Acetic Anhydride → {1-[1'-Methanesulfonyl-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 79762Notes

Reaction equation

HRID 79762 reaction equation
[CH3:1][O:2][C:3](=[O:32])[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]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC(=O)C)(=O)C.CS(Cl)(=O)=O.[CH3:45][O:46][C:47](=[O:80])[NH:48][CH:49]([C:53]([N:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[C:60]1[NH:61][CH:62]=[C:63]([C:65]2[CH:70]=[CH:69][C:68](B3OC(C)(C)C(C)(C)O3)=[CH:67][CH:66]=2)[N:64]=1)=[O:54])[CH:50]([CH3:52])[CH3:51].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:1][O:2][C:3](=[O:32])[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:68]4[CH:69]=[CH:70][C:65]([C:63]5[NH:64][C:60]([CH:56]6[CH2:57][CH2:58][CH2:59][N:55]6[C:53](=[O:54])[CH:49]([NH:48][C:47]([O:46][CH3:45])=[O:80])[CH:50]([CH3:52])[CH3:51])=[N:61][CH:62]=5)=[CH:66][CH:67]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]

Participants

9

Reactant 5

HCID 7918Acetic AnhydrideHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 178502159HCID 178502159, compoundHCID 178502208HCID 178502208, compound

Product 1

HCID 66620599{1-[1'-Methanesulfonyl-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 22.3%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
120 °C

Procedure

{1-[4-(4-Bromo-phenyl)-1′-methanesulfonyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62.9 mg, 0.119 mmol) [prepared as described for the synthesis of {1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl (Example BY)]-2-methyl-propyl}-carbamic acid methyl ester substituting the acetic anhydride with methyl sulfonyl chloride] 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 (54.6 mg, 0.110 mmol) under an argon atmosphere. Potassium carbonate (33.1 mg, 0.240 mmol) and Pd(PPh3)4 (12.7 mg, 0.011 mmol) were added, followed by DME (2.0 mL) and water (0.4 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 (20.1 mg): LCMS-ESI+: calc'd for C40H51N9O8S: 817.9 (M+). Found: 818.6 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.81 (m, 10H), 5.69 (d, J=7.5 Hz, 1H), 5.48 (dd, J=6.9, 6.9 Hz, 1H), 5.27 (dd, J=8.1, 8.1 Hz, 1H), 5.17 (d, J=8.4 Hz, 1H), 4.41 (dd, J=12.0, 7.8 Hz, 1H), 4.24 (d, J=7.2 Hz, 1H), 4.11 (m, 2H), 4.00 (d, J=8.1 Hz, 1H), 3.87 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.17 (s, 3H), 2.57 (m, 1H), 2.29-1.99 (m, 5H), 1.03-0.89 (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-042e06ac2e434eb192c8e692bd0c2104
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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