4-Methylmorpholine → (R)-N-(2-((1-benzylpyrrolidin-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide

HRID 1809862Notes

Reaction equation

HRID 1809862 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:33]([N:40]1[CH2:44][CH2:43][C@@H:42]([NH2:45])[CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CC#N>[CH2:33]([N:40]1[CH2:44][CH2:43][C@@H:42]([NH:45][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH2:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 1519354(3R)-1-benzylpyrrolidin-3-amineHCID 2777432((3-(Trifluoromethyl)benzoyl)amino)acetic acid

Product 1

HCID 44453592(R)-N-(2-((1-benzylpyrrolidin-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of (3-Trifluoromethyl-benzoylamino)acetic acid (4.2 g, 17 mmol) and NMM (2.8 mL, 25.5 mmol) in dry THF (30 mL) at −10 to −15° C. under N2, was slowly added isobutylchloroformate (2.4 mL, 17.85 mmol) via syringe. The reaction mixture gradually became pink. 15 min later, a solution of (3R)-1-benzylpyrrolidin-3-amine (3.0 g, 17 mmol) in THF (15 mL) was dropwise added to the above mixed anhydride over 20 min, maintaining reaction temperature <−10° C. The reaction mixture became a dark red color. 1 h later, the reaction mixture was allowed to warm to rt, and quenched with water (25 mL), extracted with EtOAc×3, dried, filtered and concentrated to give an orange solid. MeCN was added and concentrated to remove EtOAc. Then MeCN (15-20 mL) was added to afford a slurry, which was chilled in ice bath and stirred for 30 min. After filtration, the solid product was rinsed with cold MeCN (10-15 mL) until the filtrate was colorless After dried under high vacuum overnight, a pale yellow solid product: 5.0 g (73%) was afforded. MS (M+H+)=406.2; 1H NMR (CDCl3) δ 8.16 (s, 1H), 8.00 (dd, 1H), 7.78 (dd, 1H), 7.57 (m, 1H), 7.25 (m, 6H), 7.06 (m, 1H), 6.39 (m, 1H), 4.48 (m, 1H), 4.04 (d, 2H), 3.62 (d, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.57 (m, 1H), 2.36 (m, 2H).

Workup

  1. customat −10 to −15° C.
  2. temperaturemaintaining
  3. customreaction temperature <−10° C
  4. custom1 h
  5. customquenched with water (25 mL)
  6. extractionextracted with EtOAc×3
  7. customdried
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give an orange solid
  11. concentrationconcentrated
  12. customto remove EtOAc
  13. additionThen MeCN (15-20 mL) was added
  14. customto afford a slurry, which
  15. temperaturewas chilled in ice bath
  16. filtrationAfter filtration
  17. washthe solid product was rinsed with cold MeCN (10-15 mL) until the filtrate
  18. customAfter dried under high vacuum overnight
  19. customa pale yellow solid product: 5.0 g (73%) was afforded

Sources & evidence

ORD record
ord-edb79e29d7c64dca9eedf6b59be4faf9
Source dataset
uspto-grants-2013_01
Patent number
US08362003B2

Reaction notes

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