Diisopropylethylamine → HCID 25171612, compound

HRID 1480567Notes

Reaction equation

HRID 1480567 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OC[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>CC(C)=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[CH2:49][C:50]([F:53])([F:52])[F:51])[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 141328493,3,3-Trifluoropropyl trifluoromethanesulfonate2×HCID 25170562(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone

Product 1

HCID 25171612HCID 25171612, compound

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 180AcetoneSolvent

Procedure

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone (28 mg, 0.53 mmol; see Example 3) was slurried in acetone (0.4 mL) and treated with diisopropylethylamine (0.032 mL, 0.18 mmol), 4-dimethylaminopyridine (“DMAP”; 0.0006 g, 0.005 mmol) and 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.016 g, 0.066 mmol). The reaction mixture was heated to reflux for 9 hours. Additional 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.016 g, 0.066 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was concentrated using N2 (g) and chromatographed on SiO2 eluting with 2% MeOH/methylene chloride. After chromatography, the product was dissolved in ethyl acetate and washed 3 times with saturated NH4Cl, once with saturated NaHCO3, once with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The residue was concentrated from dioxane, treated with 4M HCl in dioxane (2 mL) and concentrated in vacuo. The salt was redissolved in MeOH and re-concentrated three times. The salt was dissolved in a minimal amount of MeOH and added dropwise to Et2O. The salt was filtered and washed with Et2O then dried under vacuum (12.8 mg, 39%). MS (ESI+) [M+H] 538.2/540.1. 1H NMR (CD3OD, 400 MHz) δ □8.58 (s, 1H), 7.47-7.36 (m, 4H), 5.31 (t, 1H), 4.48-3.96 (m, 3H), 3.91-3.44 (m, 7H), 2.35-2.27 (m, 1H), 2.23-2.13 (m, 1H), 2.05-1.88 (m, 2H), 1.84-1.71 (m, 1H), 1.68-1.56 (m, 1H), 1.19 (d, 3H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux for 9 hours
  3. temperaturethe mixture was heated
  4. temperatureat reflux for 16 hours
  5. concentrationThe reaction was concentrated
  6. customchromatographed on SiO2 eluting with 2% MeOH/methylene chloride
  7. dissolutionAfter chromatography, the product was dissolved in ethyl acetate
  8. washwashed 3 times with saturated NH4Cl
  9. dry with materialonce with saturated NaHCO3, once with saturated NaCl, dried over Na2SO4
  10. concentrationconcentrated in vacuo
  11. concentrationThe residue was concentrated from dioxane
  12. additiontreated with 4M HCl in dioxane (2 mL)
  13. concentrationconcentrated in vacuo
  14. dissolutionThe salt was redissolved in MeOH
  15. concentrationre-concentrated three times
  16. dissolutionThe salt was dissolved in a minimal amount of MeOH
  17. additionadded dropwise to Et2O
  18. filtrationThe salt was filtered
  19. washwashed with Et2O
  20. customthen dried under vacuum (12.8 mg, 39%)

Sources & evidence

ORD record
ord-151968b2c97b4373b38afa6ddff61eea
Source dataset
uspto-grants-2016_08
Patent number
US09409886B2

Reaction notes

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