Hydrogen Bromide → 2-(2,6-Difluorophenyl)-1-[(2,6-difluorophenyl)methyl]benzimidazol-4-amine

HRID 2182079

Reaction equation

HRID 2182079 reaction equation
FC1C=CC=C(F)C=1CN1C2C=CC=CC=2N=C1C1C(F)=CC=CC=1F.FC1C=CC=C(F)C=1C(Cl)=O.Cl[Sn]Cl.Cl.CC(OC(C)=O)=O.[BH4-].[Na+].OS(O)(=O)=O.N([O-])=O.[Na+].Br.[F:61][C:62]1[CH:88]=[CH:87][CH:86]=[C:85]([F:89])[C:63]=1[CH2:64][N:65]1[C:69]2[CH:70]=[CH:71][CH:72]=[C:73]([N+:74]([O-])=O)[C:68]=2[N:67]=[C:66]1[C:77]1[C:82]([F:83])=[CH:81][CH:80]=[CH:79][C:78]=1[F:84]>C1COCC1.CC(O)=O>[NH2:74][C:73]1[C:68]2[N:67]=[C:66]([C:77]3[C:82]([F:83])=[CH:81][CH:80]=[CH:79][C:78]=3[F:84])[N:65]([CH2:64][C:63]3[C:62]([F:61])=[CH:88][CH:87]=[CH:86][C:85]=3[F:89])[C:69]=2[CH:70]=[CH:71][CH:72]=1

Participants

13

Reactant 10

HCID 260Hydrogen BromideHCID 313Hydrochloric Acid2×HCID 1118Sulfuric AcidHCID 7918Acetic AnhydrideHCID 24479Stannous Chloride2×HCID 874382,6-Difluorobenzoyl chlorideHCID 4688471H-Benzimidazole, 2-(2,6-difluorophenyl)-1-((2,6-difluorophenyl)methyl)-HCID 4926701-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazoleHCID 4311764Sodium borohydrideHCID 23668193Sodium Nitrite

Product 1

HCID 4926752-(2,6-Difluorophenyl)-1-[(2,6-difluorophenyl)methyl]benzimidazol-4-amine

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

FIG. 9 provides a schematic approach for the preparation of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole substituted with chloro, bromo, nitro, amino, acetylamino, dimethylamino groups at the C-4 position of the benzimidazole ring. In this Figure, “a” comprises 2,6-difluorobenzoyl chloride, pyridine: TBF (1:1); “b” comprises AcOH reflux; “c” comprises 2,6-F2-BnBr, NaH,THF; “d” comprises SnCl2, AcOH, HCl; “e” comprises Ac2O, THF; “f” comprises H2CO, NaBH4, H2SO4; and “g” comprises NaNO2, HBr or HCl. As shown in this Figure, reduction of the 4-nitro group of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (Example 83) was accomplished with tin (II) chloride, which gives 4-amino-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole 3300 (Example 85). Compound 3300 was used to prepare 4-bromo-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 86) and 4-chloro-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 87) via the Sandmeyer reactions (i.e., methods known in the art). Monoacylation of compound 3300 with acetic anhydride gave 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88), while treatment of 3300 with formaldehyde and sodium borohydride yielded the dimethylamino compound 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-N,N-dimethylaminobenzimidazole (Example 89).

Workup

  1. customFIG. 9 provides a schematic approach
  2. temperaturereflux

Sources & evidence

ORD record
ord-219cbc99e40c40f880e708c3a61d2e70
Source dataset
uspto-grants-2005_05
Patent number
US06894068B2

Linked notes

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