Diisopropylethylamine → (2S,4R)-methyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)pyrrolidine-2-carboxylate

HRID 596108Notes

Reaction equation

HRID 596108 reaction equation
[OH:1][C:2]([C:4](F)(F)F)=[O:3].O[C:9](C(F)(F)F)=O.[NH2:15][C:16]1[C:21]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:31])[CH:23]=2)=[CH:20][C:19]([C@H:32]2[CH2:36][C@@H](C(OC)=O)[NH:34][CH2:33]2)=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C@@H:75]([C:78]1[CH:83]=[CH:82][CH:81]=[C:80]([Cl:84])[CH:79]=1)[CH2:76][OH:77]>CN(C=O)C>[NH2:15][C:16]1[N:17]=[CH:18][C:19]([C@@H:32]2[CH2:33][NH:34][C@H:4]([C:2]([O:1][CH3:9])=[O:3])[CH2:36]2)=[CH:20][C:21]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:27])[NH:74][C@@H:75]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([Cl:84])[CH:79]=2)[CH2:76][OH:77])=[C:24]([F:31])[CH:23]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59694427(S)-2-amino-2-(3-chlorophenyl)ethanolHCID 1317346254-(2-amino-5-((3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl)pyridin-3-yl)-2-fluorobenzoic acid-2TFA

Product 1

HCID 118045925(2S,4R)-methyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)pyrrolidine-2-carboxylateYield 13.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-(2-amino-5-((3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl)pyridin-3-yl)-2-fluorobenzoic acid-2TFA (35 mg, 0.060 mmol), HATU (34 mg, 0.089 mmol), and DIEA (0.104 mL, 0.596 mmol) in DMF (2 mL) was treated with (S)-2-amino-2-(3-chlorophenyl)ethanol (51 mg, 0.348 mmol). At completion, the reaction was washed with water and brine, then dried over MgSO4 and concentrated. The crude material was purified by reverse phase prep HPLC to provide (2S,4R)-methyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)pyrrolidine-2-carboxylate (4.2 mg, 9%). LCMS (m/z): 513.2, 515.2 (MH+), 0.58 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.97-7.86 (m, 3H), 7.49-7.40 (m, 3H), 7.39-7.34 (m, 2H), 7.33-7.26 (m, 1H), 5.19 (t, J=5.87 Hz, 1H), 4.62 (dd, J=7.63, 10.76 Hz, 1H), 3.93-3.77 (m, 6H), 3.74-3.61 (m, 1H), 2.87 (td, J=6.90, 13.21 Hz, 1H), 2.33-2.21 (m, 1H).

Workup

  1. washAt completion, the reaction was washed with water and brine
  2. dry with materialdried over MgSO4
  3. concentrationconcentrated
  4. customThe crude material was purified by reverse phase prep HPLC

Sources & evidence

ORD record
ord-f7024074b5e6447bb5d733f6751b308e
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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