Water → HCID 59694448, compound

HRID 899405Notes

Reaction equation

HRID 899405 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([N:29]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][O:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)=[N:17][N:18]=2)=[CH:2]1.O.O.NN>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:29])[CH2:12][O:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)=[N:17][N:18]=2)=[CH:2]1

Participants

5

Reactant 3

HCID 962WaterHCID 24654Hydrazine hydrate (1:1)HCID 59694486HCID 59694486, compound

Product 1

HCID 59694448HCID 59694448, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

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. customAfter removing all the solvent
  2. customthe residue was subjected to a C18 reverse phase HPLC separation

Sources & evidence

ORD record
ord-c8b9b550ab1043418ed2d2883856abfb
Source dataset
uspto-grants-2008_04
Patent number
US07354944B2

Reaction notes

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