Hydrochloric Acid → (5)-2-amino-4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenoxy)-4-oxobutanoic acid hydrochloride

HRID 716095Notes

Reaction equation

HRID 716095 reaction equation
C(OC([NH:8][C@@H:9]([CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[CH2:32][CH2:31][N:30]([C@@H:33]3[CH2:37][CH2:36][N:35]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)[C:34]3=[O:46])[CH2:29][C@H:28]2[F:47])=[CH:23][CH:22]=1)=[O:19])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.[ClH:48].C(OCC)C>C(Cl)Cl>[ClH:48].[NH2:8][C@@H:9]([CH2:17][C:18]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]2[CH2:32][CH2:31][N:30]([C@@H:33]3[CH2:37][CH2:36][N:35]([CH2:38][C:39]4[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=4)[C:34]3=[O:46])[CH2:29][C@H:28]2[F:47])=[CH:25][CH:26]=1)=[O:19])[C:10]([OH:12])=[O:11]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 3283Diethyl EtherHCID 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)succinate

Product 1

HCID 118207675(5)-2-amino-4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenoxy)-4-oxobutanoic acid hydrochlorideYield 57%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (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 (0.032 g, 0.049 mmol) in DCM (2 mL) at −20° C. was added HCl in diethyl ether (2.0 ml, 2.0 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 YMC Triart C18 (150×19 mm) 5 μm column using a gradient of 10% solvent B to 40% solvent B over 7 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 17 mg (57%) of (S)-2-amino-4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenoxy)-4-oxobutanoic acid hydrochloride, the titled compound of example 5 as an off-white solid. LC-MS (Method A) RT=1.808 min, (M+H)+=498.2 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J=8.5 Hz, 2H), 7.21-7.03 (m, 8H), 6.75 (d, J=8.5 Hz, 1H), 4.95-4.72 (m, 1H), 4.42-4.24 (m, 3H), 4.10 (t, J=5.3 Hz, 1H), 4.07-4.01 (m, 1H), 3.93-3.84 (m, 1H), 3.83-3.68 (m, 1H), 3.33-3.10 (m, 5H), 3.04 (br. s., 1H), 2.93 (br. s., 1H), 2.89-2.71 (m, 2H), 2.26 (s, 3H), 1.96 (br. s., 1H), 1.82 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.

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 YMC Triart C18 (150×19 mm) 5 μm column
  4. customover 7 minutes
  5. concentrationActive fractions were concentrated by lyophilization

Sources & evidence

ORD record
ord-e3418e0436cf4606a5f259be11a60ca3
Source dataset
uspto-grants-2015_11
Patent number
US09187506B2

Reaction notes

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