Diisopropylethylamine → (2R,4S)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate

HRID 1618335Notes

Reaction equation

HRID 1618335 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][C@@H:35]5[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C@@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]5)=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 70099181-tert-butyl 2-methyl (2S,4R)-4-aminopyrrolidine-1,2-dicarboxylateHCID 667654164-(4-(1-(4-Chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid

Product 1

HCID 68182905(2R,4S)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylateYield 84.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (400 mg, 0.834 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (224 mg, 0.917 mmol), PyBOP (651 mg, 1.250 mmol), and Hunig's Base (0.728 mL, 4.17 mmol) were stirred in DCM (Volume: 10 mL) for 3 days. The solvent was removed and the crude material was purified by silica gel chromatography using 60% EtOAc/hexanes to give (2R,4S)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate (500 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.33-1.41 (m, 4H), 1.43 (s, 9H), 2.25-2.48 (m, 2H), 3.39-3.47 (m, 1H), 3.78 (s, 3H), 3.81-3.90 (m, 1H), 4.46 (td, J=7.7, 4.8 Hz, 1H), 4.64 (qd, J=5.8, 5.6 Hz, 1H), 4.85-4.93 (m, 2H), 7.20-7.32 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.92 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 706.1.

Workup

  1. customThe solvent was removed
  2. customthe crude material was purified by silica gel chromatography

Sources & evidence

ORD record
ord-497493afc4ca4a87aeddc0627cec15a9
Source dataset
uspto-grants-2014_07
Patent number
US08765944B2

Reaction notes

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