Sodium Chlorite → 6-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylic acid

HRID 338259

Reaktionsgleichung

Reaktionsgleichung von HRID 338259
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:29].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:29])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1

Komponenten

8

Edukt 3

HCID 23668197Sodium Chlorite2×HCID 23673460Sodium Phosphate, Monobasic, Dihydrate2×HCID 86698603methyl 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate

Produkt 1

HCID 866986056-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylic acidAusbeute 46,3 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 962WaterLösungsmittel2×HCID 6342AcetonitrileLösungsmittelHCID 6386tert-ButanolLösungsmittelHCID 105532-Methyl-2-buteneLösungsmittel2×

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a solution of methyl 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate (124 mg, 0.325 mmol) in acetonitrile (4 mL) and tert-butanol (4 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (327 mg, 3.59 mmol) and sodium phosphate monobasic dihydrate (761 mg, 4.875 mmol) in water (2 mL). After the resulting mixture was stirred for 2 hours at room temperature, additional sodium chlorite (435.5 mg, 4.79 mmol) and sodium phosphate monobasic dihydrate (1.014 g, 6.5 mmol) in water (2 mL) and 2-methyl-2-butene (1 mL) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via prep-HPLC to give 6-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylic acid (60 mg, 46%) as a white solid. The racemic mixture was separated by preparative chiral SFC to give 16 mg of peak 1 or Example 14A (>99% ee, ret time=4.73 minutes), and 17 mg of peak 2 or Example 14B (>93% ee, ret time=5.33 minutes) using ChiralPak AD-H Minigram-1, 60/40 CO2/MeOH 0.2% isopropylamine, 10 mL/min, 120 Bar. MS (ES+) 398.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (br, 1H), 11.97 (s, 1H), 8.08 (d, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 7.38 (m, 4H), 3.81 (m, 1H), 3.61 (s, 3H), 3.54 (m, 1H), 3.40 (m, 2H), 3.28 (m, 1H), 2.25 (m, 1H), 2.00 (m, 1H).

Aufarbeitung

  1. stirringThe resulting mixture was stirred at room temperature for 16 h
  2. customThe reaction mixture was evaporated in vacuo
  3. extractionthe aqueous residue was extracted with EtOAc (3×20 mL)
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in DMSO
  7. custompurified via prep-HPLC

Quellen und Nachweise

ORD-Eintrag
ord-41c1590c66e94070bd0c3137b73b8838
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08889730B2

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