Diazomethane → [4-(4-Chlorobenzyl)-7-fluoro-5-bromo-1,2,3,4-tetrahydrocyclopenta[B]indol-3-YL]acetic acid

HRID 1436212Notes

Reaction equation

HRID 1436212 reaction equation
[Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[N+](=C)=[N-].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1.CCOCC>[Br:1][C:2]1[C:10]2[N:9]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:8]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1

Participants

7

Reactant 4

HCID 9550DiazomethaneHCID 24758Sodium hydrideHCID 693291-(Bromomethyl)-4-chlorobenzeneHCID 161093712-(5-Bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid

Product 1

HCID 18476687[4-(4-Chlorobenzyl)-7-fluoro-5-bromo-1,2,3,4-tetrahydrocyclopenta[B]indol-3-YL]acetic acidYield 78.9%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at −78° C. The suspension was stirred for 10 min at 0° C., cooled again to −78° C. and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 0° C. and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to yield 2.35 g of the title compound as a pale brown solid.

Workup

  1. customexcess until complete consumption of the acid
  2. customThen, the solvents were removed under vacuum
  3. customTo a solution of the crude methyl ester thus formed in 20 mL of DMF
  4. temperaturecooled again to −78° C.
  5. waitAfter 5 min
  6. temperaturethe temperature was warmed to 0° C.
  7. stirringthe mixture was stirred for 20 min
  8. customAt this time, the reaction was quenched by the addition of 2 mL of AcOH
  9. additionthis mixture was poured into a separatory funnel
  10. additioncontaining 1N HCl/EtOAc
  11. customThe layers were separated
  12. washthe organic layer was washed with brine
  13. dry with materialdried over anhydrous Na2SO4
  14. concentrationconcentrated
  15. customThe crude material was further purified by trituration with EtOAc/hexanes

Sources & evidence

ORD record
ord-2aaa4a732b29466399f006d433f2a1a5
Source dataset
uspto-grants-2009_11
Patent number
US07618994B2

Reaction notes

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