A method for preparing non-peptide selective vasopressin antagonist
An inert solvent, selected technology, applied in the field of preparation of tolvaptan, a selective non-peptidin arginine vasopressin V2 receptor antagonist, can solve problems such as difficulties in the preparation of analogues
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[0143] The preparation method of described formula (IV) compound comprises steps:
[0144] (1) In an inert solvent, react the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (IV);
[0145]
[0146] The step (1) is preferably carried out in the presence of a base catalyst. The base is not particularly limited, and may be an organic base and / or an inorganic base commonly used in the art; preferably, the organic base is selected from the group consisting of triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, DBU, or a combination thereof; the inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or a combination thereof.
[0147] The solvent is not particularly limited, preferably a solvent selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, xylene, or a combination thereof.
[014...
Embodiment 1
[0223] (1) Synthesis of Compound (Ⅳ)
[0224]Dissolve p-chloroaniline (41.0g, 321.39mmol) in dichloromethane (600mL), add triethylamine (65.04g, 642.78mmol), stir for 15min, then slowly add 4-nitro-2-methyl Benzoyl chloride (76.98g, 385.67mmol) was reacted at room temperature for 1h, and the reaction was completed by TLC detection. Pour the reaction solution into water (300mL), wash the organic phase water with water (100mL) and brine (100mL) successively, dry over anhydrous sodium sulfate, and spin off dichloromethane to obtain the product compound (Ⅳ) (82.22g, 88%) .
[0225] 1 H-NMR(400MHz,DMSO):δ8.33(s,1H),8.29(s,1H),8.18(s,1H),7.78~7.74(m,2H),7.49~7.45(m,2H), 2.48(s,3H). C 14 h 11 ClN 2 o 3 (M+H) + Calcd: 290.0458, found: 290.0455.
[0226] (2) Synthesis of compound (Ⅵ)
[0227] Compound (Ⅳ) (40.0g, 137.60mmol) was dispersed in acetonitrile (300mL), and ethyl 4-bromobutyrate (Ⅴ) (29.52g, 151.36mmol) and anhydrous sodium carbonate (29.17g, 275.20mmol) were added...
Embodiment 2
[0241] (1) Synthesis of Compound (Ⅳ)
[0242] Dissolve p-chloroaniline (40.0g, 313.55mmol) in dichloromethane (600mL), add diisopropylethylamine (81.05g, 627.10mmol), stir for 15min, and then slowly add 4-nitro-2 -Methylbenzoyl chloride (75.10g, 376.26mmol), reacted at room temperature for 1h, detected by TLC, the reaction was complete. Pour the reaction solution into water (300mL), wash the organic phase water with water (100mL) and brine (100mL) successively, dry over anhydrous sodium sulfate, and spin off dichloromethane to obtain the product compound (Ⅳ) (82.49g, 90.5%) .
[0243] (2) Synthesis of compound (Ⅵ)
[0244] Compound (Ⅳ) (40.0g, 137.60mmol) was dispersed in acetonitrile (300mL), and ethyl 4-bromobutyrate (Ⅴ) (29.52g, 151.36mmol) and anhydrous potassium carbonate (38.04g, 275.20mmol) were added , stirring and heating to reflux for 4.5h, TLC detection, the reaction was complete. Pour the reaction solution into water (100mL), spin off THF, extract with dichloro...
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