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1,4-Dioxane → 1-[2-[3-(2-Dimethylamino-ethoxy)-phenyl]-5-(2-hydroxy-1,1-dimethyl-ethyl)-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 formate salt

HRID 630975
Notes
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Reaction equation

HRID 630975 reaction equation
ClC(Cl)(Cl)C[O:4][C:5](=[O:50])[NH:6][C:7]1[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36](OCCOC3CCCCO3)[CH:35]=2)[N:9]=[C:10]([C:12]([CH3:33])([CH3:32])[CH2:13][O:14][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1.[CH3:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][N:55]1[C:60]1[N:64]2[CH:65]=[C:66]([O:69][C@H:70]3[C:79]4[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=4)[C@@H:73]([NH2:80])[CH2:72][CH2:71]3)[CH:67]=[CH:68][C:63]2=[N:62][N:61]=1.[CH3:81][CH2:82][N:83]([CH:87](C)C)[CH:84](C)C.[O:90]1CCOCC1>>[CH:5]([OH:50])=[O:4].[CH3:84][N:83]([CH3:87])[CH2:82][CH2:81][O:90][C:36]1[CH:35]=[C:34]([N:8]2[C:7]([NH:6][C:5]([NH:80][C@@H:73]3[C:74]4[C:79](=[CH:78][CH:77]=[CH:76][CH:75]=4)[C@H:70]([O:69][C:66]4[CH:67]=[CH:68][C:63]5[N:64]([C:60]([N:55]6[CH2:56][CH2:57][CH2:58][CH2:59][C@@H:54]6[CH3:53])=[N:61][N:62]=5)[CH:65]=4)[CH2:71][CH2:72]3)=[O:50])=[CH:11][C:10]([C:12]([CH3:32])([CH3:33])[CH2:13][OH:14])=[N:9]2)[CH:39]=[CH:38][CH:37]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 4

HCID 312751,4-DioxaneHCID 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 86687287(5-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 117665960
1-[2-[3-(2-Dimethylamino-ethoxy)-phenyl]-5-(2-hydroxy-1,1-dimethyl-ethyl)-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 formate salt
Yield 72%

Conditions

Temperature
70 °C

Procedure

A solution of Intermediate 153f (377 mg, 0.48 mmol) in 1,4-dioxane (4.8 mL) was treated with Intermediate 81d (164 mg, 0.43 mmol) and DIPEA (0.095 mL, 0.54 mmol) and the mixture was stirred at 70° C. for 30 mins then at 50° C. for 64 h then at 70° C. for 22 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 0-7% MeOH in DCM to give the title compound as a brown glass (320 mg, 72%). LCMS (Method 3): Rt 5.66 min, m/z 1017.7 [MH+].

Workup

  1. waitat 50° C. for 64 h
  2. waitat 70° C. for 22 h
  3. concentrationThe cooled solution was concentrated in vacuo
  4. customthe residue was partitioned between DCM and water
  5. customThe phases were separated
  6. extractionthe aqueous layer was extracted with DCM (×2)
  7. washThe combined organic phase was washed with brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated in vacuo to a brown gum
  10. customThe gum was purified by FCC

Sources & evidence

ORD record
ord-13b448e807ae40d1896154346c95eb61
Source dataset
uspto-grants-2016_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09315503B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes