Hydrochloric Acid → (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-amino-3-methylbutanoate hydrochloride

HRID 716091Notes

Reaction equation

HRID 716091 reaction equation
C(OC([NH:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:43].C(OCC)C>C(Cl)Cl>[ClH:43].[NH2:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 3283Diethyl EtherHCID 118207672(5)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate

Product 1

HCID 118207667(S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-amino-3-methylbutanoate hydrochlorideYield 44%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (0.025 g, 0.043 mmol) in DCM (1.5 mL) at −20° C. was added HCl in diethyl ether (2.5 ml, 2.50 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a Sunfire C18 (250×20 mm) 5 μm column using a gradient of 10% solvent B to 75% solvent B over 12 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 10.2 mg (44%) of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-amino-3-methylbutanoate hydrochloride, the titled compound of example 2 as an off-white solid. LC-MS (Method A) RT=2.20 min, (M+H)+=482.2. 1H NMR: (400 MHz, DMSO-d6) δ ppm 8.64-8.78 (m, 3H) 7.38-7.46 (m, 2H) 7.23 (d, J=8.53 Hz, 2H) 7.18 (s, 4H) 5.04-5.26 (m, 1H) 4.42 (d, J=9.54 Hz, 3H) 4.17-4.23 (m, 2H) 3.29-3.40 (m, 4H) 3.19-3.28 (m, 2H) 2.30 (s, 6H) 2.04-2.19 (m, 2H) 1.11 (dd, J=12.55, 7.03 Hz, 6H). 19F NMR (376 MHz, DMSO-d6) δ −183.904.

Workup

  1. customThe solvent was then removed in vacuo
  2. customto provide a pale yellow semisolid
  3. customThe crude product was then purified by RP-HPLC on a Sunfire C18 (250×20 mm) 5 μm column
  4. customover 12 minutes
  5. concentrationActive fractions were concentrated by lyophilization

Sources & evidence

ORD record
ord-12d48679f37d4359b68b9a4c9349b168
Source dataset
uspto-grants-2015_11
Patent number
US09187506B2

Reaction notes

Loading…