Hydrochloric Acid → HCID 53358566, compound

HRID 1807071Notes

Reaction equation

HRID 1807071 reaction equation
C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[N:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][N:6]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 53358817HCID 53358817, compound

Product 1

HCID 53358566HCID 53358566, compoundYield 61.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester prepared in Example 138 (0.2 g, 0.33 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 20 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid as a white foam (0.12 g). In a manner similar to the method described in Examples 1e, rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid (0.12 g, 0.2 mmol) was reacted with 2-amino-2-methyl-1-propanol (Aldrich) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide as a white solid (30 mg, 22%).

Workup

  1. extractionThe mixture was extracted ethyl acetate twice
  2. washThe combined organic extracts were washed with water, brine
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-a9f9489451974875a7099a1424be2356
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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