Diisopropylethylamine → (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1-methyl-1-methylcarbamoyl-ethyl)-phenyl]-amide

HRID 1807328Notes

Reaction equation

HRID 1807328 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[C:26]([F:54])=[C:27]([C@@H:31]2[C@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33][C@H:32]2[C:51](O)=[O:52])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:51]([C@@H:32]2[C@@H:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=3[F:54])[C@@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33]2)=[O:52])=[CH:7][CH:6]=1)([C:9](=[O:10])[NH:11][CH3:12])[CH3:14]

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 59249226rel-(3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-D-prolineHCID 673676632-(4-amino-phenyl)-N-methyl-isobutyramide

Product 1

HCID 53357618(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1-methyl-1-methylcarbamoyl-ethyl)-phenyl]-amideYield 40.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

Reagent 2-(4-amino-phenyl)-N-methyl-isobutyramide (130 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL) then iPr2NEt (0.375 mL, 2.15 mmol) was added and stirred at 25° C. In three portions chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.214 mmol) and 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25° C. for 5 hours, complete by LCMS. The mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1-methyl-1-methylcarbamoyl-ethyl)-phenyl]-amide as an off-white solid (56 mg, 40.8%) HRMS (ES+) m/z Calcd for C34H36Cl2F2N4O2+H [(M+H)+]: 641.2256. found: 641.2256.

Workup

  1. stirringThe reaction mixture was stirred at 25° C. for 5 hours, complete by LCMS
  2. washwashed with water
  3. customThe organic phase was separated
  4. concentrationconcentrated under reduced pressure
  5. customThe compound was purified by RP-HPLC (30-95% acetonitrile/water)

Sources & evidence

ORD record
ord-9ec265f49290471784664fe2e4d3f0ed
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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