Diisopropylethylamine → HCID 67409845, compound

HRID 2060728Notes

Reaction equation

HRID 2060728 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:63])[CH2:60][O:61][CH3:62])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27]([NH:63][C@H:59]([C:56]3[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=3)[CH2:60][O:61][CH3:62])=[O:28])[CH2:25][CH2:26]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 10703453HCID 10703453, compoundHCID 67398072HCID 67398072, compound

Product 1

HCID 67409845HCID 67409845, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirring suspension of Example B3 (65 mg, 0.164 mmol), TBTU (79 mg, 0.246 mmol) and (R)-1-(4-fluorophenyl)-2-methoxyethanamine (40.5 mg, 0.197 mmol; prepared according to the published method: J. Med. Chem. (1999), 42(24), 4981) in DMF (2 ml) was added DIEA (0.171 ml, 0.984 mmol). The resulting clear solution was stirred at RT overnight. After stirring overnight, the reaction was diluted with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with satd. NaHCO3 (1×), satd. LiCl (2×), and brine (1×), dried (MgSO4), evaporated in vacuo and purified by reverse phase chromatography. Pure fractions were pooled, treated with satd. NaHCO3 (pH 8) and extracted with EtOAc (3×). The combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), and evaporated to afford N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide as an oil. This was dissolved in 4:1 MeCN/H2O, treated with certified 0.1N HCl (1.37 ml, 1.0 eq), frozen and lyophilized to afford 63 mg (66% yield) of the HCl salt as a solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.49-8.48 (m, 2H), 8.44-8.42 (m, 1H), 8.18 (brs, 1H), 7.89-7.85 (m, 1H), 7.54 (brs, 1H), 7.48-7.35 (m, 4H), 7.16-7.11 (m, 2H), 6.92 (brs, 1H), 5.13-5.06 (m, 1H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.49-3.46 (m, 1H), 3.25 (s, 3H), 1.45-1.33 (m, 4H); MS (ESI) m/z: 516.1 (M+H+).

Workup

  1. customprepared
  2. stirringAfter stirring overnight
  3. additionthe reaction was diluted with satd
  4. extractionNaHCO3 and extracted with EtOAc (2×)
  5. washThe combined organics were washed with satd
  6. dry with materialLiCl (2×), and brine (1×), dried (MgSO4)
  7. customevaporated in vacuo
  8. custompurified by reverse phase chromatography
  9. additiontreated with satd
  10. extractionNaHCO3 (pH 8) and extracted with EtOAc (3×)
  11. washThe combined organics were washed with satd
  12. dry with materialNaHCO3 (1×), brine (1×), dried (MgSO4)
  13. customevaporated

Sources & evidence

ORD record
ord-01736d166aa742569e841831b3b14132
Source dataset
uspto-grants-2012_10
Patent number
US08278331B2

Reaction notes

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