Sodium borohydride → 2-{5-[5-((S)-2-Ethyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-3'-hydroxymethyl-1-methyl-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-6,7,8,9-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

HRID 592726Notes

Reaction equation

HRID 592726 reaction equation
[CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH:48]=[CH:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:10][O:11][CH2:12]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH:48]=[CH:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1)[CH3:2]

Participants

4

Reactant 2

HCID 4311764Sodium borohydrideHCID 86684289(S)-4-(5-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

Product 1

HCID 866842902-{5-[5-((S)-2-Ethyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-3'-hydroxymethyl-1-methyl-6-oxo-1,6-dihydro-[3,4']bipyridinyl-2'-yl}-6,7,8,9-tetrahydro-2H-pyrazino[1,2-a]indol-1-oneYield 35.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of 165a (100 mg, 0.15 mmol) in methanol (10 mL) was added NaBH4 (34 mg, 0.90 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. Then the mixture was quenched with water (8 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 165 (35 mg, 35%) as light yellow solid. MS-ESI: [M+H]+ 663. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.35 (dd, J=2.0 Hz, 9.0 Hz, 1H), 7.27-7.23 (m, 2H), 6.83-6.81 (m, 2H), 4.97 (bs, 1H), 4.59-4.55 (m, 2H), 4.49-4.32 (m, 4H), 3.61 (s, 3H), 3.51-3.47 (m, 1H), 3.42-3.37 (m, 1H), 3.17-3.16 (m, 1H), 3.01-2.98 (m, 1H), 2.76-2.74 (m, 2H), 2.63-2.61 (m, 3H), 2.55-2.54 (m, 1H), 2.19-2.16 (m, 1H), 2.12-2.07 (m, 1H), 1.90-1.85 (m, 2H), 1.77-1.66 (m, 3H), 1.27-1.25 (m, 1H), 0.79 (t, J=7.0 Hz, 3H).

Workup

  1. customThen the mixture was quenched with water (8 mL)
  2. concentrationconcentrated under reduced pressure
  3. extractionThe residue was extracted with dichloromethane (3×10 mL)
  4. washThe combined organic layer was washed with brine (30 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-7ac2925b5dce498d80b980bf5237a360
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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