Potassium Hydroxide → (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

HRID 80792

Reaktionsgleichung

Reaktionsgleichung von HRID 80792
[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:51])=[C:8]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:29]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:30]=4[C:31]([CH3:48])=[CH:32][N:33]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[C@H:20]([CH3:28])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[NH4+].[OH-].[OH-].[K+]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:51])=[C:8]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:29]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:30]=4[C:31]([CH3:48])=[CH:32][NH:33]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[C@H:20]([CH3:28])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]

Komponenten

5

Edukt 3

HCID 14797Potassium HydroxideHCID 14923Ammonium HydroxideHCID 71240630(R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Produkt 1

HCID 71240517(R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A mixture of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (52 mg, 0.080 mmol), prepared in a manner similar to that described in Example 25, methanesulfonyl chloride (0.01 mL, 0.096 mmol) and DIEA (0.042 mL, 0.240 mmol) in DCM (3 mL) was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc, washed successively with sat NaHCO3, and brine, dried over Na2SO4 and concentrated. The resulting residue was purified via FCC (5-50% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 727.4 (M+H)+. To a solution of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.055 mmol) in MeOH (4 mL), NH4OH (0.325 mL, 8.25 mmol) and KOH (27.8 mg, 0.495 mmol) was added. The mixture was heated in a microwave reactor 100° C. for 1 h. The mixture was then filtered and concentrated. The resulting residue was purified via FCC (0-45% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (d, J=2.02 Hz, 1 H) 7.40-7.43 (m, 1 H) 7.24 (dd, J=7.33, 1.01 Hz, 1 H) 7.09-7.16 (m, 3 H) 7.02 (d, J=1.26 Hz, 1 H) 6.87 (dd, J=7.83, 1.26 Hz, 1 H) 4.03-4.16 (m, 3 H) 3.70-3.84 (m, 2 H) 3.56 (d, J=12.88 Hz, 1 H) 3.33-3.42 (m, 2 H) 3.23-3.28 (m, 1 H) 3.14 (dd, J=12.88, 3.54 Hz, 1 H) 2.92-3.06 (m, 6 H) 2.79-2.90 (m, 1H) 2.22 (s, 3 H) 2.03 (s, 3 H) 1.32 (d, J=6.82 Hz, 3 H) 1.19 (dd, J=6.95, 1.89 Hz, 6 H); MS (ESI+) m/z 573.4 (M+H)+.

Aufarbeitung

  1. filtrationThe mixture was then filtered
  2. concentrationconcentrated
  3. customThe resulting residue was purified via FCC (0-45% EtOAc/heptane)

Quellen und Nachweise

ORD-Eintrag
ord-d6530dbae2144a1993ef397b27b0a8a4
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846656B2

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