Triethylamine → N-((1R,3S)-3-((2-Chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide

HRID 527071Notes

Reaction equation

HRID 527071 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11](C(O)=O)[CH2:10]2)[C:5]([F:18])=[CH:4][N:3]=1.N(P([O:31][C:32]1C=CC=CC=1)(OC1C=CC=CC=1)=O)=[N+]=[N-].C([N:40](CC)CC)C.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:40][C:32]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:31])[CH2:10]2)[C:5]([F:18])=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 31268PyrrolidineHCID 123414Diphenylphosphoryl azideHCID 86667448(1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid2×

Product 1

HCID 86667450N-((1R,3S)-3-((2-Chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
85 °C

Procedure

A solution of (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid, 67d, (8.2 g, 30.0 mmol), (azido(phenoxy)phosphoryl)oxybenzene (9.7 mL, 45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) in THF (200 mL) was degassed under nitrogen for 15 minutes. The reaction mixture was heated at 85° C. for 30 minutes until LC/MS indicated complete consumption of carboxylic acid, 67d. To the reaction mixture was added pyrrolidine (7.5 mL, 90.0 mmol) and the reaction was heated at 85° C. for an additional 15 min. The mixture was diluted into brine and extracted with EtOAc. The organic phase was separated, dried over MgSO4. The product was isolated (6.25 g) by filtration after partial removal of solvent in vacuo: 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=2.8 Hz, 2H), 5.04 (d, J=8.1 Hz, 2H), 4.09 (ddd, J=26.9, 13.4, 5.6 Hz, 4H), 3.91-3.71 (m, 2H), 3.32 (t, J=6.5 Hz, 7H), 2.45 (d, J=11.5 Hz, 2H), 2.08 (dd, J=22.1, 12.0 Hz, 4H), 1.96-1.82 (m, 9H), 1.54 (dd, J=18.6, 8.5 Hz, 2H), 1.22-1.01 (m, 6H).

Workup

  1. customconsumption of carboxylic acid, 67d
  2. temperaturethe reaction was heated at 85° C. for an additional 15 min
  3. extractionextracted with EtOAc
  4. customThe organic phase was separated
  5. dry with materialdried over MgSO4
  6. customThe product was isolated (6.25 g)
  7. filtrationby filtration
  8. customafter partial removal of solvent in vacuo

Sources & evidence

ORD record
ord-6410e9f18e294ed2978051341049e792
Source dataset
uspto-grants-2016_05
Patent number
US09345708B2

Reaction notes

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