Diisopropylethylamine → (1-Isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methanol

HRID 1468953Notes

Reaction equation

Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Si]([O:29][CH2:30][C:31]1[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:37]2[N:36]3[CH2:44][CH2:45][NH:46][CH:47]([CH:48]([CH3:50])[CH3:49])[C:35]3=[CH:34][C:33]=2[CH:32]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[CH:48]([CH:47]1[C:35]2=[CH:34][C:33]3[CH:32]=[C:31]([CH2:30][OH:29])[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:37]=3[N:36]2[CH2:44][CH2:45][N:46]1[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)([CH3:50])[CH3:49]

Participants

Conditions

Temperature: 110 °C

Procedure

A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (80 mg, 0.44 mmol), 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (crude, from step 9), and DIEA (115 μL, 0.66 mmol) in i-PrOH/CH2Cl2 (2 mL/1 mL) was stirred at 110° C. for 30 h. The solvent was removed under reduced pressure and the crude residue was purified by silica chromatography and SFC separation on a chiral column to give isomers of (1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methanol (75 mg, 72% yield for two steps). Isomer 1: Analytical chiral HPLC: tR=11.8 min in 15 min chromatography (Method: AD-H—5—5—40—2.35ML). LC-MS m/z 469 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.65 (d, J=4.8 Hz, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 6.52 (s, 1H), 5.91-5.89 (m, 1H), 5.14-5.09 (m, 1H), 5.06 (s, 2H), 4.47-4.42 (m, 1H), 4.12-4.05 (m, 1H), 3.94-3.86 (m, 1H), 3.26 (s, 3H), 2.37-2.29 (m, 1H), 1.17 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H). Isomer 2: Analytical chiral HPLC: tR=9.7 min in 15 min chromatography (Method: AD-H—5—5—40—2.35ML). LC-MS m/z 469 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.65 (d, J=4.8 Hz, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 6.52 (s, 1H), 5.91-5.89 (m, 1H), 5.14-5.09 (m, 1H), 5.06 (s, 2H), 4.47-4.42 (m, 1H), 4.12-4.05 (m, 1H), 3.94-3.86 (m, 1H), 3.26 (s, 3H), 2.37-2.29 (m, 1H), 1.17 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).

Workup

customThe solvent was removed under reduced pressure
customthe crude residue was purified by silica chromatography and SFC separation on a chiral column

Sources & evidence

ORD record: ord-b2d98696d3d944e4b04cb961829c94ad
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09006245B2

Reaction notes

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