p-Toluenesulfonic acid → 1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one

HRID 633396Notes

Reaction equation

HRID 633396 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H: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.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C:33]1[C:34]([F:47])=[CH:35][C:36]([Br:46])=[C:37]([N:39]2[C:43](=[O:44])[N:42]([CH3:45])[N:41]=[N:40]2)[CH:38]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:32][C:33]3[C:34]([F:47])=[CH:35][C:36]([Br:46])=[C:37]([N:39]4[C:43](=[O:44])[N:42]([CH3:45])[N:41]=[N:40]4)[CH:38]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 516892Sodium BicarbonateHCID 86704490(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amineHCID 867044951-(5-amino-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one

Product 1

HCID 867044941-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-oneYield 53%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
110 °C

Procedure

(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (1.4525 g. 4.86 mmol) and p-toluenesulfonic acid (1.7288 g, 9.09 mmol) were weighed out and added to a large reaction tube containing 1-(5-amino-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.10 g, 7.29 mmol). 42 mL isopropyl alcohol was added, and the tube was sealed and heated overnight at 110° C. The reaction was basified with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. Product solution was filtered, concentrated onto a plug of silica, and purified by column chromatography. Pure fractions were combined, concentrated and dried under high vacuum to give 1.4063 g of the title compound (53% yield).

Workup

  1. additionadded to a large reaction tube
  2. customthe tube was sealed
  3. extractionextracted three times with ethyl acetate
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationProduct solution was filtered
  7. concentrationconcentrated onto a plug of silica
  8. custompurified by column chromatography
  9. concentrationconcentrated
  10. customdried under high vacuum

Sources & evidence

ORD record
ord-bf1cc5c7b62242e0bc028f725756891d
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

Loading…