1,2-Dimethoxyethane → {1-[1'-Acetyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1',2',4',5'-tetrahydro-1H-[2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 2039052Notes

Reaction equation

HRID 2039052 reaction equation
[CH3:1][O:2][C:3](=[O:31])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28](=[O:30])[CH3:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:32][O:33][C:34](=[O:67])[NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][CH:49]=[C:50]([C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[CH:54][CH:53]=2)[N:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:1][O:2][C:3](=[O:31])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:55]4[CH:56]=[CH:57][C:52]([C:50]5[NH:51][C:47]([CH:43]6[CH2:44][CH2:45][CH2:46][N:42]6[C:40](=[O:41])[CH:36]([NH:35][C:34]([O:33][CH3:32])=[O:67])[CH:37]([CH3:39])[CH3:38])=[N:48][CH:49]=5)=[CH:53][CH:54]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28](=[O:30])[CH3:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 178502159HCID 178502159, compoundHCID 178502205HCID 178502205, compound

Product 1

HCID 66620952{1-[1'-Acetyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1',2',4',5'-tetrahydro-1H-[2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl esterYield 29.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

{1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (150 mg, 0.304 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]carbamic acid methyl ester (151 mg, 0.304 mmol) under an argon atmosphere. Potassium carbonate (83.9 mg, 0.608 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol) were added, followed by DME (8 mL) and water (2 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[1′-Acetyl-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (69.8 mg): LCMS-ESI+: calc'd for C41H51N9O7: 781.9 (M+); Found: 782.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.82 (m, 10H), 5.68 (m, 1H), 5.59-5.37 (m, 2H), 5.25 (m, 1H), 4.34 (m, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.11-4.02 (m, 2H), 3.88 (m, 1H), 3.66 (s, 6H), 3.47 (d, J=7.2 Hz, 1H), 2.60 (m, 1H), 2.29-2.10 (m, 8H), 1.05-0.89 (m, 12H).

Workup

  1. customAll volatiles were removed in vacuo
  2. dissolutionthe crude material was dissolved in DMF
  3. custompurified via RP-HPLC (eluent: water/MeCN w 0.1% TFA)

Sources & evidence

ORD record
ord-cdbffa5a6e364a1baf7a1e18a9d2b6f7
Source dataset
uspto-grants-2013_11
Patent number
US08575118B2

Reaction notes

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