A long-acting and low-addiction hnk derivative and its preparation method
A drug and compound technology, applied in the field of long-acting and low-addiction HNK derivatives and their preparation, can solve the problems of limiting the long-acting effect of depression, adverse physical and mental effects of patients, etc.
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Embodiment 1
[0087] Embodiment 1: the synthesis of (2R,6R)-6-hydroxy demethyl ketamine (HNK)
[0088]
[0089] Step 1: In a two-neck bottle or a three-necked bottle, add 50 grams of magnesium powder, and slowly add a mixed solution of 119.2 grams of bromocyclopentane and THF dropwise after initiation. After the dropwise addition, reflux for 2-4 hours to obtain 1.6mol / L Cyclopentyl Grignard Reagent. Add 840 mg of CuBr to the mixture of THF and o-chlorobenzonitrile (50.0 g), and add cyclopentyl Grignard reagent (1.6 mol / L, 280 ml) dropwise under ice-bath conditions. Reflux for 1 hour after the dropwise addition, cool to room temperature, add 100ml of water, then add 200ml of 15% dilute sulfuric acid solution, stir overnight, spin dry THF, extract with EA, dry, and pass through a silica gel column to obtain compound A 2-chlorophenyl ring Amyl ketone 60g, yield 80%.
[0090] Step 2: According to the reported method (Bioorganic & Medicinal Chemistry 2013, 12, 5098), 20 g (96 mmol) of compo...
Embodiment 2
[0098] Embodiment 2: the synthesis of compound I6
[0099]
[0100] Compound G (170mg, 0.5mmol) was dissolved in 3mL dry THF, dry triethylamine (0.28mL, 2mmol) was added, then 3-furoyl chloride (130mg, 1mmol) was added under ice-bath conditions, and then within 1 hour Slowly rise to room temperature, stir overnight, then add sodium bicarbonate solution, extract with EA, spin the solvent and vacuum dry, pass through a silica gel column to obtain compound H 6 N-Boc-(2R,6R)-6-(3-furyl)formyloxydemethylketamine 173mg, yield 80%. 1 H NMR (400MHz, CDCl 3 ):8.11(br,1H),7.81-7.79(brs,1H),7.42-7.28(m,4H),6.67(brs,1H),6.63(m,1H),5.35-5.31(m,1H), 3.92-3.87(m,1H),2.39-2.33(m,1H),1.94-1.74(m,4H),1.30(brs,9H). 13 CNMR (100MHz, CDCl 3 ): 202.5, 168.5, 161.4, 153.3, 148.4, 143.8, 134.3, 133.7, 131.4, 131.1, 129.8, 126.3, 118.5, 109.1, 79.4, 73.5, 67.2, 38.5, 35.8, 28.2, 19.8.
[0101] Compound H 6 (170mg) was dissolved in 3mL of dry THF, gaseous HCl was introduced to saturation at r...
Embodiment 3
[0102] Embodiment 3: the synthesis of compound C and D
[0103]
[0104] Compounds C and D were prepared by the following preparation methods.
[0105]
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