1-(5-amino-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one → HCID 71811596, compound

HRID 1754448Notes

Reaction equation

HRID 1754448 reaction equation
Cl.[CH3:2][C:3]1([CH3:22])[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)[CH2:9][C@H:8]2[N:4]1[CH2:5][CH2:6][CH2:7]2.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:37][C:38]([CH3:49])([CH3:48])[CH2:39][O:40][Si](C(C)(C)C)(C)C)=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH3:36])[N:32]=[N:31]2)[CH:29]=1>CC(O)C>[NH3:4].[CH3:34][OH:35].[CH3:2][C:3]1([CH3:22])[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([O:37][C:38]([CH3:49])([CH3:48])[CH2:39][OH:40])=[C:28]([N:30]4[C:34](=[O:35])[N:33]([CH3:36])[N:32]=[N:31]4)[CH:29]=3)[N:14]=2)[CH2:9][C@H:8]2[N:4]1[CH2:5][CH2:6][CH2:7]2

Participants

5

Reactant 2

HCID 867044881-(5-amino-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-oneHCID 867044914-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-chloropyrimidine-5-carbonitrile hydrochloride

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 71811596HCID 71811596, compoundYield 157.3%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-chloropyrimidine-5-carbonitrile hydrochloride (200 mg, 0.584 mmol, 1.00 equiv), 1-(5-amino-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (255 mg, 0.643 mmol, 1.10 equiv), and PTSA monohydrate (225 mg, 1.17 mmol, 2.00 equiv) in IPA (20 mL) was heated at 70° C. overnight. After the first day, in the morning, LCMS indicated a ratio of OTBS-protected product:product=3:1. Thus, more PTSA monohydrate (56 mg, 0.292 mmol, 0.50 equiv) was added and temperature was raised to reflux. The reaction was checked by LCMS in the afternoon, which indicated a ratio of OTBS-protected product:product=1.5:1. Thus, more PTSA monohydrate (56 mg, 0.292 mmol, 0.50 equiv) was added and refluxing was continued. On the second day, in the morning, LCMS indicated a ratio of OTBS-protected product:product=1:4.5. Thus, more PTSA monohydrate (112 mg, 0.585 mmol, 1.00 equiv) was added and refluxing was continued. The reaction awas checked by LCMS in the afternoon, which indicated a ratio of OTBS-protected product:product=1:8. Thus, more PTSA monohydrate (56 mg, 0.292 mmol, 0.50 equiv) was added and refluxing was continued. On the third day, LCMS indicated the reaction was completed. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The residue was taken in water, EtOAc, and aqueous 1N NaOH. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc 2×. The organic layer was dried (Na2SO4), filtered, and the solvent removed under vacuum. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 94:6 using 1% 2M NH3/MeOH increments to give compound 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(1-hydroxy-2-methylpropan-2-yloxy)-3-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile (compound 83) (252 mg, 79%) as a solid.

Workup

  1. temperaturetemperature was raised
  2. temperatureto reflux
  3. temperaturerefluxing
  4. temperaturerefluxing
  5. temperaturerefluxing
  6. customOn the third day, LCMS
  7. temperatureAfter cooling to ambient temperature
  8. concentrationthe crude mixture was concentrated to dryness
  9. customThe aqueous and organic layers were partitioned
  10. extractionthe aqueous layer was extracted with EtOAc 2×
  11. dry with materialThe organic layer was dried (Na2SO4)
  12. filtrationfiltered
  13. customthe solvent removed under vacuum
  14. customThe crude product was purified by flash chromatography
  15. washeluted with DCM

Sources & evidence

ORD record
ord-1c9a59b1e5754d978e6ae70e22783c44
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

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