Water → (S)-1-tert-Butyl 4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl) 2-((tert-butoxycarbonyl)amino)succinate

HRID 716094Notes

Reaction equation

HRID 716094 reaction equation
[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34](=[O:48])[C@@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C:37](O)=[O:38])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([O:43][C:41]([NH:40][C@@H:35]([CH2:36][C:37]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:38])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])=[O:42])([CH3:47])([CH3:46])[CH3:45]

Participants

7

Reactant 4

HCID 962WaterHCID 10868DicyclohexylcarbodiimideHCID 7010517(3S)-4-(tert-butoxy)-3-{[(tert-butoxy)carbonyl]amino}-4-oxobutanoic acidHCID 91820646(3R)-3-[(3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl]-1-[(4-methylphenyl)methyl]pyrrolidin-2-one

Product 1

HCID 118207674(S)-1-tert-Butyl 4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl) 2-((tert-butoxycarbonyl)amino)succinateYield 72.6%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol) in DCM (5 mL) was added (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (0.118 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction was stirred at rt for 18 hours. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 25% ethyl acetate in petroleum ether to provide the purified product (37 mg, 68%) as an off-white semi solid. LC-MS (Method A) RT=2.55 min, (M+H)+=654.4. 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.34 (m, 2H), 7.20-6.98 (m, 6H), 4.82-4.53 (m, 1H), 4.43-4.24 (m, 2H), 4.11 (d, J=14.1 Hz, 1H), 3.58 (t, J=8.8 Hz, 1H), 3.48-3.39 (m, 1H), 3.22-3.07 (m, 3H), 3.02 (dd, J=16.1, 6.5 Hz, 1H), 2.87 (dd, J=15.8, 7.8 Hz, 1H), 2.78-2.63 (m, 2H), 2.38-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.03 (m, 1H), 1.98-1.86 (m, 1H), 1.78 (br. s., 1H), 1.74-1.58 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted with DCM (3×15 mL)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated to a crude product
  5. customThe crude product was purified by preparative TLC
  6. washeluting with 25% ethyl acetate in petroleum ether

Sources & evidence

ORD record
ord-43fdd3e876de43488e13adb28c2aa17b
Source dataset
uspto-grants-2015_11
Patent number
US09187506B2

Reaction notes

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