1-Hydroxybenzotriazole → HCID 58972249, compound

HRID 20383Notes

Reaction equation

HRID 20383 reaction equation
[CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5](/[CH:7]=[C:8](\[CH3:12])/[C:9]([OH:11])=O)=[O:6])[CH2:2][CH3:3].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:38]([O:42][C:43]([N:45]1[C@@H:50]([C@@H:51]([OH:63])[C@@H:52]([NH2:62])[CH2:53][C:54]2[CH:59]=[C:58]([F:60])[CH:57]=[C:56]([F:61])[CH:55]=2)[CH2:49][O:48][C@@H:47]([CH2:64][O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:38]([O:42][C:43]([N:45]1[C@@H:50]([C@@H:51]([OH:63])[C@@H:52]([NH:62][C:9](=[O:11])/[C:8](/[CH3:12])=[CH:7]/[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[CH2:13][CH2:14][CH3:15])[CH2:53][C:54]2[CH:59]=[C:58]([F:60])[CH:57]=[C:56]([F:61])[CH:55]=2)[CH2:49][O:48][C@@H:47]([CH2:64][O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68557956(2R,5R)-5-[(1S,2S)-2-Amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-cyclohexyloxymethylmorpholine-4-carboxylic acid tert-butyl esterHCID 86615362(E)-3-dipropylcarbamoyl-2-methylacrylic acid

Product 1

HCID 58972249HCID 58972249, compoundYield 45.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Dissolve (E)-3-dipropylcarbamoyl-2-methylacrylic acid (0.029 g, 0.134 mmol) in dichloromethane (1.3 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.028 g, 0.148 mmol) then 1-hydroxybenzotriazole (HOBT) (0.023 g, 0.148 mmol). Stir at room temperature for 30 minutes. To this stirring solution add (2R,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-cyclohexyloxymethylmorpholine-4-carboxylic acid tert-butyl ester (0.065 g, 0.134 mmol) in dichloromethane (1.5 mL). Stir for 2.5 hours, quench with 10% aqueous potassium carbonate (20 mL), and dilute with dichloromethane (75 mL). Extract the organic layer, wash with 5% aqueous citric acid (25 mL), saturated aqueous sodium chloride (30 mL), dry (magnesium sulfate) and purify (silica gel chromatography, eluting with 30:70 to 70:30 ethyl acetate:hexanes) to give the title compound as a white foam (0.041 g, 45.2%).

Workup

  1. stirringStir for 2.5 hours
  2. customquench with 10% aqueous potassium carbonate (20 mL)
  3. additiondilute with dichloromethane (75 mL)
  4. extractionExtract the organic layer
  5. washwash with 5% aqueous citric acid (25 mL), saturated aqueous sodium chloride (30 mL)
  6. dry with materialdry (magnesium sulfate)
  7. custompurify
  8. wash(silica gel chromatography, eluting with 30:70 to 70:30 ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-fc477d80da624dcba419d8c1cdbf27e3
Source dataset
uspto-grants-2010_06
Patent number
US07745438B2

Reaction notes

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