Triethylamine → Benzoic acid, 3-methoxy-4-[[1-methyl-5-[[(4,4,4-trifluoro-2-methylbutyl)amino]carbonyl]-1H-indol-3-yl]methyl]-, methyl ester, (R)-

HRID 1975433Notes

Reaction equation

HRID 1975433 reaction equation
Cl.[CH3:2][C@H:3]([CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:4][NH2:5].[C:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH2:24][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:11](=[O:12])[NH:5][CH2:4][C@H:3]([CH3:2])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH:15]=2)[N:19]([CH3:23])[CH:18]=1)[C:29]([O:31][CH3:32])=[O:30]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 9998178Methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoateHCID 12004108HCID 12004108, compound

Product 1

HCID 10050661Benzoic acid, 3-methoxy-4-[[1-methyl-5-[[(4,4,4-trifluoro-2-methylbutyl)amino]carbonyl]-1H-indol-3-yl]methyl]-, methyl ester, (R)-Yield 55.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A mixture of (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (9.79 g), methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (20.55 g), 4-dimethylaminopyridine (7.45 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.07 g) and triethylamine (9.3 mL) was dissolved in dry methylene chloride (240 mL) and the solution was stirred under an inert atmosphere for 18 h. The mixture was diluted with methylene chloride (200 mL) and washed twice with 1N hydrochloric acid. The combined acid washes were back extracted with methylene chloride and the combined organic extracts were washed (water, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with 97:3 methylene chloride:ethyl acetate to give methyl (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (14.48 g, 55%) as a white solid; mp 150°-151° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CH3), 1.98-2.08 (m, 1H, CHCH3) 2.12-2.44 (m, 2H, CF3CH2), 3.30-3.58 (m, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, ARCH2Ar'), 6.23 (br t, 1H, NHCO).

Workup

  1. washwashed twice with 1N hydrochloric acid
  2. extractionThe combined acid washes were back extracted with methylene chloride
  3. washthe combined organic extracts were washed (water, brine)
  4. dry with materialdried (MgSO4)
  5. customevaporated
  6. customThe residue was purified by flash chromatography
  7. washeluting with 97:3 methylene chloride

Sources & evidence

ORD record
ord-c140cbb13a214dca8be74befbfca1bcf
Source dataset
uspto-grants-1994_02
Patent number
US05286740

Reaction notes

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