Ethyl Acetate → 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol

HRID 1809025Notes

Reaction equation

HRID 1809025 reaction equation
[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[CH2:38][CH:39]([C:41]1([OH:45])[CH2:44][NH:43][CH2:42]1)[OH:40].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:43]2[CH2:42][C:41]([CH:39]([OH:40])[CH2:38][CH:34]3[O:33][CH2:37][CH2:36][O:35]3)([OH:45])[CH2:44]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]

Participants

7

Reactant 4

HCID 8857Ethyl Acetate2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 220256632-(2-Fluoro-4-iodoanilino)-3,4-difluorobenzoic acidHCID 670517803-[2-(1,3-Dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol

Product 1

HCID 670518421-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-olYield 36%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent2×

Procedure

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (287 mg, 0.730 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (178 mg, 1.46 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 10 minutes and then 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol, 36% yield): MS (EI) for C21H20F3IN2O5: 565 (MH+).

Workup

  1. stirringthe mixture was stirred for 15 h
  2. customThe mixture was partitioned between ethyl acetate and 5% lithium chloride
  3. washThe organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine
  4. dry with materialwas dried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-9fcbf2740af447d48706b4fd78cd76a2
Source dataset
uspto-grants-2013_01
Patent number
US08362002B2

Reaction notes

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