Diisopropylethylamine → 2-[5-(4'-{2-[1-(5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 2039263Notes

Reaction equation

HRID 2039263 reaction equation
[F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([N:11]=[C:12]=[O:13])(OC)[C:6]([OH:8])=O.CN([C:19]([O:23]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:40]([O:44][C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][C:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[NH:70][C:71]([CH:74]5[CH2:78][CH2:77][CH2:76][NH:75]5)=[N:72][CH:73]=4)=[CH:65][CH:64]=3)=[CH:59][CH:58]=2)=[CH:55][N:56]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:40]([O:44][C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][C:54]([C:57]2[CH:58]=[CH:59][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[NH:70][C:71]([CH:74]5[CH2:78][CH2:77][CH2:76][N:75]5[C:6](=[O:8])[CH:5]([NH:11][C:12]([O:23][CH3:19])=[O:13])[CH2:4][CH2:3][C:2]([F:1])([F:14])[F:15])=[N:72][CH:73]=4)=[CH:65][CH:64]=3)=[CH:61][CH:62]=2)=[CH:55][N:56]=1)=[O:46])([CH3:43])([CH3:41])[CH3:42]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 666204412-{5-[4'-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 866488925,5,5-Trifluoro-2-methoxy-carbonylamino-pentanoic acid

Product 1

HCID 666209712-[5-(4'-{2-[1-(5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 59%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid methyl ester (194 mg, 0.80 mmol) in methanol (3 mL) was added an aqueous LiOH solution (1M, 2 mL, 2 mmol). The resulting solution was stirred at room temperature for 45 minutes and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give clean 5,5,5-Trifluoro-2-methoxy-carbonylamino-pentanoic acid. To a solution of the pentanoic acid in dimethylformamide (2 mL) was added HATU (300 mg, 0.79 mmol). After stirring for 5 minutes, a solution of 2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (412 mg, 0.79 mmol) in dimethylformamide (1.9 mL) was added to the reaction, followed immediately by diisopropylethylamine (275 μL, 1.58 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), concentrated and purified by flash chromatography to yield 2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (340 mg, 59%). LCMS-ESI+: calculated for C38H44F3N7O5: 735.34; observed [M+1]+: 736.05.

Workup

  1. stirringThe reaction was stirred for 1 hour at room temperature
  2. washThe organic layer was washed with water and brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. custompurified by flash chromatography

Sources & evidence

ORD record
ord-5deb0e74c66f4f56b22f53f65a624643
Source dataset
uspto-grants-2013_11
Patent number
US08575118B2

Reaction notes

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