Cesium carbonate → 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-((R)-2-hydroxypropoxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile

HRID 1754453Notes

Reaction equation

HRID 1754453 reaction equation
[CH3:1][C:2]1([CH3:36])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[C:25]([N:27]4[C:31](=[O:32])[N:30]([CH3:33])[N:29]=[N:28]4)[C:24]([OH:34])=[CH:23][C:22]=3[F:35])[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:44][C@H:45]([OH:47])[CH3:46]>CN(C)C(=O)C>[CH3:1][C:2]1([CH3:36])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[C:25]([N:27]4[C:31](=[O:32])[N:30]([CH3:33])[N:29]=[N:28]4)[C:24]([O:34][CH2:44][C@H:45]([OH:47])[CH3:46])=[CH:23][C:22]=3[F:35])[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 59886861(R)-1-Iodopropan-2-olHCID 1363444081-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-cyanopyrimidin-2-ylamino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one

Product 1

HCID 862759344-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-((R)-2-hydroxypropoxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrileYield 23.8%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)-2-fluoro-4-hydroxyl-phenylamino)pyrimidine-5-carbonitrile (467 mg, 1.0 eq.) was added to N,N-dimethylacetamide (4.7 ml, 0.2M), followed by Cs2CO3 (922 mg, 3.0 eq.) and 3-iodo-2-(R)-propanol (0.88 g, 5.0 eq.) and heated at 100° C. under nitrogen overnight. It was cooled to room temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate (10 ml) and treated with saturated NaHCO3 (10 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml), and the combined organic solution was washed with brine (10 ml), and dried with Na2SO4. Solid was filtered off, and the organic solution was concentrated under reduced pressure. 5 ml of ethyl acetate was added to the residue, silica gel was added to form a thick paste, and was concentrated under reduced pressure. This silica gel mixture was loaded onto the Combiflash chromatography and product was eluted using 2N NH3 in MeOH (0-20%)/Ethyl Acetate (100%-80%) gradient to yield 124 mg of product as a light beige solid.

Workup

  1. temperatureIt was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. additionThe residue was treated with ethyl acetate (10 ml)
  4. additiontreated with saturated NaHCO3 (10 ml)
  5. extractionThe aqueous layer was extracted with ethyl acetate (2×10 ml)
  6. washthe combined organic solution was washed with brine (10 ml)
  7. dry with materialdried with Na2SO4
  8. filtrationSolid was filtered off
  9. concentrationthe organic solution was concentrated under reduced pressure
  10. addition5 ml of ethyl acetate was added to the residue, silica gel
  11. additionwas added
  12. customto form a thick paste
  13. concentrationwas concentrated under reduced pressure
  14. washwas eluted

Sources & evidence

ORD record
ord-1b50bc09a8c74d0c903c5c0a9f3c6544
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

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