Sodium hydride → HCID 59694486, compound

HRID 899404Notes

Reaction equation

HRID 899404 reaction equation
[OH:1][CH2:2][C@@H:3]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[H-].[Na+].Br[C:28]1[S:32][C:31]([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[CH:39]=[N:38][CH:37]=[CH:36]3)=[N:30][N:29]=1>CN1CCCC1=O>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][C@H:3]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH2:2][O:1][C:28]2[S:32][C:31]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[N:38][CH:37]=[CH:36]4)=[N:30][N:29]=2)=[CH:6]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 44471694HCID 44471694, compoundHCID 59694443HCID 59694443, compound

Product 1

HCID 59694486HCID 59694486, compound

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

(S)-2-(1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl)isoindoline-1,3-dione (150 mg, 0.47 mmol) and 60% sodium hydride in mineral oil (37.6 mg, 0.94 mmol) was mixed in 2 ml N-methylpyrrolidinone. After stirring for ten minutes, compound 1b suspended in 2 ml N-methylpyrrolidinone was added and the reaction mixture was stirred at 20° C. for an hour. The reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride. The ethylacetate phase was washed with more saturated aqueous ammonium chloride and dried over anhydrous sodium sulfate. After removing the ethylacetate, the remaining residue was subjected to a silica gel column chromatography separation to yield the intermediate 2-((S)-3-(1H-indol-3-yl)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-yl)isoindoline-1,3-dione (3a). Compound 3a was dissolved in 4 ml ethyl alcohol, 0.5 ml water and 0.5 ml hydrazine monohydrate in a microwave heating tube. The tube was heated at 100° C. under microwave for five minutes. After removing all the solvent, the residue was subjected to a C18 reverse phase HPLC separation to yield (2S)-1-(1H-indol-3-yl)-3-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-amine (3) (2.4 mg) as a TFA salt. 1H NMR (400 MHz, Methanol-d4): δ 3.08 (m, 1H), 3.12 (m, 1H), 3.58 (m, 2H), 3.74 (m, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.32 (m, 2H), 8.46 (d, J=8.8 Hz, 1H), 8.53 (m, 2H), 8.72 (s, 1H), 9.60 (s, 1H); MS (API-ES) m/z (%): 402 (95%, M++1), 424 (100%, M+Na+); HRMS (ESI): calculated for C22H19N5OS [M+1]: 402.1388; found: 402.1394.

Workup

  1. additionwas added
  2. stirringthe reaction mixture was stirred at 20° C. for an hour
  3. customThe reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride
  4. washThe ethylacetate phase was washed with more saturated aqueous ammonium chloride
  5. dry with materialdried over anhydrous sodium sulfate
  6. customAfter removing the ethylacetate
  7. customthe remaining residue was subjected to a silica gel column chromatography separation

Sources & evidence

ORD record
ord-8f32500b49d6465e8503118862598003
Source dataset
uspto-grants-2008_04
Patent number
US07354944B2

Reaction notes

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