Triethylamine → (E)-3-(2-{1-[(3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzoimidazol-5-yl)acrylic acid

HRID 1661356Notes

Reaction equation

HRID 1661356 reaction equation
[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10]C(C(O)=O)=C[CH:13]=3)[N:8](C)[C:7]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27](=[O:45])/[CH:28]=[CH:29]/[C:30]1[CH:44]=[CH:43][C:33]2[N:34]([CH3:42])[C:35]([C:37]3([NH2:41])[CH2:40][CH2:39][CH2:38]3)=[N:36][C:32]=2[CH:31]=1.C[O:47][C:48](=O)/[CH:49]=[CH:50]/C1C=CC(NC)=C(N)C=1.[CH3:61]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[OH-].[Na+]>CS(C)=O.C(O)(=O)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:49]([C:48]([NH:41][C:37]4([C:35]5[N:34]([CH3:42])[C:33]6[CH:43]=[CH:44][C:30](/[CH:29]=[CH:28]/[C:27]([OH:26])=[O:45])=[CH:31][C:32]=6[N:36]=5)[CH2:38][CH2:39][CH2:40]4)=[O:47])=[CH:50][CH:13]=3)[N:8]([CH3:61])[C:7]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 5142713-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58866234(E)-3-(3-amino-4-methylaminophenyl)acrylic acid methyl esterHCID 58866235(E)-3-[2-(1-aminocyclobutyl)-1-methyl-1H-benzoimidazol-5-yl]acrylic acid methyl ester

Product 1

HCID 11410564(E)-3-(2-{1-[(3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzoimidazol-5-yl)acrylic acidYield 78%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 679Dimethyl SulfoxideSolvent

Procedure

A solution of 3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid 4-1, prepared using procedures described in WO 03/010141 (31.1 mg, 0.97 mmol), (E)-3-[2-(1-aminocyclobutyl)-1-methyl-1H-benzoimidazol-5-yl]acrylic acid methyl ester 4-2, prepared from the ethyl ester analogue of compound 2-4, using an analogous procedure to that described in Example 3 (27.7 mg, 0.97 mmol), HATU (47.9 mg, 0.126 mmol) and Et3N (58 μL, 0.42 mmol) in DMSO (2 mL) was stirred at RT for 3 h. After that period, NaOH (280 μL, 2.5N) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was neutralized with the addition of a few drops of acetic acid, and purified on a reversed phase C18, semi-preparative HPLC column (using a solvent gradient from 5% to 100% MeCN in H2O (all solvents contain 0.1% trifluoroacetic acid)) to isolate the final inhibitor (E)-3-(2-{1-[(3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzoimidazol-5-yl)acrylic acid 4-3 (compound 4001, Table 4) as a white amorphous solid in >95% homogeneity (45 mg, 78% yield).

Workup

  1. waitAfter that period
  2. stirringthe reaction mixture was stirred at RT for 16 h
  3. custompurified on a reversed phase C18, semi-preparative HPLC column (

Sources & evidence

ORD record
ord-1be1bd2cfe2849b1a59db7e16dc282c5
Source dataset
uspto-grants-2011_10
Patent number
US08030309B2

Reaction notes

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