Benzenesulfonyl chloride → {1-[1'-Benzenesulfonyl-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 417514Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:37])[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]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(=O)NC(C(N1C(C2NC=C(C3C=CC(Br)=CC=3)N=2)CN(C(=O)C)C1)=O)C(C)C.C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:79][O:80][C:81](=[O:114])[NH:82][CH:83]([C:87]([N:89]1[CH2:93][CH2:92][CH2:91][CH:90]1[C:94]1[NH:95][CH:96]=[C:97]([C:99]2[CH:104]=[CH:103][C:102](B3OC(C)(C)C(C)(C)O3)=[CH:101][CH:100]=2)[N:98]=1)=[O:88])[CH:84]([CH3:86])[CH3:85].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:37])[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:102]4[CH:103]=[CH:104][C:99]([C:97]5[NH:98][C:94]([CH:90]6[CH2:91][CH2:92][CH2:93][N:89]6[C:87](=[O:88])[CH:83]([NH:82][C:81]([O:80][CH3:79])=[O:114])[CH:84]([CH3:86])[CH3:85])=[N:95][CH:96]=5)=[CH:100][CH:101]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]

Participants

Conditions

Temperature: 120 °C

Procedure

{1-[1′-Benzenesulfonyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (63.1 mg, 106.9 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]-2-methyl-propyl}-carbamic acid methyl ester (Example BY)]substituting the acetic anhydride with phenyl 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 (53.1 mg, 106.9 mmol) under an argon atmosphere. Potassium carbonate (29.2 mg, 0.212 mmol) and Pd(PPh3)4 (12.2 mg, 0.0106 mmol) were added, followed by DME (2.5 mL) and water (0.8 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′-Benzenesulfonyl-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 (27.9 mg): LCMS-ESI+: calc'd for C45H53N9O8S: 880.2 (M+). Found: 881.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 8.01 (d, J=7.5 Hz, 2H), 7.90-7.76 (m, 11H), 7.65 (t, J=7.8 Hz, 2H), 5.59 (d, J=8.7 Hz, 1H), 5.25 (dd, J=7.5, 7.5 Hz, 1H), 5.19 (d, J=8.7 Hz, 1H), 4.67 (dd, J=7.5, 7.5 Hz, 1H), 4.32-4.22 (m, 2H), 4.08 (m, 2H), 3.85 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.44 (d, J=6.6 Hz, 1H), 2.57 (m, 1H), 2.29-1.99 (m, 5H), 0.99-0.86 (m, 12H).

Workup

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

Sources & evidence

ORD record: ord-92123fcfd92e40028d6196be97b1c334
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08088368B2

Reaction notes

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