2-Methyl-2-butene → 5-[4-(1-carboxycyclobutyl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

HRID 338411Notes

Reaction equation

HRID 338411 reaction equation
[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]([C:19]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[C:23]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([OH:32])=[O:12])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1)([OH:25])=[O:24]

Participants

8

Reactant 4

HCID 105532-Methyl-2-buteneHCID 23668197Sodium ChloriteHCID 23672064Monosodium phosphateHCID 866987471-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclobutanecarboxylic acid

Product 1

HCID 866987485-[4-(1-carboxycyclobutyl)phenyl]-6-chloro-1H-indole-3-carboxylic acidYield 31.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclobutane carboxylic acid (120 mg, 0.30 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (550 mg, 6.00 mmol) and sodium phosphate monobasic (800 mg, 6.00 mmol) in water (3 mL) dropwise via additional funnel. The ice water bath was removed, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 39% MeCN in water (0.1% TFA) to 39% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min;) to give the title compound (35 mg, 27% yield) as a white solid. MS (ES+) 392.0 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.03 (s, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 4H), 2.90-2.84 (m, 2H), 2.62-2.54 (m, 2H), 2.11-1.97 (m, 1H), 1.95-1.91 (m, 1H).

Workup

  1. customThe ice water bath was removed
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. customto give a residue, which
  4. customwas purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 39% MeCN in water (0.1% TFA) to 39% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min;)

Sources & evidence

ORD record
ord-bf2890de7f634c6d863d2a3f5c53e3bf
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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