Triphenylphosphine → 1-(3-methoxypropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide

HRID 1184164Notes

Reaction equation

HRID 1184164 reaction equation
[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[O:11].[CH3:38][O:39][CH2:40][CH2:41][CH2:42]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:38][O:39][CH2:40][CH2:41][CH2:42][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][NH:15][CH2:14]1)=[O:11]

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 741163-Methoxy-1-propanolHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 58355717tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino)-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Product 1

HCID 583551451-(3-methoxypropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamideYield 27.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

tert-Butyl (3S, 5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (700 mg), 3-methoxypropan-1-ol (123 mg) and triphenylphosphine (465 mg) were dissolved in THF (20 ml), diisopropyl azodicarboxylate (40% toluene solution: 896 mg) was added, and the mixture was stirred at room temperature for 60 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was saturated aqueous sodium hydrogen carbonate and saturated washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:3) was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (3 ml), 4M hydrogen chloride-ethyl acetate (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) and ethyl acetate-methanol (93:7) was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (10 ml), sulfuric acid (42 mg) was added, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-methanol to give the object product (180 mg) as crystals.

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washsaturated washed with brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customThe solvent was evaporated under reduced pressure
  5. washa fraction eluted with ethyl acetate-hexane (1:9-1:3)
  6. concentrationwas concentrated under reduced pressure
  7. dissolutionThe obtained substance was dissolved in ethyl acetate (3 ml)
  8. addition4M hydrogen chloride-ethyl acetate (3 ml) was added
  9. stirringthe mixture was stirred at room temperature for 15 hr
  10. extractionextracted with ethyl acetate
  11. dry with materialThe extract was dried over anhydrous sodium sulfate
  12. customThe solvent was evaporated under reduced pressure
  13. washa fraction eluted with ethyl acetate-hexane (1:9-1:0) and ethyl acetate-methanol (93:7)
  14. concentrationwas concentrated under reduced pressure
  15. dissolutionThe obtained substance was dissolved in ethyl acetate (10 ml)
  16. additionsulfuric acid (42 mg) was added
  17. customthe solvent was evaporated under reduced pressure
  18. dissolutionThe residue was dissolved in ethanol (10 ml)
  19. customthe solvent was evaporated under reduced pressure
  20. customThe residue was crystallized from ethyl acetate-methanol

Sources & evidence

ORD record
ord-b48ce2f69c814474afb6189b9e961810
Source dataset
uspto-grants-2014_03
Patent number
US08664380B2

Reaction notes

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