Method for producing high purity antimer of (2s,3s)-1-tert-butoxy carbonyl-3-hydroxy-2-phenyl piperidine
A technology of tert-butoxycarbonyl and tert-butyldiphenyl, applied in the field of heterocyclic compounds, can solve problems such as difficult operation control, and achieve the effect of simple separation
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Embodiment 1
[0024] Step 1 Synthesis of (S)-2,3,4,5-tetrahydro-5-oxo-2-furancarboxylic acid 4
[0025] Add distilled water (150mL) to a three-neck round-bottomed flask filled with L-glutamic acid (22.406g, 0.15mol), and simultaneously add 1M H 2 SO 4 (91.5mL, 0.092moL) and 2M NaNO 2 (91.5mL, 0.19moL), stirred at room temperature overnight. Concentrate and extract with acetone (5 x 100 mL) at reflux. The acetone extracts were combined and concentrated to obtain compound 4 as a light yellow viscous liquid. Compound 4 was directly subjected to the next reaction without further purification.
[0026] Step 2 Synthesis of (S)-N-(4-methoxybenzyl)-2,3,4,5-tetrahydro-5-oxo-2-furancarboxamide 5
[0027] Take compound 4 (6.263g, 0.048mol) and thionyl chloride (10.6mL, 0.15mmoL) and stir at 40°C for 8h, then evaporate the excess thionyl chloride under reduced pressure. Under nitrogen protection, anhydrous dichloromethane (40 mL) and triethylamine (10 mL, 0.072 moL) were added. At -30°C, a solut...
Embodiment 2
[0041] Step 1 Synthesis of (S)-N-(4-methoxybenzyl)-2,3,4,5-tetrahydro-5-oxo-2-furancarboxamide (S)-5
[0042] The preparation of compound 4 was the same as in Example 1, and the compound 5 was prepared according to the method of preparing 5 from 4 in Example 1, that is, compound 4 and thionyl chloride were stirred at 65° C. for 4 h. Excess thionyl chloride was distilled off under reduced pressure. Under nitrogen protection, anhydrous dichloromethane, triethylamine and p-methoxybenzylamine were added. Stirring at 0°C for 4 h gave compound 5 with a yield of 65%.
[0043] Step 2 Synthesis of (S)-3-hydroxy-1-(4-methoxybenzyl)-2,6-piperidinedione (S)-6
[0044] Under nitrogen protection, a mixture of compound 5, (7.100g, 28.51mmol) and potassium tert-butoxide (1.600g, 14.29mmol) was added into anhydrous tetrahydrofuran (60mL) at -40°C, and stirred at this temperature for 3h. A saturated solution of ammonium chloride (20 mL) was added and extracted with ethyl acetate (30 mL×3). ...
Embodiment 3
[0056] Step 1 (S)-4——→(S)-5
[0057] The preparation of compound 4 is the same as that in Example 1, according to the method of making (S)-5 from (S)-4 in Example 1, compound 4 and acetyl chloride were stirred at 40°C for 8h, and the rest of the operations were the same to obtain (S)- 5. The yield is 50%.
[0058] Step 2 (S)-5——→(S)-6
[0059] Under nitrogen protection, a solution of compound 5 (347 mg, 1.40 mmol) in THF (3 mL) was added to a mixture of sodium hydride (53 mg, 60%) and THF (10 mL). Stir at 0 °C for 15 h. Add saturated ammonium chloride solution (2 mL) and water (5 mL) to the reaction mixture successively, extract with ethyl acetate (10 mL×3), dry over anhydrous sodium sulfate, concentrate, recrystallize, and pass the mother liquor through a column to obtain 138 mg of compound 6, Yield 40%.
[0060] Step 3 (S)-6——→(S)-7
[0061] Compound 7 was prepared by the method of Example 1
[0062] Step 4 (S)-7——→(S)-8
[0063] Compound 8 was prepared according to t...
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