Diethyl Ether → (S)-2-Amino-N-((6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-((S)-1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-3-methylbutanamide

HRID 75899Notes

Reaction equation

HRID 75899 reaction equation
[NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.C(OC([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOCC>C(Cl)Cl.CO>[NH2:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38]([NH:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1)=[O:39]

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 83693Boc-L-ValineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67454991(S)-3-(Aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine

Product 1

HCID 67456824(S)-2-Amino-N-((6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-((S)-1-(4-fluorophenyl)ethylamino)pyridin-3-yl)methyl)-3-methylbutanamideYield 26.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.10 g, 0.26 mmol), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.06 g, 0.26 mmol), and HBTU (0.10 g, 0.26 mmol) in DCM (3 ml) was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was then passed through a silica plug. The resulting foam was placed in dioxane (4 ml) and 4 M HCl in dioxane (1 ml) was then added, and the reaction was stirred for 3 hours. The reaction was then concentrated to give a solid which was dissolved in a minimal amount of MeOH (0.5 ml) with stirring, followed by fast addition of ether (50 ml). The resulting solid was filtered, washed with ether, and dried to give the title compound (0.033 g, 26%). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J=10.7 Hz, 1H), 7.49-7.46 (m, 2H), 7.07-7.02 (m, 2H), 5.80 (s, 1H), 5.09-5.04 (m, 1H), 4.58 (dd, J=15.4, 6.8 Hz, 1H), 4.26 (dd, J=15.4, 5.2 Hz, 1H), 3.71 (d, J=6.0 Hz, 1H), 2.23-2.18 (m, 1H), 2.01-1.97 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.19-1.13 (m, 2H), 1.05-1.03 (m, 6H), 0.85-0.81 (m, 2H). MS: Calcd.: 483. Found: [M+H]+ 484.

Workup

  1. customThe reaction was then quenched with a saturated aqueous solution of NaHCO3
  2. extractionextracted with DCM (2×50 ml)
  3. dry with materialThe combined organic fractions were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. addition4 M HCl in dioxane (1 ml) was then added
  7. concentrationThe reaction was then concentrated
  8. customto give a solid which
  9. stirringwith stirring
  10. filtrationThe resulting solid was filtered
  11. washwashed with ether
  12. customdried

Sources & evidence

ORD record
ord-658754936be944018002c3121c511fb9
Source dataset
uspto-grants-2014_09
Patent number
US08835465B2

Reaction notes

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