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1-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one → 1-(5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one

HRID 1754430
Notes
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Reaction equation

HRID 1754430 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:35][CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]2)[CH:27]=1>CC(O)C>[NH3:3].[CH3:32][OH:33].[F:20][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:26]([N:28]3[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]3)[CH:27]=2)=[N:3][CH:4]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 2

HCID 582872111-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-oneHCID 86704443N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 718114411-(5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one
Yield 173.3%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (Racemic, single diastereomer; 200 mg, 0.669 mmol, 1 equiv), 1-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (Described in WO2011068898, 273 mg, 0.937 mmol, 1.4 equiv), and PTSA monohydrate (127 mg, 0.669 mmol, 1 equiv) in IPA (7 ml) were heated to 70° C. for 3 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness and taken in water, EtOAc, and 1N NaOH. The layers were separated. The organic layer was washed with 1N NaOH (×2), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 96:4 using 1% 2M NH3/MeOH increments to give compound 1-(5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (Compound 51) (racemic, single diastereomer; 321 mg, 87%) as a solid.

Workup

  1. temperatureAfter cooling to ambient temperature
  2. concentrationthe crude mixture was concentrated to dryness
  3. customThe layers were separated
  4. washThe organic layer was washed with 1N NaOH (×2)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe crude product was purified by flash chromatography
  9. washeluted with DCM

Sources & evidence

ORD record
ord-c6323c53cf8d4e2fa2f62c2f37c6451c
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09169249B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes