Triethylamine → HCID 68228514, compound

HRID 2370338Notes

Reaction equation

HRID 2370338 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])[N:20]([CH2:35][CH2:36][O:37][CH3:38])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1.OC1C2N=NNC=2C=CC=1.[NH:50]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:51]([C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH:52]([CH3:54])[CH3:53].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[C:65]([O:64][C:62](=[O:63])[NH:50][CH:51]([C:55](=[O:56])[NH:57][CH2:58][C:59](=[O:60])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])[N:20]([CH2:35][CH2:36][O:37][CH3:38])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1)[CH:52]([CH3:53])[CH3:54])([CH3:66])([CH3:68])[CH3:67]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7014901BOC-VAL-GLY-OHHCID 67261087HCID 67261087, compoundHCID 178418300HCID 178418300, compound

Product 1

HCID 68228514HCID 68228514, compoundYield 72%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indol-3-yl]-methanone hydrochloride (100 mg, 0.18 mmol) was dissolved in DMF (2.6 mL) under nitrogen and stirred at 0° C. for 5 min. To this was added sequentially hydroxybenzotriazole (77 mg, 0.57 mmol), BOC-Val-Gly-OH (59 mg, 0.21 mmol), triethylamine (0.05 mL, 0.36 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg, 0.21 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (30 mL). The brine was back extracted with ethyl acetate (2×30 mL) and the organic fractions were combined and washed with 10% citric acid (2×30 mL), sat sodium bicarbonate solution (2×30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by SiO2 column chromatography using 5% MeOH/CH2Cl2 as the eluent to afford (1-{[(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-methyl]-carbamoyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (100 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.40-7.30 (m, 2H), 7.28-7.21 (m, 2H), 7.18-7.10 (m, 1H), 7.08-7.00 (m, 1H), 6.98-6.85 (m, 1H), 5.00-4.90 (br s, 1H), 4.30 (t, 2H), 3.85-3.70 (br m, 2H), 3.73 (t, 2H), 3.47 (s, 2H), 3.33 (s, 3H), 3.20-2.90 (br m, 2H), 1.90-1.60 (br m, 6H), 1.30-1.24 (m, 10H), 1.80-1.70 (br m, 6H); 19F NMR (282 MHz, CDCl3) δ −57.60 (s, 1F); MS m/z: [M+H]+=779.

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. stirringstirred overnight
  3. washwashed with brine (30 mL)
  4. extractionThe brine was back extracted with ethyl acetate (2×30 mL)
  5. washwashed with 10% citric acid (2×30 mL)
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give the crude product which
  10. customwas purified by SiO2 column chromatography

Sources & evidence

ORD record
ord-e811c860f298484684cf147bd7128259
Source dataset
uspto-grants-2014_04
Patent number
US08710080B2

Reaction notes

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