Preparation background and overview of N-2pyridine-B-alanine ethyl ester
N-2pyridine-B-alanine ethyl ester, also known as ethyl 3-(pyridine-2-amino)propionate, is a very critical intermediate in the pharmaceutical field. For example, dabigatran etexilate (English name Dabigatranetexilate) is a new direct thrombin inhibitor. This drug was developed by Boehringer Ingelheim of Germany and was first launched in Germany and the UK in April 2008. It was the first new class of oral anticoagulant drugs to be launched in 50 years after warfarin. 3-[(3-Amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate ethyl ester is a key intermediate in the synthesis of dabigatran etexilate, and N-2pyridine- B-Alanine ethyl ester is the key raw material for the synthesis of 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionic acid ethyl ester.
Preparation of N-2pyridine-B-alanine ethyl ester
Preparation report of N-2pyridine-B-alanine ethyl ester 1.
Add 20.0g 2-aminopyridine, 276.8ml ethyl acrylate and 6.36ml glacial acetic acid in sequence to a 100ml three-necked flask. The external temperature was raised to 85°C and the internal temperature was 80°C. Stir overnight. HPLC monitored the reaction. After 12h, After the 2-aminopyridine reaction is complete, bring the system to room temperature, then add 110ml 2NHCl and stir. There is some heat during the stirring process. After 30 minutes, add 50ml ethyl acetate to extract, separate the liquids, collect the water phase, and then use 50ml ethyl acetate to Wash the water phase, separate the liquids, combine the water phases, then add 15.8g sodium carbonate solid and 100ml ethyl acetate for extraction under stirring, separate the liquids to collect the organic phase, then use 25ml ethyl acetate to extract the water phase, and combine the organic phases , spin dry ethyl acetate dimethyl sulfoxide. Then add 34g DMF and 170g water, stir for 1 hour and then filter with suction to obtain N-2pyridine-B-alanine ethyl ester with a yield of 80% and a HPLC purity of 98%. 1HNMR (MHz, CDCl3) δ8.06 (d, J＝3.9Hz, 1H), 7.36 (t, J＝7.1Hz, 1H), 6.53( t, J=5.5Hz, 1H), 6.36 (d, J=8.3Hz, 1H), 4.91 (s, 1H), 4.21-4.03 (m, 2H), 3.68-3.52 (m, 2H), 2.60 (dd , J＝8.0, 3.8Hz, 2H), 1.34-1.05(m, 3H).
Preparation Report 2 of N-2pyridine-B-alanine ethyl ester,
(1) Put an electromagnetic stirrer of appropriate size into a 500mL round-bottomed flask, weigh 50g o-aminopyridine and place it in the bottle, and add 50mL absolute ethanol;
(2) Stir until the solid is dissolved or mostly dissolved, then add 56.5mL ethyl acrylate to step (1);
(3) Stir for a moment and slowly add 9mL of trifluoromethanesulfonic acid dropwise;
(4) Add nitrogen protection, stir and reflux for 18 hours in an oil bath at 120-160°C;
(5) After the reaction is completed, the reaction solution is washed with petroleum ether at a temperature of 35-40°C and a pressure of 0.09-0.1MPa, and then concentrated under reduced pressure;
(7) The concentrated solution was washed with petroleum ether/ethyl acetate (volume ratio 5:1), recrystallized, and suction filtered to obtain white flake crystals.
The white flaky crystals are N-2pyridine-B-alanine ethyl ester, with a yield of 80% and a purity of 99% (HPLC).
References
[1][Chinese invention] Synthesis method of CN201410136663.63-(pyridin-2-ylamino)ethyl propionate
[2][Chinese invention] CN201510319624.4 Preparation method of ethyl 3-(pyridin-2-ylamino)propionate
