4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride → 1-[5-((S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-pyrrolidin-2-yl)-pyridin-3-yl]-1H-indole-3-carboxylic acid ethyl ester

HRID 880614Notes

Reaction equation

HRID 880614 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH:20]=2)[CH:7]=1)=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]([CH3:46])[C@@H:34]([CH3:45])[C:35]([NH:37][C@@H:38]([CH:42]([CH3:44])[CH3:43])[C:39](O)=[O:40])=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:39](=[O:40])[C@@H:38]([NH:37][C:35](=[O:36])[C@@H:34]([N:33]([C:31]([O:30][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:32])[CH3:46])[CH3:45])[CH:42]([CH3:44])[CH3:43])[CH:20]=2)[CH:7]=1)=[O:5])[CH3:2]

Participants

5

Reactant 3

HCID 27340594-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlorideHCID 679739571-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-1H-indole-3-carboxylic acid ethyl esterHCID 86702355HCID 86702355, compound

Product 1

HCID 679736671-[5-((S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-pyrrolidin-2-yl)-pyridin-3-yl]-1H-indole-3-carboxylic acid ethyl esterYield 65%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-1H-indole-3-carboxylic acid ethyl ester (I-2A-2b: 0.25 g, 0.75 mmol) and (S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoic acid (0.26 g, 0.86 mmol, prepared from (S)-2-amino-3-methyl-butyric acid methyl ester and (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid via amide coupling followed ester hydrolysis) in THF (41 mL) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (0.25 g, 0.89 mmol). The mixture was warmed to room temperature, stirred for 3 hours, then quenched with water (20 mL) and concentrated under reduced pressure to remove THF. The remaining mixture was extracted with EtOAc (3×40 mL) and the organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography using 90-100% EtOAc/heptane to give the titled compound as a white solid (0.30 g, 65%).

Workup

  1. customquenched with water (20 mL)
  2. concentrationconcentrated under reduced pressure
  3. customto remove THF
  4. extractionThe remaining mixture was extracted with EtOAc (3×40 mL)
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationconcentrated under reduced pressure
  7. customto give an oil
  8. customThis oil was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-4957e3a7fdd346f787e68e79e4aa1746
Source dataset
uspto-grants-2015_03
Patent number
US08993523B2

Reaction notes

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