Hydrochloric Acid → rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide

HRID 1807003Notes

Reaction equation

HRID 1807003 reaction equation
F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[C:10]([F:49])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:45])([CH3:44])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37]C(=O)C(F)(F)F)[NH:17][CH:16]2[C:46](O)=[O:47])[CH:12]=[CH:13][CH:14]=1.CC1(C)O[C@@H]([CH2:56][CH2:57][NH2:58])CO1.CN(C([O:67]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+].Cl>C(Cl)Cl.O1CCCC1>[OH:67][C@H:2]([CH2:3][OH:5])[CH2:56][CH2:57][NH:58][C:46]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:49])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:44])([CH3:45])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[NH:17]1)=[O:47]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 282937772-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-amineHCID 86640421rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-{2,2-dimethyl-4-[2-(2,2,2-trifluoro-acetoxy)-ethoxy]-butyl}-pyrrolidine-2-carboxylic acid trifluoroacetic acid

Product 1

HCID 86640422rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amideYield 25%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

In a manner similar to the method described in Examples 117d and 117e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-{2,2-dimethyl-4-[2-(2,2,2-trifluoro-acetoxy)-ethoxy]-butyl}-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 119c (0.37 g, 0.58 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.5 mL, 2.9 mmol) in CH2Cl2 at room temperature for 20 h, then treated with aqueous saturated K2CO3 solution in tetrahydrofuran, followed by reaction with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a light yellow solid (90 mg, 25%).

Sources & evidence

ORD record
ord-6e4dc0c8a6d24b33935a3c26229473a0
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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