Nitrogen → (5-{2-[(2',3',4'-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester

HRID 383588

Reaction equation

HRID 383588 reaction equation
N#N.[CH3:3][O:4][C:5](=[O:39])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[C:29]([O:35]C)[C:28]=3[O:37]C)[CH:24]=[CH:25][CH:26]=2)=[O:20])=[CH:10][CH:11]=1.B(Br)(Br)Br.O>C(Cl)Cl.CO>[OH:37][C:28]1[C:29]([OH:35])=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]2[S:8][C:7]([CH2:6][C:5]([OH:39])=[O:4])=[CH:11][CH:10]=2)=[O:20])[CH:22]=1.[CH3:3][O:4][C:5](=[O:39])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:35])[C:28]=3[OH:37])[CH:24]=[CH:25][CH:26]=2)=[O:20])=[CH:10][CH:11]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 962WaterHCID 25134Boron tribromideHCID 16116291(5-{2-[(2',3',4'-Trimethoxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester

Product 2

HCID 16116557(5-{2-[(2',3',4'-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acidYield 13%HCID 59819857(5-{2-[(2',3',4'-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl esterYield 23%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
-78 °C

Procedure

(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve (5-{2-[(2′,3′,4′-Trimethoxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (47) (66 mg, 0.13 mmol) in anhydrous DCM (3.4 mL) at −78° C., add dropwise a 1M solution of BBr3 in DCM (1.05 mL, 1.05 mmol) and stir for additional 30 min at −78° C. After slowly warming up stir the reaction solution for additional 4 h at rt. Cool reaction mixture to 0° C., add dropwise water and DCM under vigorous stirring followed by MeOH to homogenize the mixture. Partition the hydrolized reaction mixture between water and EtOAc, extract the aqu. layer with EtOAc (3×), wash combined organic layer with brine and dry it with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain (5-{2-[(2′,3′,4′-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid (48) (8 mg, 13%) as a white solid and (5-{2-[(2′,3′,4′-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (49) (14 mg, 23%) as a brown foam. 1H NMR (400 MHz, CD3OD) (48): 3.86 (s, 2H); 6.49 (d, 1H, J=8.6 Hz); 6.74 (d, 1H, J=8.6 Hz); 6.98 (d, 1H, J=3.0 Hz); 7.19 (d, 1H, J=3.3 Hz); 7.36 (t, 1H, J=7.6 Hz); 7.43 (t, 1H, J=7.6 Hz); 7.51 (t, 1H, J=7.8 Hz); 7.62 (d, 1H, J=7.8 Hz); 7.71-7.84 (m, 3 Hz); 8.08 (br.s 1H); (49): 3.66 (s, 3H); 3.88 (s, 2H); 6.49 (d, 1H, J=8.3 Hz); 6.74 (d, 1H, J=8.3 Hz); 6.97 (d, 1H, J=3.5 Hz); 7.19 (d, 1H, J=3.5 Hz); 7.36 (td, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.43 (td, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.51 (t, 1H, J=7.8 Hz); 7.62 (dd, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.73 (d, 1H, J=7.8 Hz); 7.81 (Ψdd, 2H, J1=7.6 Hz, J2=1.5 Hz); 8.09 (br.s 1H).

Workup

  1. custom(The following reaction
  2. temperatureAfter slowly warming up
  3. stirringstir the reaction solution for additional 4 h at rt
  4. temperatureCool
  5. customreaction mixture to 0° C.
  6. stirringunder vigorous stirring
  7. stirringto homogenize the mixture
  8. customPartition the hydrolized reaction mixture between water and EtOAc
  9. extractionextract the aqu
  10. washlayer with EtOAc (3×), wash
  11. dry with materialdry it with Na2SO4
  12. customPurify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95)

Sources & evidence

ORD record
ord-b1dcd94e1a9b4dad96fcc41a2befa78e
Source dataset
uspto-grants-2013_02
Patent number
US08367677B2

Linked notes

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