Formic Acid → (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)-1-methylpyrrolidin-2-yl)ethanone

HRID 1480561Notes

Reaction equation

HRID 1480561 reaction equation
Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.C=O.[CH:37](O)=O.C([O-])(O)=O.[Na+].Cl.O1CCOCC1>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:37])[C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:6][CH:5]=1

Participants

8

Reactant 6

HCID 284Formic AcidHCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 66845704HCID 66845704, compound

Product 1

HCID 25170985(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)-1-methylpyrrolidin-2-yl)ethanone

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

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 di-hydrochloride (0.213 g, 0.4027 mmol) was treated with 37% aqueous formaldehyde (0.1109 mL, 4.027 mmol), formic acid (0.1519 mL, 4.027 mmol) and water (400 uL). The mixture was heated to reflux for 6 hours. After cooling, the reaction was neutralized with saturated NaHCO3 and then extracted with methylene chloride. The aqueous was extracted with methylene chloride (2×). The combined organic portions were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to chromatography on SiO2 and eluted with a stepped gradient from 2% MeOH/1% NH4OH/dichloromethane to 5% MeOH/1% NH4OH/dichloromethane. The free base was collected and concentrated in vacuo. The residue was concentrated from MeOH and then re-dissolved in MeOH. The solution was treated with HCl in dioxane (4M, 1 mL, 4 mmol). The solution was concentrated in vacuo, re-suspended in MeOH and re-concentrated three times. The solution was re-dissolved in MeOH (0.25 mL+0.125 mL wash) and added dropwise to a stirred flask containing Et2O (15 mL). The suspension was stirred for 30 minutes. The suspension was then filtered, washed with Et2O and dried under a blanket of nitrogen. (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)-1-methylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.117 g, 62%). MS (ESI+) [M+H] 470.1/472.1. 1H NMR (CD3OD, 400 MHz) δ 8.57 (s, 1H), 7.47-7.41 (dd, 4H), 5.31 (t, J=8.0 Hz, 1H), 4.54 (d, J=9.1 Hz, 1H), 4.25-4.16 (m, 2H), 4.11-4.05 (m, 1H), 3.93-3.62 (m, 6H), 3.51-3.42 (m, 1H), 3.26-3.17 (m, 1H), 2.95 (s, 3H), 2.34-2.26 (m, 1H), 2.23-2.06 (m, 3H), 2.05-1.92 (m, 1H), 1.85-1.73 (m, 1H), 1.21-1.16 (d, 3H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 6 hours
  3. temperatureAfter cooling
  4. extractionextracted with methylene chloride
  5. extractionThe aqueous was extracted with methylene chloride (2×)
  6. dry with materialThe combined organic portions were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. washeluted with a stepped gradient from 2% MeOH/1% NH4OH/dichloromethane to 5% MeOH/1% NH4OH/dichloromethane
  9. customThe free base was collected
  10. concentrationconcentrated in vacuo
  11. concentrationThe residue was concentrated from MeOH
  12. dissolutionre-dissolved in MeOH
  13. concentrationThe solution was concentrated in vacuo
  14. concentrationre-concentrated three times
  15. dissolutionThe solution was re-dissolved in MeOH (0.25 mL+0.125 mL wash)
  16. additionadded dropwise to a stirred flask
  17. additioncontaining Et2O (15 mL)
  18. filtrationThe suspension was then filtered
  19. washwashed with Et2O
  20. customdried under a blanket of nitrogen
  21. custom(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)-1-methylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.117 g, 62%)

Sources & evidence

ORD record
ord-40595b2d3772483d8ba5eb4c616eb4de
Source dataset
uspto-grants-2016_08
Patent number
US09409886B2

Reaction notes

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