Methanol → HCID 59802494, compound

HRID 1672143Notes

Reaction equation

HRID 1672143 reaction equation
ClC1C(C(O)=O)=CC=C2C=1NC=C2.CO.[Cl:16][C:17]1[C:18]([C:32]([OH:34])=[O:33])=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[C:22]2[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[Cl:16][C:17]1[C:18]([C:32]([OH:34])=[O:33])=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[C:22]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1

Participants

6

Reactant 3

HCID 887Methanol2×HCID 21133924HCID 21133924, compoundHCID 59802492HCID 59802492, compound

Product 1

HCID 59802494HCID 59802494, compoundYield 94.4%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

To a mixture of 7-chloro-1H-indole-6-carboxylic acid (3.8 g, about 19.4 mmol) in MeOH (50 ml) at r.t. under N2 was added cyclohexanone (6.13 ml, 59.1 mmol), followed by a solution of NaOMe in MeOH (17.5 ml, 76.6 mmol, 25% wt). The reaction mixture was stirred at reflux for 16 hr. After cooling to r.t., the mixture was added another bath of cyclohexanone (6.13 ml, 59.1 mmol), followed by another solution of NaOMe in MeOH (17.5 ml, 76.5 mmol, 25% wt), and then re-stirred at reflux for another 7 hr. After cooling to r.t., the mixture was evaporated, added with water (100 ml), acidified with hydrochloric acid (5N) and left standing at r.t. overnight. The aqueous mixture was decanted, and the residue washed twice with hydrochloric acid (30 ml, 1N) and twice with water (30 ml). The residue was further washed three times with hexane, and then dried to give 5.5 g of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid. Another 2.6 g of the product was obtained from another reaction using 2.27 g of 7-chloro-1H-indole-6-carboxylic acid. Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=275.94, 277.94, HPLC Rt=1.750 min. To a mixture of the 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid (8.1 g) obtained from above in a mixture of THF/MeOH (25 ml/25 ml) at r.t. under N2 was added Pd(OH)2/C (764 mg, 20%). The mixture was then flushed with a stream of hydrogen gas using a balloon, and then stirred under hydrogen (using a balloon) for 27 hr. After removing the hydrogen balloon, the mixture was then flushed with a stream of N2, and then filtered through a cake of celite. The filtrate was evaporated to give 7-chloro-3-cyclohexyl-1H-indole-6-carboxylic acid (7.7 g). Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=278.01, 280.00, HPLC Rt=1.773 min.

Workup

  1. customB=100, Gradient time=2 min, Flow Rate=5 ml/min, Column
  2. customThe mixture was then flushed with a stream of hydrogen gas
  3. customfor 27 hr
  4. customAfter removing the hydrogen balloon
  5. customthe mixture was then flushed with a stream of N2
  6. filtrationfiltered through a cake of celite
  7. customThe filtrate was evaporated

Sources & evidence

ORD record
ord-8f3be767908742a1938c4a91a8955d06
Source dataset
uspto-grants-2011_08
Patent number
US07998951B2

Reaction notes

Loading…