1-(5-amino-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one → 1-(2-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one

HRID 1754447Notes

Reaction equation

HRID 1754447 reaction equation
Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][C@@H:10]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]([CH3:20])([CH3:19])[CH2:11]2)[C:6]([F:21])=[CH:5][N:4]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][C:37]([CH3:48])([CH3:47])[CH2:38][O:39][Si](C(C)(C)C)(C)C)=[C:27]([N:29]2[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]2)[CH:28]=1>CC(O)C>[NH3:4].[CH3:33][OH:34].[OH:39][CH2:38][C:37]([CH3:48])([O:36][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:3]2[N:8]=[C:7]([NH:9][C@@H:10]3[CH2:18][C@H:17]4[N:13]([CH2:14][CH2:15][CH2:16]4)[C:12]([CH3:20])([CH3:19])[CH2:11]3)[C:6]([F:21])=[CH:5][N:4]=2)=[CH:28][C:27]=1[N:29]1[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]1)[CH3:47]

Participants

5

Reactant 2

HCID 867044881-(5-amino-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-oneHCID 86704489(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 718116371-(2-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-oneYield 139.1%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of (7R,8aS)—N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (775 mg, 2.31 mmol, 1.00 equiv), 1-(5-amino-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (1.00 g, 2.54 mmol, 1.10 equiv), and PTSA monohydrate (880 mg, 4.62 mmol, 2.00 equiv) in IPA (80 mL) was heated to reflux for 3 d as monitored by LCMS. After the first day, in the morning, LCMS indicated a ratio of OTBS-protected product:product=1.5:1. Thus, more PTSA monohydrate (220 mg, 1.16 mmol, 0.50 equiv) was added and refluxing was continued. The reaction was checked by LCMS in the afternoon, which indicated a ratio of OTBS-protected product:product=1:1.2. Thus, more PTSA monohydrate (220 mg, 1.16 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=1:6.5. Thus, more PTSA monohydrate (220 mg, 1.16 mmol, 0.50 equiv) was added and refluxing was continued. The reaction was checked by LCMS in the afternoon, which indicated a ratio of OTBS-protected product:product=1:9. Thus, more PTSA monohydrate (220 mg, 1.16 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 1-(2-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (compound 86) (870 mg, 70%) as a solid.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 3 d
  3. temperaturerefluxing
  4. temperaturerefluxing
  5. temperaturerefluxing
  6. temperaturerefluxing
  7. customOn the third day, LCMS
  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-32f10cd7eae4424eb943d2478271e007
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

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