Methanesulfonyl chloride → (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

HRID 80791

Reaktionsgleichung

Reaktionsgleichung von HRID 80791
[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[CH3:48][S:49](Cl)(=[O:51])=[O:50].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=4)(=[O:35])=[O:36])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:49]([CH3:48])(=[O:51])=[O:50])[C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]

Komponenten

6

Edukt 3

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 71240422(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

Produkt 1

HCID 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

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

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. customprepared in a manner similar to
  2. washwashed successively with sat NaHCO3, and brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customThe resulting residue was purified via FCC (5-50% EtOAc/heptane)

Quellen und Nachweise

ORD-Eintrag
ord-3338363d3d1541ee9bd2fc02c8882350
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846656B2

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