Synthetic Route of 2566-44-1, In the chemical reaction process,reaction time,type of solvent,can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product.An updated downstream synthesis route of 2566-44-1 as follows.
A solution of diisopropyl (E)-diazene-l,2-dicarboxylate (0.024 mF, 0.121 mmol) in (0305) THF (0.2 mF) was added dropwise to a mixture ofN-((S)-l-((3P)-3-(4-chloro-l-(2,2- difluoroethyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-lH-indazol-7-yl)-7-hydroxy-4- oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3- (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c]pyrazol-l-yl)acetamide (0.04 g, 0.040 mmol), 2-cyclopropylethan-l-ol (10.42 mg, 0.121 mmol) and triphenylphosphine (0.034 g, 0.129 mmol)in Tetrahydrofuran (THF) (0.8 mL) at rt. The reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was stirred for 18 h and then concentrated in vacuo. The crude residue was taken up in DCM (0.5 mL) and TFA (0.25 mL). Triflic acid (8.48 pL, 0.096 mmol) was added. The resultant purple solution was stirred for 1 h and then concentrated in vacuo. The crude residue was taken up in ethyl acetate (1.5 mL), washed with saturated aqueous NaHCCh (1 mL), and concentrated in vacuo. The crude product was purified by preparatory HPLC using the following conditions: Column: Zorbax Eclipse Plus C18, 21.2 x 100 mm, 5 pm particles; Solvent A = 0.1% Formic Acid in 100% Water. Solvent B = Acetonitrile. Flow Rate = 40 mL/min. Start % B = 59.4 Final % B = 79.4. Gradient Time = 7 min, then a 2 min hold at 98% B. Wavelength = 215 and 254 nm. ESI + Range: 150 to 1500 dalton. Sample was loaded at 59.4% B and afforded N-((S)-l-((3P)-3-(4-chloro-l-(2,2-difluoroethyl)-3- (methylsulfonamido)-lH-indazol-7-yl)-7-(2-cyclopropylethoxy)-4-oxo-3,4- dihydropyrido [2,3 -d]pyrimidin-2-yl)-2-(3 ,5 -difluorophenyl)ethyl)-2-((3bS,4aR)-3 – (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c]pyrazol-l-yl)acetamide (0.0041 g, 4.14 pmol, 10 % yield). NMR (500 MHz, (0306) METHAN OL-d4) d ppm 8.42 – 8.53 (m, 1 H) 7.21 – 7.40 (m, 2 H) 7.00 – 7.13 (m, 1 H) 6.55 – 6.83 (m, 4 H) 5.88 – 6.18 (m, 1 H) 5.50 – 5.71 (m, 2 H) 4.53 – 4.79 (m, 5 H) 4.30 – 4.42 (m, 1 H) 3.87 – 4.00 (m, 1 H) 3.39 – 3.45 (m, 1 H) 3.23 – 3.26 (m, 3 H) 3.06 – 3.13 (m, 1 H) 2.55 – 2.62 (m, 1 H) 2.40 – 2.47 (m, 2 H) 1.70 – 1.74 (m, 3 H) 1.35 – 1.39 (m, 2 H) 0.99 – 1.04 (m, 1 H). LC/MS retention time = 1.40 min; m/z = 932.2 [M+H]+ Column: Acquity BEH C 18, 2.1 x 30 mm, 1.7 pm particles; Solvent A = 0.1% Formic acid in 100% Water. Solvent B = 0.1% Formic Acid in 100% Acetonitrile. Flow Rate = 0.8 mL/min. Start % B = 5. Final % B = (0307) 95. Gradient Time = 1.7 min, then a 0.2 min hold at 95% B. Wavelength = 215 and 254 nm. ESI+ Range: 150 to 1500 Dalton. System: Agilent 1290 Infinity II
These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route,2566-44-1, its application will become more common.
Reference:
Patent; VIIV HEALTHCARE UK (NO.5) LIMITED; IWUAGWU, Christiana; PEESE, Kevin M.; (0 pag.)WO2020/58844; (2020); A1;,
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