Hydrochloric Acid → {2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester

HRID 1751444Notes

Reaction equation

HRID 1751444 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:59][O:60][C:61]([NH:63][CH:64]([CH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1)[C:65]([OH:67])=O)=[O:62].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.C1COCC1.[Li+].[OH-]>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:45]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:22]=[CH:21][C:20]4[C:25](=[CH:26][CH:27]=[C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:65](=[O:67])[CH:64]([NH:63][C:61]([O:60][CH3:59])=[O:62])[CH:68]6[CH2:73][CH2:72][O:71][CH2:70][CH2:69]6)=[N:17][CH:16]=5)[CH:19]=4)[CH:24]=3)=[CH:29][CH:30]=2)=[CH:38][N:37]=1)=[O:57]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 585162412-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidHCID 696730252-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 69672814{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl esterYield 37%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 3939Lithium HydroxideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.26 mmol) in CH2Cl2 (2.5 mL) and MeOH (0.1 mL) was added HCl (in dioxanes, 4 M, 0.7 mL, 2.80 mmol). The solution was stirred at room temperature for 3 h and concentrated to dryness. The resulting solid was slurried in CH2Cl2 (4 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.12 g, 0.54 mmol), HATU (0.12 g, 0.33 mmol), and DIPEA (0.2 mL, 1.15 mmol) were added. The resulting solution was stirred at room temperature for 1 h. The solution was diluted with THF and LiOH (2.5 M, 0.1 mL) was added. The solution was concentrated to dryness and the crude oil was diluted with DMF and purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide {2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (0.083 g, 37%). LCMS-ESI+: calc'd for C49H52N8O7: 864.40 (M+); Found: 866.01 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. stirringThe resulting solution was stirred at room temperature for 1 h
  3. additionwas added
  4. concentrationThe solution was concentrated to dryness
  5. additionthe crude oil was diluted with DMF
  6. custompurified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid))

Sources & evidence

ORD record
ord-1cba050c9ceb432a8b695189b03e1d8f
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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