Diisopropylethylamine → 1-{5-tert-Butyl-2-[3-((R)-2-hydroxy-1-methyl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

HRID 630964Notes

Reaction equation

HRID 630964 reaction equation
ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 86687106(1S,4R)-4-[3-((S)-2-Methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCID 89624169{5-tert-Butyl-2-[3-((R)-2-hydroxy-1-methyl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 896241701-{5-tert-Butyl-2-[3-((R)-2-hydroxy-1-methyl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaYield 61%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A solution of Intermediate 151c (102 mg, 0.22 mmol) in 1,4-dioxane (2.0 mL) was treated with Intermediate 81d (75 mg, 0.20 mmol) and DIPEA (0.043 mL, 0.25 mmol) and the mixture was stirred at 70° C. for 7.5 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a yellow glass (84 mg, 61%). LCMS (Method 3): Rt 3.75 min, m/z 693.5 [MH+].

Workup

  1. waitat 50° C. for 64 h
  2. concentrationThe cooled solution was concentrated in vacuo
  3. customthe residue was partitioned between DCM and water
  4. customThe phases were separated
  5. extractionthe aqueous layer was extracted with DCM (×2)
  6. washThe combined organic phase was washed with brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated in vacuo to a brown gum
  9. customThe gum was purified by FCC

Sources & evidence

ORD record
ord-0930d0c477c64bbdaccfd93713d8925b
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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