Diisopropylethylamine → (1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 72034Notes

Reaction equation

HRID 72034 reaction equation
[CH3:1][O:2][C:3]([NH:5][C:6](=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][NH:85]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][N:85]6[C:7](=[O:9])[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[C:10]6[CH2:15][CH2:14][O:13][CH2:12][CH2:11]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49]

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 59611013Methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acidHCID 66620476{2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride

Product 1

HCID 66620834(1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl esterYield 50%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours 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 methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield {1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%). LCMS-ESI+: calculated for C46H52N8O7: 828.95; observed [M+1]+: 830.32. 1H-NMR: 400 MHz, (CD3OD) δ: 8.24-8.07 (m, 3H), 7.96-7.76 (m, 7H), 7.45-7.34 (m, 2H), 5.28-5.18 (m, 2H), 4.27-4.23 (m, 1H), 4.05-3.98 (m, 1H), 3.94-3.86 (m, 1H), 3.84-3.41 (m, 12H), 2.48-1.98 (m, 13H), 1.02-0.90 (m, 6H) ppm.

Workup

  1. stirringThe reaction was stirred for 1 hour at room temperature
  2. washThe organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. custompurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record
ord-0a709b812adb4f7e911e71ecf2faa04a
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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