1-Hydroxybenzotriazole → 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide

HRID 1062300Notes

Reaction equation

HRID 1062300 reaction equation
[Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([NH:39][O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32]([CH3:40])([CH3:31])[O:36]1)=[O:9]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 14814202(S)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamineHCID 222859232-(2-Chloro4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid

Product 1

HCID 865914595-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamideYield 90.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A 1L single necked round-bottomed flask equipped with a magnetic stirrer was charged with a solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid (59.6 g, 135 mmol) in dry tetrahydrofuran (300 mL). The solution was cooled to 0° C. in an ice-acetone bath. To this solution was added diisopropylethylamine (34.8 g, 270 mmol), (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (29.7 g, 202 mmol), 1-hydroxybenzotriazole (30.93 g, 202 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (89.32 g, 202 mmol). After 30 minutes, the cooling bath was removed, and the reaction was stirred at ambient temperature for 18 hrs. The solvent was evaporated in vacuo, and the residue was dissolved in diethyl ether. The organic solution was washed with 10% aqueous sodium hydroxide (3×500 mL) and brine, and dried (MgSO4). The solution was concentrated to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (69.9 g) as a pale yellow solid that was used directly in the next hydrolysis reaction.

Workup

  1. customthe cooling bath was removed
  2. customThe solvent was evaporated in vacuo
  3. dissolutionthe residue was dissolved in diethyl ether
  4. washThe organic solution was washed with 10% aqueous sodium hydroxide (3×500 mL) and brine
  5. dry with materialdried (MgSO4)
  6. concentrationThe solution was concentrated

Sources & evidence

ORD record
ord-ec743061356d43459a8991652495680b
Source dataset
uspto-grants-2005_11
Patent number
US06960614B2

Reaction notes

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