Diisopropylethylamine → (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate

HRID 521385Notes

Reaction equation

HRID 521385 reaction equation
CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:34][C@H:35]1[C:43]2[C:42]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[CH2:37][CH2:36]1.[C:50]([O:54][C:55]([N:57]1[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59][C@H:58]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([C@@H:64]([C@H:58]2[N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59]2)[C:65]([N:47]2[CH2:48][CH2:49][CH:44]([C:42]3[C:43]4[C@H:35]([CH3:34])[CH2:36][CH2:37][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:45][CH2:46]2)=[O:66])=[CH:73][CH:72]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59564936(S)-2-((S)-1-(tert-Butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acidHCID 67438320(R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Product 1

HCID 67436379(S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylateYield 84.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

DIPEA (174 μL, 1.00 mmol) and O-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) were added to a solution of (R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (22 mg, 0.10 mmol) and (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (20 mg, 0.054 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with DCM (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution) to give (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid (26 mg, 84%). 1H NMR (CD3OD, 500 MHz) δ 8.73 (s, 3H), 7.42 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.73-4.70 (m, 2H), 4.40-4.35 (m, 1H), 3.89-3.86 (m, 1H), 3.76-3.70 (m, 2H), 3.49-3.43 (m, 1H), 3.25-3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.86-2.70 (m, 3H), 2.34-2.25 (m, 1H), 2.16-2.13 (m, 1H), 1.83-1.67 (m, 2H), 1.54 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H), 1.25-1.20 (m, 3H).

Workup

  1. customThe reaction was quenched with saturated NH4Cl
  2. extractionextracted with DCM (2×10 mL)
  3. dry with materialThe combined organics were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution)

Sources & evidence

ORD record
ord-96403f48336d4ce7b23d4b329309f594
Source dataset
uspto-grants-2016_05
Patent number
US09328091B2

Reaction notes

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