2,4-Dichlorobenzaldehyde → (3S)-1-(5-bromopyrimidin-2-yl)-N-[(2,4-dichlorophenyl)methyl]pyrrolidin-3-amine

HRID 252127Notes

Reaction equation

HRID 252127 reaction equation
[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C1COCC1.C(O)(C)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:19][C:18]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=3[Cl:16])[CH2:9]2)=[N:6][CH:7]=1

Participants

9

Reactant 4

HCID 134042,4-DichlorobenzaldehydeHCID 14798Sodium Hydroxide2×HCID 5049666Sodium triacetoxyborohydrideHCID 66854146(S)-1-(5-bromopyrimidin-2-yl)-pyrrolidine-3-amine

Product 1

HCID 11503055(3S)-1-(5-bromopyrimidin-2-yl)-N-[(2,4-dichlorophenyl)methyl]pyrrolidin-3-amine

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 1140TolueneSolvent3×HCID 3776IsopropanolSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

Combine (S)-1-(5-bromopyrimidin-2-yl)-pyrrolidine-3-amine (10.0 g, 35.84 mmol) and 30% aqueous sodium hydroxide (1.18 equiv., 4 mL) in water (30 mL), THF (75 mL), and toluene (75 mL). Separate the layers, extract the aqueous layer with 1:1 THF:toluene (50 mL). Combine the organic layers and extract with water (10 mL). Evaporate the organic layer at reduced pressure to give a residue. Combine the residue and toluene (75 mL) and evaporate at reduced pressure to give a residue. Again, combine the residue and toluene (75 mL) and evaporate at reduced pressure to give a residue Combine the residue and toluene (12.9 g) and dry THF (53.2 g), add 2,4-dichlorobenzaldehyde (0.94 equivalent, 33.6 mmol, 6.0 g), and stir. After 1 hour, add sodium triacetoxyborohydride (65.9 mmol, 2.5 equiv., 14.4 g) in 5 portions over about 50 minutes. After 22 hours, slowly add water (16 mL), Stir for 2 hours and then basify to pH=14 by addition of 30% aqueous sodium hydroxide (20 mL). Separate the aqueous layer and extract with 1/1 toluene/THF (120 mL). Combine the organic layers and extract with water (30 mL). Evaporate the solvents at reduced pressure to give a residue. Combine the residue and isopropanol (130 mL) and evaporate at reduced pressure to give a residue. Twice more, combine the residue and isopropanol (130 mL) and evaporate at reduced pressure to give a mass of about 90 g. Slowly cool to room temperature and agitate for about 3 hours to give a solid. Collect the solid by filtration, rinse with isopropanol (10 mL), and dry at 40° C. under vacuum for 15 hours to give the title compound.

Workup

  1. customSeparate the layers
  2. extractionextract the aqueous layer with 1:1 THF
  3. extractionCombine the organic layers and extract with water (10 mL)
  4. customEvaporate the organic layer at reduced pressure
  5. customto give a residue
  6. customevaporate at reduced pressure
  7. customto give a residue
  8. customevaporate at reduced pressure
  9. customto give a residue Combine the residue and toluene (12.9 g) and dry THF (53.2 g)
  10. waitAfter 22 hours
  11. customSeparate the aqueous layer
  12. extractionextract with 1/1 toluene/THF (120 mL)
  13. extractionCombine the organic layers and extract with water (30 mL)
  14. customEvaporate the solvents at reduced pressure
  15. customto give a residue
  16. customevaporate at reduced pressure
  17. customto give a residue
  18. customevaporate at reduced pressure
  19. customto give a mass of about 90 g
  20. stirringagitate for about 3 hours
  21. customto give a solid
  22. customCollect the solid
  23. filtrationby filtration
  24. washrinse with isopropanol (10 mL)
  25. customdry at 40° C. under vacuum for 15 hours

Sources & evidence

ORD record
ord-a5b9a60e11f04c92827753ff5e1e6695
Source dataset
uspto-grants-2011_01
Patent number
US07868014B2

Reaction notes

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