Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)-2-methoxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid

HRID 923565Notes

Reaction equation

HRID 923565 reaction equation
[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=[CH:8][C:4]=1C(O)=O.[CH2:28]([O:35][C:36]1[CH:62]=[CH:61][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][NH:50][CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])=[C:45]([O:59][CH3:60])[CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CN([C:66]([O:70]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH2:28]([O:35][C:36]1[CH:62]=[CH:61][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([CH2:51][C:52]([OH:54])=[O:53])[C:66](=[O:70])[C:4]3[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]([F:24])([F:26])[F:25])=[CH:11][C:3]=3[O:2][CH3:1])=[C:45]([O:59][CH3:60])[CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]

Participants

6

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 710767972-Methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acidHCID 892531174-(((2-(Tert-butoxy)-2-oxoethyl)amino)methyl)-3-methoxyphenyl 4-(heptyloxy)benzoate

Product 1

HCID 892530942-(N-(4-((4-(heptyloxy)benzoyl)oxy)-2-methoxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acidYield 9.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Prepared using General Procedures 6 then 8: To a stirred solution of 2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-23 (107 mg, 0.278 mmol), TEA (77 μl, 0.556 mmol) and 4-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)-3-methoxyphenyl 4-(heptyloxy)benzoate INT-26 (135 mg, 0.278 mmol) in DMF (3 mL) was added HATU (111 mg, 0.292 mmol) and left at room temperature for 2 h. The reaction mixture was diluted with EA (50 mL). The organic phase was washed with brine (2×100 mL) then pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes. The isolated material was taken up into DCM (3 mL) and TFA (2 mL) and stirred at room temperature for 2 h. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 21 mg (9.4%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)-2-methoxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid 316 as a white powder. LCMS-ESI (m/z) calculated for C42H45F3N2O10: 794; found 795 [M+H]+, tR=10.02 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.75-12.57 (br s, 1H), 10.33 (s, 0.5H), 10.30 (s, 0.5H), 8.12-8.00 (m, 2H), 7.52-7.41 (m, 2H), 7.32 (d, J=8.3 Hz, 0.5H), 7.26-7.03 (m, 6.5H), 6.97 (d, J=2.2 Hz, 0.5H), 6.92-6.85 (m, 1H), 6.81 (dd, J=8.2, 2.1 Hz, 0.5H), 5.00-4.70 (br s, 1H), 4.35 (s, 1H), 4.09 (td, J=6.6, 2.5 Hz, 2H), 3.88-3.83 (m, 5H), 3.82 (s, 2H), 3.77 (s, 3H), 3.70 (s, 1.5H), 3.64 (s, 1.5H), 1.80-1.70 (m, 2H), 1.48-1.24 (m, 8H), 0.93-0.84 (m, 3H).

Workup

  1. customPrepared
  2. washThe organic phase was washed with brine (2×100 mL)
  3. customthen pre-absorbed onto silica gel
  4. custompurified by chromatography (EA/isohexanes
  5. stirringAfter stirring for 2 h
  6. concentrationthe solvent was concentrated
  7. customthe product was purified by preparative HPLC

Sources & evidence

ORD record
ord-8d678016d49240548edc2340f0acbbeb
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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