Hydrochloric Acid → tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate

HRID 1402504Notes

Reaction equation

HRID 1402504 reaction equation
[C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=4)=[O:36])=[C:30]([F:45])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:55]1N=N[C:57]2C=CC=N[C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C1COCC1.Cl>CN(C=O)C.O>[CH2:56]([NH:55][C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=4)=[O:36])=[C:30]([F:45])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:46])[CH3:57]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67042314(2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid

Product 1

HCID 67042748tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid (80 mg, 0.13 mmol), HATU (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of 2-Methylamine in THF solution (0.1 ml, 0.2 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 4˜5% MeOH/CHCl3 to give tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate as white solid. Yield: 40 mg, 48%.

Workup

  1. stirringThe mixture was stirred for another 10 minutes
  2. filtrationThe precipitates were filtered
  3. washwashed with water
  4. customdried in vacuo
  5. customto give the crude, which
  6. customwas purified by silica gel chromatography
  7. washeluting with 4˜5% MeOH/CHCl3

Sources & evidence

ORD record
ord-5c513da05f024497a3305f2bcf7fad1e
Source dataset
uspto-grants-2014_12
Patent number
US08906944B2

Reaction notes

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