Diisopropylethylamine → 3-{[Butyl(methyl)amino]methyl}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methylbenzamide Dihydrochloride

HRID 14117

Reaction equation

HRID 14117 reaction equation
[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:55].Cl.[NH2:57][C@@H:58]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:59]([OH:72])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH:69]([CH3:71])[CH3:70])[CH:64]=1>C(OCC)(=O)C.O1CCCC1.CO.O>[ClH:55].[ClH:55].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([NH:57][C@@H:58]([CH2:73][C:74]1[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=1)[C@H:59]([OH:72])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH:69]([CH3:71])[CH3:70])[CH:64]=1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21086167Methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoateHCID 57487288HCID 57487288, compound

Product 1

HCID 686069563-{[Butyl(methyl)amino]methyl}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methylbenzamide Dihydrochloride

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Procedure

Analogous to the method in Example SP-188, methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (50 mg, 0.2 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (17 mg, 0.4 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (2 mL), and diisopropylethylamine (140 μL, 0.8 mmol), HATU (95 mg, 0.25 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in Example SP-170, Step 4 (85 mg, 0.2 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 566.3 [M+H]+.

Workup

  1. additionis added (17 mg, 0.4 mmol)
  2. concentrationThe solution is concentrated under reduced pressure
  3. dissolutionThe residue is redissolved in DMF (2 mL)
  4. additionare added
  5. stirringThe reaction stirred at room temperature 16 h
  6. washwashed with water, saturated sodium bicarbonate, brine
  7. dry with materialdried (sodium sulfate)
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customPurification by flash column chromatography (silica, 8% methanol/methylene chloride)

Sources & evidence

ORD record
ord-12c8a870b46746faa4b8ef4b154461f2
Source dataset
uspto-grants-2010_06
Patent number
US07727997B2

Linked notes

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