Isothiazole heterocyclic compound, and preparation method, pharmaceutical composition and application thereof
A technology of isothiazoles and compounds, applied in the field of medicinal chemistry, can solve the problems of being unable to take orally, only injecting or dripping, unstable in the body, etc., and achieve the effect of inhibiting growth and high inhibitory activity
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[0502] Example 1: 1-(3-(2-Chloro-3-(1,4-benzodioxan-6-yl)anilino)isothiazolo[4,5-b]pyrazine-6-idene Methyl)pyrrolidin-3-ol
[0503]
[0504] 3-Hydroxy-5-methylpyrazine-2-carboxamide:
[0505] To the 100mL reaction flask, add glyoxal (40% aqueous solution, 21.6ml, 120mmol) and NaHSO in turn 3 (15.6 g, 150 mmol), start stirring, then slowly add the prepared NaOH aqueous solution (500 mg, 12.5 mmol, 39 ml of water) dropwise to the solution, react at 80 ° C after the dropwise addition, and slowly add 2-aminopropane after the reaction for 1 h Diamide (11.7 g, 100 mmol), continue to react at 80 ° C for 3 h, stop heating, and add NaA after cooling to room temperature C (20.5 g, 250 mmol) and H 2 O 2 (16.4 ml) and stirred at room temperature overnight. The reaction solution was suction filtered to obtain 9.7 g of a pink solid. Yield: 63.4%. 1 H NMR (400MHz, DMSO-d 6 )δ13.40(s,1H),8.64(s,2H),7.39(s,1H),2.21(s,3H).
[0506] 3-Chloro-5-methylpyrazine-2-carbonitrile:
[0507]...
Example Embodiment
[0518] Example 2: 1-(3-(2-Chloro-3-(1,4-benzodioxan-6-yl)anilino)isothiazolo[4,5-b]pyridine-6-methylene yl)pyrrolidin-3-ol
[0519]
[0520] 2-cyano-3-nitro-5-methylpyridine:
[0521] 2-Bromo-3-nitro-5-methylpyridine (1 g, 4.61 mmol) and CuCN (454 mg, 5.07 mmol) were added to the three-necked flask, replaced with argon, and 5 ml of DMF was added to the syringe, and the reaction was carried out at 70° C. for 4 h. Cool to room temperature, add EA / H 2 O (40ml / 20ml), filtered through celite, separated, the organic phase was washed once with 20ml of water, washed once with 20ml of ammonium chloride / ammonia, the aqueous phase was extracted twice with 20ml of EA, the organic phases were combined, and washed with 20ml of saturated brine for 1 and dried over anhydrous sodium sulfate. Evaporated to dryness under reduced pressure, and prepared under medium pressure (PE:EA 4:1-2:1) to obtain 347 mg of a yellow-white solid. Yield: 46.14%. HRMS(ESI)m / z:164.04453[M+H] + . 1 H NMR (...
Example Embodiment
[0535] Example 3: (S)-1-(3-(2-Chloro-3-(1,4-benzodioxan-6-yl)anilino)isothiazolo[4,5-b]pyrazine -6-Methylene)pyrrolidin-3-ol
[0536]
[0537] Use (S)-3-hydroxypyrrolidine instead of racemic 3-hydroxypyrrolidine, the operation is the same as that in Example 1, to obtain (S)-1-(3-(2-chloro-3-(1,4-benzodi) Oxan-6-yl)anilino)isothiazolo[4,5-b]pyrazin-6-methylene)pyrrolidin-3-ol as a yellow solid. HRMS(ESI)m / z:496.11857[M+H] + .
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