Preparation method for alvimopan
A kind of technology of compound and intermediate, applied in the field of preparation of avimopan, can solve problems such as long steps and low yield, and achieve the effect of improving process and yield
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Embodiment 1
[0022] Example 1: (S)-2-(((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)methyl)-3-phenyl Preparation of Propionic Acid (Compound II).
[0023]
[0024] Add 0.4g of Compound I, 4ml of hydrobromic acid, and 4ml of glacial acetic acid into a 50ml single-necked flask. The system turns into a yellow clear solution. Stir and heat to reflux. When heated to 60°C, the system turns lavender and reacts for 5h. TLC detected that the reaction was complete, the temperature dropped to room temperature, added 20ml of water, stirred, extracted with 50ml of ethyl acetate for 3 times, combined the organic phase, washed with 50ml of water for 3 times, dried the organic phase with anhydrous sodium sulfate, and suction filtered. The filtrate was evaporated under reduced pressure to obtain 0.3 g, yield: 88%.
[0025] MS (+1): 368.
[0026] 1 HNMR: δ (ppm, CDCl 3 ), 11.1(s, 1H), 7.21-7.01(m, 6H), 6.76(m, 1H), 6.85(m, 1H), 6.53(d, 1H), 5.0(s, 1H), 2.98-2.90( m, 3H), 2.76-2.41(m, 2H), ...
Embodiment 2
[0027] Example 2: 2-((S)-2-(((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)methyl)-3 - Preparation of ethyl amphetamine (amphetamino)acetate (compound III).
[0028]
[0029] Add 0.4g of compound II and 15ml of THF to a 25ml three-necked flask, protect it with nitrogen, stir and react for 1 hour, then add 10ml of the THF solution of 0.3g ethyl glycine, and react for 5 hours. TLC shows that the raw materials have basically reacted, and add 30ml of water, 50ml of ethyl acetate*3 times of extraction, the organic phase was rotary evaporated under reduced pressure to obtain 0.4g of a muddy yellow viscous liquid with a yield of 81%.
[0030] MS (+1): 453
[0031] 1 HNMR: δ (ppm, CDCl 3 ), 7.21-7.01(m, 6H), 6.85(d, 1H), 6.76(s, 1H), 6.53(d, 1H), 5.0(s, 1H), 4.12(m, 2H), 3.51(s, 2H), 2.63-2.38(m, 4H), 2.44-2.04(m, 8H), 2.0(m, 1H), 1.88-1.63(m, 2H), 1.44(s, 3H), 1.30(t, 3H) , 1.06 (d, 3H).
Embodiment 3
[0032] Example 3: 2-((S)-2-(((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)methyl) dihydrate - Preparation of 3-phenylpropanoic acid amino) acetic acid (almovepam)
[0033]
[0034] Add 0.8g of compound IV, 16.5ml of absolute ethanol: water (4.5:1) into a 50ml single-necked bottle, stir, add 6.5ml of 1mol / L NaOH solution, and react at room temperature 25°C for 2h. Adjust the pH to 6 with concentrated hydrochloric acid, stir for 2 hours, remove the ethanol by rotary evaporation under reduced pressure, extract with 50ml*3 times of chloroform, combine the organic phases, and obtain 0.4g brown viscous liquid after rotary evaporation under reduced pressure, with a yield of 53%. Impurity needs to be purified by column chromatography.
[0035] MS (+1): 425.
[0036] 1 HNMR: δ (ppm, CDCl 3), 11.0(s, 1H), 8(m, 1H), 7.21-7.01(m, 6H), 6.85(d, 1H), 6.76(s, 1H), 6.53(d, 1H), 5.0(s, 1H), 4.14(s, 2H), 3.05(m, 1H), 2.91-2.66(m, 2H), 2.47(d, 2H), 2.33-2.04(m, 5H), 1.88-1.63(m,...
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