Diisopropylethylamine → (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one

HRID 408009Notes

Reaction equation

HRID 408009 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:66]1[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([N:66]5[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]5)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:12][CH2:13]2)=[N:6][CH:7]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2759336(3R)-pyrrolidin-3-ol hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67469835(S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid

Product 1

HCID 54670799(S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-oneYield 33%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (Example 153, Step B; 0.10 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. (R)-pyrrolidin-3-ol hydrochloride (0.058 g, 0.66 mmol) was added and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL), washed with HCl (1N, 10 mL), NaOH (1N, 10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse phase HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.038 g, 0.072 mmol, 33% yield). Mass spectrum (apci) m/z=521.0 (M+H).

Workup

  1. stirringthe reaction was stirred for 2 hours at ambient temperature
  2. washwashed with HCl (1N, 10 mL), NaOH (1N, 10 mL), water (10 mL), and brine (10 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customThe crude material was purified by reverse phase HPLC
  7. additionThe combined fractions were diluted with EtOAc (50 mL)
  8. washwashed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-9063d53beaff4fb28371325f012e0535
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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