3-aryloxy-3-five-membered heteroaryl-propylamine compound as well as crystal form and application thereof
A compound, heteroaryl technology, applied in the field of 3-aryloxy-3-pentaaryl-propylamine compounds
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[0451] A preferred preparation method of the hydrochloride crystal form A of the compound of formula I-1 according to the present invention comprises the steps of:
[0452] (a) After the compound of formula I-1 is mixed with ethyl acetate, hydrochloric acid is added dropwise at 5-15°C to adjust the pH of the system to 6-8, and a solid is precipitated in the reaction, and the hydrochloride crystal form of the compound of formula I-1 is obtained by filtration a.
[0453] In another preferred example, in the step (a), the reaction time is 3-8 minutes, preferably 5 minutes.
[0454] In another preferred example, in the step (a), the weight volume (kg:L) ratio of the compound of formula I-1 to the organic solvent is 0.2-2:2-30, preferably 0.4-1.0:5 -18, more preferably 0.5-0.9:8-15.
[0455] The hydrochloride crystal form A of the compound of formula I-1 described in the present invention can inhibit TRPA1.
[0456] Composition and method of application
[0457] The invention p...
Embodiment 1
[0475] (R)-7-(3-Chloro-1-(thiophen-2-yl)propoxy)benzofuran (Intermediate II-1)
[0476]
[0477] Dissolve 528 mg of (S)-3-chloro-1-(thiophen-2-yl)propan-1-ol, 400 mg of 7-hydroxybenzofuran and 862 mg of triphenylphosphine in 30 mL of anhydrous THF 667 mg of diisopropyl azodicarboxylate was slowly added dropwise to the system under ice-bath conditions, and after the addition was completed, the system was transferred to room temperature for overnight reaction. After the reaction was completed, the system was spin-dried directly, and the residue was separated and purified by column chromatography to obtain Intermediate II-1 compound, 685 mg of a colorless oil, with a yield of 78.46%.
[0478] 1 H NMR (500MHz, CDCl 3)δ7.62(t, J=3.2Hz, 1H), 7.41(dd, J=1.8, 0.6Hz, 1H), 7.24(dt, J=8.1, 1.8Hz, 1H), 7.15–7.11(m, 1H ), 6.91(d, J=7.7Hz, 1H), 6.77(dd, J=8.0, 2.2Hz, 1H), 6.35(d, J=3.3Hz, 1H), 6.33(dd, J=3.3, 1.9Hz ,1H),5.75(dd,J=8.4,5.1Hz,1H),3.93(dd,J=11.1,8.2,5.4Hz,1H),3.77–3.70(m...
Embodiment 2
[0480] (R)-3-(benzofuran-7-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine (compound I-1)
[0481]
[0482] 685 mg of intermediate II-1 was dissolved in a saturated solution of sodium iodide in acetone and refluxed overnight. After the reaction, the solvent was spin-dried, water was added to the system, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was dissolved in 30 ml of tetrahydrofuran solution, and 3 ml of 40 % methylamine aqueous solution and reacted overnight. After the reaction, the solvent was spin-dried, and aqueous sodium hydroxide solution was added to the system, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (methanol / dichloro Methane=1:15), to obtain compound I-1, 336 mg of colorless oil, yield 49.97%.
[0483] 1H NMR (500M...
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