1,2-Dichloroethane → (S)-N1-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-N3-methoxy-N3-methylisophthalamide

HRID 1254386Notes

Reaction equation

HRID 1254386 reaction equation
[CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:23])[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22](=[O:23])[C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([N:35]([O:36][CH3:37])[CH3:34])=[O:28])[CH:25]=2)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 67190092(S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoic acid

Product 1

HCID 86626202(S)-N1-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-N3-methoxy-N3-methylisophthalamideYield 83%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A mixture of (S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoic acid (0.923 g, 1.77 mmol, 1.0 equiv), obtained as described above, N,O-dimethylhydroxylamine hydrochloride (0.378 g, 2.2 equiv), EDC (0.600 g, 1.8 equiv), HOBt (0.384 g, 1.6 equiv), and DIEA (3 mL, 9.7 equiv) in CH2Cl2 (20 mL) was stirred at rt for 3 d. The reaction mixture was diluted with brine and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4. After the solvent was removed, the crude product was purified by chromatography on a 40-g silica gel cartridge eluted with a gradient from 0% to 40% EtOAc in hexanes to give (S)—N1-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-N3-methoxy-N3-methylisophthalamide (0.7388 g, 83%). TLC rf=0.38 (50% EtOAc in hexanes); LC-MS (3 min) tR=2.12 min, m/z 528 (MNa+), 506 (M+H+), 478; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.84 (dt, J=7.9, 1.5 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 677 (d, J=8.2 Hz, 1H), 4.48-4.39 (m, 1H), 4.11-3.97 (m, 2H), 3.72 (dd, J=14.3, 10.5 Hz, 1H), 3.54 (s, 3H), 3.33 (s, 3H), 3.01 (dd, J=14.3, 4.1 Hz, 1H), 2.90 (s, 3H), 1.85-0.80 (m, 15H), −0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.03, 166.25, 158.12, 134.41, 130.84, 128.80, 128.12, 126.89, 63.75, 61.06, 52.51, 46.78, 40.64, 34.60, 34.35, 33.53, 33.15, 26.36, 26.13, 26.06, 17.56, −1.61.

Workup

  1. customobtained
  2. extractionextracted with CH2Cl2 (3×)
  3. dry with materialThe combined organic extracts were dried over Na2SO4
  4. customAfter the solvent was removed
  5. customthe crude product was purified by chromatography on a 40-g silica gel cartridge
  6. washeluted with a gradient from 0% to 40% EtOAc in hexanes

Sources & evidence

ORD record
ord-8d8106245f1140ac84446eeb29a13009
Source dataset
uspto-grants-2013_06
Patent number
US08455521B2

Reaction notes

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