Hydrochloric Acid → rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N-((S)-3,4-dihydroxy-butyl)-acetamide

HRID 909056Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 909056
[Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14](O)=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:38][C@@H:37]([CH2:39][CH2:40][NH2:41])[CH2:36][O:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:41][CH2:40][CH2:39][C@H:37]([OH:38])[CH2:36][OH:35])=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1

Komponenten

8

Edukt 5

HCID 313Hydrochloric AcidHCID 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 51355303rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid

Produkt 1

HCID 51355584rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N-((S)-3,4-dihydroxy-butyl)-acetamideAusbeute 42,9 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.2 g, 0.41 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.23 g, 0.6 mmol) and iPr2NEt (0.29 mL, 1.68 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The reaction mixture was quenched with water was and the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was dissolved into tetrahydrofuran (7 mL), and aqueous HCl solution (1 N, 3 mL, 3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (5% MeOH in EtOAc) to give rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N—((S)-3,4-dihydroxy-butyl)-acetamide as an off-white solid (0.1 g, 42%). HRMS (ES+) m/z Calcd for C28H33Cl2F2N3O3+H [(M+H)+]: 568.1940; Found: 568.1943.

Aufarbeitung

  1. customThe reaction mixture was quenched with water
  2. customthe organic layer was separated
  3. extractionthe aqueous layer was extracted with ethyl acetate
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. additionwas added to the solution
  7. stirringThe reaction mixture was stirred at room temperature for 0.5 h
  8. customThe solvent was removed
  9. customthe residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution
  10. customThe organic layer was separated
  11. washwashed with water, brine
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated
  14. customThe residue was purified by chromatography (5% MeOH in EtOAc)

Quellen und Nachweise

ORD-Eintrag
ord-e6ba15e1766647888e3cf45ec886bb29
Quelldatensatz
uspto-grants-2011_09
Patentnummer
US08017607B2

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