Dimethylformamide → HCID 71549998, compound

HRID 1848022Notes

Reaction equation

HRID 1848022 reaction equation
Br[C:2]1[C:3]([O:29][CH3:30])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:27]=[CH:26][C:14]4[N:15]=[C:16]([NH:18][C@@H:19]5[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]5[OH:25])[S:17][C:13]=4[CH:12]=3)[C:6]=2[CH:28]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([CH2:10][N:7]3[C:6]4[CH:28]=[C:2]([C:31]#[N:32])[C:3]([O:29][CH3:30])=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH:27]=[CH:26][C:14]=2[N:15]=1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 86681040HCID 86681040, compound

Product 1

HCID 71549998HCID 71549998, compoundYield 41%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)Catalyst2×HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst2×HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×

Conditions

Temperature
110 °C

Procedure

To a suspension of (1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.1 mmol) from Step 5 of Example 47 in DMF (1.5 mL) was added zinc cyanide (24 mg, 0.2 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol). Argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 110° C. for 15 h. The mixture was cooled to rt and argon was again bubbled into the mixture for 5 min. Additional zinc cyanide (24 mg, 0.2 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) were added to the mixture, and the reaction vessel was resealed and heated for 5 h. The mixture was cooled to rt, filtered, and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-1H-benzo[d]imidazole-6-carbonitrile (18 mg, 41%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.12 (s, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.43 (s, 1H), 7.20-7.34 (m, 2H), 5.46 (s, 2H), 4.76 (d, J=4.9 Hz, 1H), 3.90 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57-1.67 (m, 2H), 1.15-1.34 (m, 4H). LCMS (ESI) m/z 434 (M+H)+.

Workup

  1. customArgon was bubbled into the mixture for 5 min
  2. customArgon was bubbled into the mixture for an additional 5 min
  3. customThe reaction vessel was sealed
  4. temperatureThe mixture was cooled to rt
  5. customargon was again bubbled into the mixture for 5 min
  6. temperatureheated for 5 h
  7. temperatureThe mixture was cooled to rt
  8. filtrationfiltered
  9. customthe filtrate was purified by reverse-phase preparative HPLC
  10. additiona mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase

Sources & evidence

ORD record
ord-b54527aa888d46519a6d2377e225f0dc
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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