Propargyl alcohol → 3-(2-Chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol

HRID 627318Notes

Reaction equation

HRID 627318 reaction equation
Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:17]([OH:20])[C:18]#[CH:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:19]#[C:18][CH2:17][OH:20])=[CH:7][N:6]=1

Participants

6

Reactant 3

HCID 7859Propargyl alcoholHCID 2724141Tetrabutylammonium FluorideHCID 588910225-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine

Product 1

HCID 866866243-(2-Chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-olYield 56%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a yellow solution of 5-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine (18.1 g, 55.5 mmol) in THF (200 mL) were added propargyl alcohol (4.5 mL, 1.4 equiv) and a solution of tetrabutylammonium fluoride in THF (1 M, 130 mL, 2.3 equiv) and the resulting brown mixture was treated with a stream of nitrogen for 15 min (bubble in the solution). The mixture was then treated with bis(triphenylphosphine)palladium(II) chloride (2.09 g, 0.054 equiv) and heated to reflux for 5 h. After cooling, the reaction mixture was filtered through a pad of celite (rinsed with EtOAc ˜350 mL). The filtrate was concentrated to remove THF, further diluted with EtOAc (total volume 250 mL), washed with sat. NaHCO3 (2×150 mL) and water (150 mL), dried over Na2SO4, filtered and concentrated. Titration of the residue in acetone and CH2Cl2 provided 3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.65 g) in 56% yield. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 4.45 (s, 2H), 4.19 (septet, J=4.5 Hz, 1H), 1.95 (m, 2H), 1.77-1.52 (m, 10 Hz); MS m/z 280.4 (M+

Workup

  1. custombubble in the solution)
  2. temperatureheated
  3. temperatureto reflux for 5 h
  4. temperatureAfter cooling
  5. filtrationthe reaction mixture was filtered through a pad of celite (rinsed with EtOAc ˜350 mL)
  6. concentrationThe filtrate was concentrated
  7. customto remove THF
  8. additionfurther diluted with EtOAc (total volume 250 mL)
  9. washwashed with sat. NaHCO3 (2×150 mL) and water (150 mL)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-862493452cc846d7990cc149be7afc52
Source dataset
uspto-grants-2016_04
Patent number
US09309252B2

Reaction notes

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