Triethylamine → HCID 11605291, compound

HRID 1027929Notes

Reaction equation

HRID 1027929 reaction equation
[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@H:22]([C:27](O)=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([N:35](CC)CC)C.CCN(C(C)C)C(C)C.Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@H:22]([C:27]([NH:35][CH3:33])=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 81531DiisopropylethylamineHCID 6364545Methylamine hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58318667HCID 58318667, compound

Product 1

HCID 11605291HCID 11605291, compoundYield 45.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylic acid (15) (145 mg, 0.32 mmol) was dissolved in DMF (10 ml) under nitrogen. Triethylamine (0.13 ml, 0.95 mmol) was added, followed by DIPEA (0.055 ml, 0.32 mmol) and methylamine hydrochloride (0.043 g, 0.63 mmol). The mixture was cooled in an ice/water bath and HATU (180 mg, 0.47 mmol) was then added portionwise such that the temperature remained <10° C. The reaction mixture was stirred at room temperature overnight and evaporated to dryness. The residues were dissolved in EtOAc, washed with water (10 ml), brine (10 ml), dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0-90/10). Fractions containing the desired product were combined and evaporated. The resulting solids were dissolved in methanol, loaded onto an SCX column and eluted with MeOH (20 ml) followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated to give the title product as a white solid (69 mg, 40%): 1H NMR Spectrum: (DMSO-d6) δ1.63-1.69 (2H, m), 2.15-2.21 (6H, m), 2.55-2.62 (4H, m), 2.93-2.98 (1H, m), 3.94 (3H, s), 4.43-4.51 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.49-7.56 (2H, m), 7.68-7.72 (1H, m), 7.86 (1H, s), 8.39 (1H, s), 9.57 (1H, s); Mass Spectrum: (M+H)+ 474.

Workup

  1. temperatureThe mixture was cooled in an ice/water bath
  2. customremained <10° C
  3. customevaporated to dryness
  4. dissolutionThe residues were dissolved in EtOAc
  5. washwashed with water (10 ml), brine (10 ml)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customThe crudes were purified by column chromatography
  10. washeluting
  11. temperaturewith increasingly polar mixtures of methylene chloride/methanol (100/0-90/10)
  12. additionFractions containing the desired product
  13. customevaporated
  14. dissolutionThe resulting solids were dissolved in methanol
  15. washeluted with MeOH (20 ml)
  16. customevaporated

Sources & evidence

ORD record
ord-555b4fd86fb641158161072eeef6c26a
Source dataset
uspto-grants-2014_05
Patent number
US08735410B2

Reaction notes

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