Interferon gene stimulating protein compounds and preparation method thereof
A technology of compound and synthesis method, applied in the field of highly active STING protein agonists, can solve the problems such as failure to observe obvious curative effect and inability to activate human STING protein.
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Embodiment 1
[0031]
[0032] Compound 1 was prepared by the following steps:
[0033]
[0034] The first step: N-tert-butoxycarbonyl-N'-benzyloxycarbonyl-L-ornithine 1a (25g, 68mmol), triethylamine (11.5mL, 81.9mmol) were dissolved in tetrahydrofuran (100mL), in Isobutyl chloroformate (10mL, 79mmol) was added dropwise in ice bath, stirred for half an hour in ice bath, sodium borohydride (7.8g, 205mmol) was added successively, water (3mL) was added dropwise slowly, and stirring was continued in ice bath 2 hours. LC-MS monitored the completion of the reaction, added water (150mL) to quench, extracted the aqueous phase (150mL*3) with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1b (20g) as a colorless oil Liquid, 83% yield. ESI-MS(m / z):353.6[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δppm 7.39-7.25 (m, 5H), 7.19 (t, J = 5.2Hz, 1H), 6.43 (d, J = 8.3Hz, 1H), 4.98 (s, 2H), 4.53(t,J=5.4Hz,1H),3.30-3.07(m,2H),2.94...
Embodiment 6
[0045]
[0046] Compound 6 was prepared by the following steps:
[0047]
[0048] The first step: Dissolve 4-chloro-3-fluoro-5-nitrobenzonitrile 1f (4g, 20mmol) and compound 6a (10g, 37.21mmol) in acetonitrile (150mL), add potassium carbonate (8.3g, 60mmol) ), reacted at 70 °C for 24 hours under nitrogen protection, the dot plate showed that the reaction was complete, cooled to room temperature, the reactant was filtered with a solid pad of silica gel, the solid was washed with dichloromethane (100 mL), the filtrate was concentrated, and the residue was purified by column chromatography to obtain compound 6b (4.3 g), yellow oil, 54.4% yield. ESI-LC-MS (m / z): 397.5 [M+H] + .
[0049] The second step: Compound 6b (4.3 g, 10.85 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and lithium borohydride (354 mg, 16.27 mmol) was slowly added under an ice bath, and the reaction was raised to room temperature for 30 minutes. TLC showed the reaction completely. Aqueous...
Embodiment 7
[0056]
[0057] Compound 7 was prepared by the following steps:
[0058]
[0059] The first step: Compound 6 (530 mg, 1.07 mmol) was dissolved in tetrahydrofuran (10 mL), hydrogen chloride dioxane solution (4N, 10 mL) was added dropwise, and the reaction was overnight at room temperature. Compound 7a (430 mg), pale yellow solid, yield 93%, ESI-LC-MS (m / z): 396.6 [M+H] + .
[0060] The second step: Compound 7a (50mg, 115.24umol) was dissolved in tetrahydrofuran (5mL), followed by adding phenoxyacetic acid (17.5mg, 115.24umol), HOBt (17.1mg, 126.76umol), HATU (48.2mg, 126.76umol) ) and TEA (35 mg, 345.71 umol), the addition was completed and the reaction was carried out at room temperature overnight, and the reaction was completed by LC-MS monitoring. The reaction solution was directly separated by reverse-phase preparative chromatography to obtain compound 7 (13.8 mg) as a white solid with a yield of 22.53%. ESI-LC-MS(m / z): 532.5[M+H] + ; 1 HNMR(500MHz,DMSO-d6)δppm 1...
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