1,4-Dioxane → 1-[3-tert-Butyl-1'-(2-morpholin-4-yl-ethyl)-1'H-[1,4']bipyrazolyl-5-yl]-3-((1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea formate salt

HRID 630922Notes

Reaction equation

HRID 630922 reaction equation
[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=[O:59])[NH:35][C:36]1[N:40]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47]OC3CCCCO3)[CH:45]=2)[N:39]=[C:38]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:37]=1.[CH3:62][CH2:63][N:64](C(C)C)[CH:65]([CH3:67])C.[O:71]1CCOCC1>>[CH:34]([OH:59])=[O:33].[C:55]([C:38]1[CH:37]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:59])[N:40]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][N:64]3[CH2:65][CH2:67][O:71][CH2:62][CH2:63]3)[CH:45]=2)[N:39]=1)([CH3:56])([CH3:57])[CH3:58]

Participants

5

Reactant 4

HCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 86687175{3-tert-Butyl-1'-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1'H-[1,4']bipyrazolyl-5-yl}-carbamic acid 2,2,2-trichloro-ethyl esterHCID 89624184(1S,4R)-4-[3-(cis-2,6-Dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

Product 1

HCID 866872111-[3-tert-Butyl-1'-(2-morpholin-4-yl-ethyl)-1'H-[1,4']bipyrazolyl-5-yl]-3-((1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea formate saltYield 95%

Conditions

Temperature
80 °C

Procedure

A mixture of Intermediate 96c (200 mg, 0.51 mmol), Intermediate 108b (261 mg, 0.51 mmol) and DIPEA (178 μL, 1.02 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a glassy white solid %). LCMS (Method 4): Rt 3.69 min, m/z 751 [MH+].

Workup

  1. temperatureAfter cooling
  2. customthe reaction mixture was partitioned between water and DCM
  3. extractionThe aqueous phase was extracted with EtOAc (×3)
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe resultant residue was purified by FCC on silica

Sources & evidence

ORD record
ord-ef346495419842b290f751a593f02a89
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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