Bromine → 1H-​Indole-​6-​carboxylic acid, 2-​bromo-​3-​cyclopentyl-​1-​methyl-​, 1-​methylethyl ester

HRID 1907889Notes

Reaction equation

HRID 1907889 reaction equation
[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br>C(#N)C>[Br:22][C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH:10]=2

Participants

4

Reactant 2

HCID 24408BromineHCID 66835544Propan-2-yl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate

Product 1

HCID 668358531H-​Indole-​6-​carboxylic acid, 2-​bromo-​3-​cyclopentyl-​1-​methyl-​, 1-​methylethyl esterYield 87.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
-6 °C

Procedure

The mixture of isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (50.0 g, 0.175 mol) and acetonitrile (393 g) was cooled to −6±3° C. Bromine (33.6 g, 0.210 mol) was added while the batch was maintained at −6±3° C. The resulting slurry was stirred at −6±3° C. for at least 30 min. When HPLC showed ≧94% conversion (the HPLC sample must be quenched immediately with aqueous 4-methylmorpholine/sodium thiosulfate solution), the mixture was quenched with a solution of sodium thiosulfate (15.3 g) and 28.4 g 4-methylmorpholine in water (440 g) while the temperature was maintained at −5±5° C. After it was stirred at 0±5° C. for at least 2 h, the batch was filtered and rinsed with 85 wt % methanol/water solution (415 g), followed by water (500 g), and dried until water content is ≦30%. The wet cake was suspended in 2-propanol (675 g), and heated to 75±5° C. The resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g) and then with 135.0 g water at a rate to maintain the batch at 75±5° C. The suspension was stirred at 75±5° C. for at least 30 min, cooled to 15±2° C. over 30-40 min, and held at 15±2° C. for at least 1 h. The batch was filtered, rinsed with 75 wt % 2-propanol/water solution (161 g), and dried in vacuo (≦200 Torr) at 50-60° C. until the water content was ≦0.4% to give isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate as a solid (55.6 g, 87% yield) in 99.5 A % (240 nm) and 97.9 Wt %.

Workup

  1. temperaturewas maintained at −6±3° C
  2. custommust be quenched immediately with aqueous 4-methylmorpholine/sodium thiosulfate solution), the mixture
  3. customwas quenched with a solution of sodium thiosulfate (15.3 g) and 28.4 g 4-methylmorpholine in water (440 g) while the temperature
  4. temperaturewas maintained at −5±5° C
  5. stirringAfter it was stirred at 0±5° C. for at least 2 h
  6. filtrationthe batch was filtered
  7. washrinsed with 85 wt % methanol/water solution (415 g)
  8. dry with materialdried until water content
  9. temperatureheated to 75±5° C
  10. additionThe resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g)
  11. temperaturewith 135.0 g water at a rate to maintain the batch at 75±5° C
  12. stirringThe suspension was stirred at 75±5° C. for at least 30 min
  13. temperaturecooled to 15±2° C. over 30-40 min
  14. waitheld at 15±2° C. for at least 1 h
  15. filtrationThe batch was filtered
  16. washrinsed with 75 wt % 2-propanol/water solution (161 g)
  17. dry with materialdried in vacuo (≦200 Torr) at 50-60° C. until the water content

Sources & evidence

ORD record
ord-225d05bfb66b487d8f64ecc42afd67ff
Source dataset
uspto-grants-2013_12
Patent number
US08598183B2

Reaction notes

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