Hydrochloric Acid → N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(methylsulfonyl)methyl]piperidine-1-carboxamide

HRID 14309

Reaction equation

HRID 14309 reaction equation
ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[CH3:22][S:23]([CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35]C(C)(C)C)=O)[CH2:29][CH2:28]1)(=[O:25])=[O:24].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:54][C@@H:55]([CH2:69][C:70]1[CH:75]=[C:74]([F:76])[CH:73]=[C:72]([F:77])[CH:71]=1)[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH3:67])[CH:61]=1.Cl>C(Cl)Cl.CO.C(OCC)C>[F:76][C:74]1[CH:75]=[C:70]([CH:71]=[C:72]([F:77])[CH:73]=1)[CH2:69][C@H:55]([NH:54][C:33]([N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:32][CH2:31]1)=[O:35])[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH3:67])[CH:61]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 149026Tetrafluoro-m-phenylenediamine dihydrochlorideHCID 21087275Tert-butyl 4-((methylsulfonyl)methyl)piperidine-1-carboxylateHCID 57487282(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol

Product 1

HCID 68607620N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(methylsulfonyl)methyl]piperidine-1-carboxamideYield 7.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent3×

Procedure

To an ice-cold, stirred solution of triphosgene (108 mg, 0.36 mmol) and diisopropylethylamine (0.6 mL, 3.3 mmol) in methylene chloride (2.0 mL) was added amino sulfone from step 4 (210 mg, 0.98 mmol) in methylene chloride (3.5 mL) dropwise. After 5 min a solution of dihydrochloride of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (401 mg, 0.98 mmol) was added and the reaction mixture was warmed until the solution became homogeneous. The reaction mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), and saturated sodium chloride, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15:85 methanol/chloroform) provided a clear solid. The solid was dissolved in methanol (1 mL), and treated with hydrochloric acid (0.3 mL of a 1.0 M solution in diethyl ether, 0.3 mmol). The resulting precipitate was collected by filtration to provide the title compound (38 mg): mp 130-134° C.; APCI MS m/z 538 [M+H]+.

Workup

  1. temperaturethe reaction mixture was warmed until the solution
  2. washwashed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), and saturated sodium chloride
  3. dry with materialdried (magnesium sulfate)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customPurification by flash column chromatography (silica, 15:85 methanol/chloroform)
  7. customprovided a clear solid
  8. filtrationThe resulting precipitate was collected by filtration

Sources & evidence

ORD record
ord-23abda02078c49c7a833d7427136e1af
Source dataset
uspto-grants-2010_06
Patent number
US07727997B2

Linked notes

Loading…