Ammonium Chloride → rac-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoylmethoxy-phenyl)-amide

HRID 417367Notes

Reaction equation

HRID 417367 reaction equation
Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:5]2=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH4+:76].[Cl-:77]>CN(C=O)C.CCOC(C)=O>[C:32]([CH2:31][O:30][C:29]1[CH:35]=[CH:36][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:77])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:27][CH:28]=1)(=[O:33])[NH2:76]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66625572rac-(4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carbonyl]-amino}-phenoxy)-acetic acid

Product 1

HCID 77154931rac-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoylmethoxy-phenyl)-amideYield 40%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenoxy)-acetic acid prepared in Example 206 (23 mg, 0.037 mmol), N,N-diisopropylethylamine (33 mg, 0.258 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (Chem-Impex, 24 mg, 0.062 mmol) in DMF (4 mL) was stirred for 20 min before NH4Cl (6 mg, 0.099 mmol) was added. The mixture was stirred for 0.5 h and diluted with EtOAc (70 mL), washed with water (10 mL), brine (15 mL) and concentrated. The crude product was purified by flash chromatography (EtOAc/hexane, 25/75 to 95/5) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoylmethoxy-phenyl)-amide as a white solid (9 mg, 40%). MS (ES+) m/z [(M+H)+]: 613

Workup

  1. additionwas added
  2. washwashed with water (10 mL), brine (15 mL)
  3. concentrationconcentrated
  4. customThe crude product was purified by flash chromatography (EtOAc/hexane, 25/75 to 95/5)

Sources & evidence

ORD record
ord-0e39b84777f94115a923464cf674425f
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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