Diisopropylethylamine → 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone

HRID 1521545Notes

Reaction equation

HRID 1521545 reaction equation
[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]1[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([C:51](=[O:53])[CH3:52])=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]([C:41]4[N:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[C:44]([C:51](=[O:53])[CH3:52])=[CH:43][N:42]=4)[CH:36]([CH:37]([CH3:38])[CH3:39])[C:24]3=[CH:23][C:22]=2[CH:21]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 220974501-(2-Chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanoneHCID 898159068-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole

Product 2

HCID 717372741-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanoneHCID 898159068-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole

Reagents, catalysts & solvents 1

HCID 21966342Isopropanol methylene chlorideSolvent

Conditions

Temperature
60 °C

Procedure

The intermediate 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole was prepared following a procedure analogous to that described in Preparation 4. The mixture of compound 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (0.22 mmol), 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (100 mg, 0.44 mmol) and DIEA (115 μL, 0.66 mmol) in i-PrOH/CH2Cl2 (2 mL/1 mL) was stirred at 60° C. for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1) to give racemic 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone. LC-MS m/z 510 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.97 (s, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 6.54 (s, 1H), 6.01-5.90 (m, 1H), 5.25-5.15 (m, 1H), 5.07 (s, 2H), 4.52-4.47 (m, 1H), 4.15-4.04 (m, 1H), 4.00-3.93 (m, 1H), 3.26 (s, 3H), 2.55 (s, 3H), 2.41-2.32 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).

Workup

  1. customthat described in Preparation 4
  2. customThe solvent was removed under reduced pressure
  3. customthe residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1)

Sources & evidence

ORD record
ord-92d88eb8a95e47f091cd80d4fe37d835
Source dataset
uspto-grants-2015_07
Patent number
US09073931B2

Reaction notes

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