Synthesis of (2s,5r)-5-ethynyl-1-pyrrolidine-2-carbonitrile
a technology of pyrrolidine and pyrrolidine, which is applied in the direction of organic chemistry, drug compositions, metabolic disorders, etc., can solve the problems of low overall yield of the process, and the synthetic method outlined above is not suitable for large-scale preparation of the compound of formula (i) or salts
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example 1
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxo-7-(trimethylsilyl)hept-6-ynoate
[0109]A 2-L, 3-neck jacketed round bottomed flask equipped with an overhead mechanical stirrer, N2-inlet and temperature probe was charged with octylmagnesium chloride (2.1 M, 248.3 g, 0.560 mol) and tetrahydrofuran (1 vol, 102 g) and the solution was chilled to 0° C. (internal temperature). Trimethylsilyl acetylene (57.5 g, 0.585 mol) was added subsurface by syringe over about 25 min (Tmax=13° C.). The solution was stirred at 0° C. for 1 hour and was then cooled to −10° C. (internal temperature). A solution of (S)-1-tert-butyl 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (125 g, 0.509 mmol) in tetrahydrofuran (250 g) was added subsurface by rotary pump over a 2-hour period. The flask and pump were rinsed with about 25 g of tetrahydrofuran, which was added to the reaction flask. The reaction was monitored by HPLC until completion. A 2-L flask was charged with water (870 g) and NH4Cl (174 g) and the conten...
example 2
(5R)-1-(tert-butoxycarbonyl)-5-prop-1-ynyl-L-proline
[0110]A 2-L, 3-neck jacketed round-bottomed flask equipped with an overhead mechanical stirrer, N2-inlet, temperature probe and addition funnel was charged with sodium triacetoxyborohydride (93.0 g, 0.44 mol), isopropyl acetate (100 g) and an isopropyl acetate solution obtained from Example 1 (27.8 wt %, 410 g, 0.33 mol). The resulting mixture was chilled to −10° C. (internal temperature). Trifluoroacetic acid (170 g, 1.5 mol) was added dropwise by addition funnel over a 2-hour period. The internal temperature was adjusted to 10° C. and the mixture was stirred until HPLC analysis indicated complete consumption of starting material (about 15 hours). The reaction was poured into 750 g of 25% K2HPO4 (prepared by dissolving 250 g of K2HPO4 in 750 g of water). The pH of the mixture was adjusted to 6.6 using 20% KOH (prepared by dissolving 100 g of KOH in 400 g of water). The layers were separated. The organic layer was washed with 25% K...
example 3
tert-butyl (2S,5R)-2-cyano-5-ethynylpyrrolidine-1-carboxylate
Step A
[0111]A 2-L jacketed flask, equipped with an overhead stirrer and a thermocouple was charged with Example 2 product (100.2 g, 6.42 mol), isopropyl acetate (500 mL) and N-methylmorpholine (57 mL, 0.522 mol). Isobutyl chloroformate (65 mL, 0.502 mol) was added dropwise over about 15 minutes and the resulting solution was stirred at 0° C. for 1 hour. A portion of the reaction was quenched into benzyl amine and analyzed by HPLC to evaluate the progress of the mixed anhydride formation. The mixed anhydride formation was typically complete at this stage. The reaction mixture was added to cold (0° C.) 27% NH4OH solution such that the internal temperature of the quench remained below 25° C. The reaction flask was rinsed with isopropyl acetate (25 mL), which was added to the quench flask. The mixture was diluted with 26% NaCl solution (300 g, prepared by dissolving 80 g of NaCl in 220 g of water) and the layers were separated...
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