intermediate 2, namely levorotine. The liquid phase purity is 98%, the optical purity is 99.5% e.e, and the yield is 85.1%, which can be directly used in the next reaction. 1 HNMR (CDCl 3 ,400M)δ: 8.58(d,J=8.0Hz,1H), 8.47(d,J=8.2Hz,1H), 7.70~7.66(m,1H...
Embodiment 3
[0073] Example 3: Preparation of L-nicotine
[0074] 5kg methanol, 10kg intermediate 2, 8kg paraformaldehyde and 8kg formic acid system were added to a 50L three-neck flask at 25°C, and the reaction was carried out under reflux at 90°C for 5h. The system was concentrated to remove the organic solvent, adjusted to pH=11 with an aqueous sodium hydroxide solution, extracted three times with ethyl acetate, each with 10 kg, and the combined organic phases were concentrated to obtain crude nicotine and then distilled under reduced pressure to obtain pure L-nicotine. Color transparent liquid, optical purity 99.6% e.e. The fraction weight of the pure product was 9.29 kg, the yield was 84.9%, and the chemical purity was 99.7%. 1 HNMR (400MHz, CDCl 3 )δ: 8.47~8.44(br,2H), 7.61(d,J=8.0Hz,1H), 7.20~7.16(m,1H), 3.18(t,J=8.0Hz,1H), 3.11(t,J =8.0Hz,1H), 2.25~2.19(m,1H), 2.13~2.09(m,1H), 2.08(s,3H), 1.89~1.87(m,1H), 1.76~1.66(m,2H). LC-MS Calc: 162.24, Detec. M+1: 163.20. The obtained pu...
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