Hydrochloric Acid → (1-{2-[5-(2'-Cyano-4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3h-imidazol-4-yl}-biphenyl-4-yl)-1h-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 79808Notes

Reaction equation

HRID 79808 reaction equation
C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][C:25]=3[C:39]#[N:40])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.C(O[C:46]([N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[C:53]1[NH:54][C:55](Br)=[CH:56][N:57]=1)=[O:47])(C)(C)C.[C:59](=[O:62])([O-:61])[O-].[K+].[K+].[C:65](=O)(O)[O-].[Na+].Cl.[CH3:71][O:72][C:73]([NH:75][CH:76]([CH:80]([CH3:82])[CH3:81])C(O)=O)=[O:74].[CH3:83][N:84](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN([CH:113]([CH3:115])[CH3:114])C(C)C>COCCOC.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C.ClCCl>[CH3:71][O:72][C:73](=[O:74])[NH:75][CH:76]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:55]4[NH:54][C:53]([CH:49]5[CH2:50][CH2:51][CH2:52][N:48]5[C:46](=[O:47])[CH:83]([NH:84][C:59]([O:61][CH3:65])=[O:62])[CH:113]([CH3:114])[CH3:115])=[N:57][CH:56]=4)=[CH:26][C:25]=3[C:39]#[N:40])=[CH:22][CH:23]=2)=[CH:16][N:17]=1)=[O:5])[CH:80]([CH3:82])[CH3:81]

Participants

15

Reactant 8

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 516892Sodium Bicarbonate2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 138211012-((Methoxycarbonyl)amino)-3-methylbutanoic acidHCID 56605248tert-Butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 666211932-{5-[2'-Cyano-4'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 66620955(1-{2-[5-(2'-Cyano-4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3h-imidazol-4-yl}-biphenyl-4-yl)-1h-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterYield 37%

Reagents, catalysts & solvents 6

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

2-{5-[2′-Cyano-4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g, 2.96 mmol), 2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (935 mg, 2.96 mmol), Pd(PPh3)4 (171 mg, 0.148 mmol), Pd(dppf)Cl2 (121 mg, 0.148 mmol) and a 2 M aqueous solution of potassium carbonate (3 mL, 6 mmol) were suspended in 1,2-dimethoxyethane and degassed for 11 min. The stirred reaction mixture was heated to 85° C. for 100 min, then poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted 3 times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (5% to 10% MeOH/DCM) to afford the Suzuki coupled product (438 mg, 23%). This material (174 mg, 0.268 mmol) was treated with 4 M HCl in dioxane (4 mL). Solubility was poor so 2 mL dichloromethane and 4 mL DMF were added. After stirring for 40 min, the mixture was concentrated. The crude residue was treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (103 mg, 0.590 mmol), HATU (255 mg, 0.670 mmol) and DMF (5 mL) and cooled to 0° C. DIPEA (0.470 mL, 2.68 mmol) was added and the reaction mixture was stirred for 4 hours then poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted 3 times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was brought up in DMF and water and purified by reverse phase preparative HPLC, giving (1-{2-[5-(2′-Cyano-4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (75 mg, 37%). (MeOH-d4, 400 MHz) 8.19-7.35 (m, 11H), 5.18 (m, 2H), 4.24 (m, 2H), 4.03-4.86 (m, 4H), 3.65 (s, 6H), 2.37-2.00 (m, 10H), 1.00-0.90 (m, 12H); MS (ESI) m/z 764 [M+H]+.

Workup

  1. customdegassed for 11 min
  2. customThe stirred reaction mixture
  3. extractionextracted 3 times with ethyl acetate
  4. dry with materialThe combined organic layers were dried over magnesium sulfate
  5. concentrationconcentrated
  6. customThe crude residue was purified by silica column chromatography (5% to 10% MeOH/DCM)
  7. customto afford the Suzuki
  8. additionwere added
  9. concentrationthe mixture was concentrated
  10. temperaturecooled to 0° C
  11. stirringthe reaction mixture was stirred for 4 hours
  12. extractionextracted 3 times with ethyl acetate
  13. dry with materialThe combined organic layers were dried over magnesium sulfate
  14. concentrationconcentrated
  15. customwater and purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-e43de56c249c45ae82c03a22c06e65b2
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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