Hydrochloric Acid → HCID 67051798, compound

HRID 1808982Notes

Reaction equation

HRID 1808982 reaction equation
[OH:1][C:2]1([CH:13]([N+:17]([O-:19])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH2:5][N:4]([C:6]([O:8]C(C)(C)C)=O)[CH2:3]1.Cl.[F:21][C:22]1[C:23]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])C(O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C.CO>[F:21][C:22]1[C:23]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:24]([C:6]([N:4]2[CH2:3][C:2]([CH:13]([N+:17]([O-:19])=[O:18])[CH:14]([CH3:15])[CH3:16])([OH:1])[CH2:5]2)=[O:8])[CH:28]=[CH:29][C:30]=1[F:31]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 220256632-(2-Fluoro-4-iodoanilino)-3,4-difluorobenzoic acidHCID 67051626HCID 67051626, compound

Product 1

HCID 67051798HCID 67051798, compoundYield 90.5%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

1,1-Dimethylethyl 3-hydroxy-3-(2-methyl-1-nitropropyl)azetidine-1-carboxylate (105 mg, 0.38 mmol) was taken into methanol (1 mL) followed by addition of 4 N anhydrous hydrogen chloride in dioxane (1 mL) and the acidic solution was allowed to stand for 15 minutes at room temperature then concentrated and dried in vacuo to an amorphous residue. 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (150 mg, 0.38 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, was taken into DMF (0.7 mL) followed by addition of PyBOP (198 mg, 0.38 mmol) and the solution was allowed to stir for minutes at room temperature. The above amine hydrochloride salt and DIPEA (190 μL, 1.1 mmol) in DMF solution (0.7 mL) was added and the mixture was allowed to stir for one hour at room temperature. The mixture was partitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid and the organic phase washed three times with water then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using 1.5:1 hexanes:ethyl acetate as eluent to give 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 90% yield) as an amorphous solid. 1H-NMR (400 MHz, CDCl3): 8.41 (br s, 1H), 7.41 (dd, 1H), 7.34 (d, 1H), 7.09 (br m, 1H), 6.81 (q, 1H), 6.65-6.60 (m, 1H), 4.49 (d, 1H), 4.15-4.09 (m, 4H), 3.66 (s, 1H), 2.56-2.46 (m, 1H) 1.03 (d, 6H).

Workup

  1. concentrationthen concentrated
  2. customdried in vacuo to an amorphous residue
  3. stirringto stir for one hour at room temperature
  4. customThe mixture was partitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid
  5. washthe organic phase washed three times with water
  6. dry with materialbrine and dried over anhydrous magnesium sulfate
  7. filtrationFiltration and concentration
  8. customafforded a residue that
  9. customwas further purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-a32892ee243745de8b3652106c2c30ba
Source dataset
uspto-grants-2013_01
Patent number
US08362002B2

Reaction notes

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