2-Fluoroaniline → {4-[3-(2-Fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonic acid diisopropyl ester

HRID 1431033Notes

Reaction equation

HRID 1431033 reaction equation
[CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=2)[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[F:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH:38][C:19]([C:18]1[CH:17]=[C:16]([CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:22]=1)[O:15][C:14]1[CH:13]=[CH:12][C:11]([P:5](=[O:4])([OH:7])[OH:6])=[CH:30][CH:29]=1)=[O:20].[CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:24]=[C:23]([O:25][CH:26]([CH3:27])[CH3:28])[CH:22]=[C:18]([C:19](=[O:21])[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[F:35])[CH:17]=2)=[CH:13][CH:12]=1)(=[O:6])[O:7][CH:8]([CH3:10])[CH3:9])([CH3:2])[CH3:3]

Participants

9

Reactant 4

HCID 95842-FluoroanilineHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 585289143-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid

Product 2

HCID 58528947{4-[3-(2-Fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonic acidHCID 86659571{4-[3-(2-Fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonic acid diisopropyl esterYield 110.2%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (prepared as in Example 3 Step E) (530 mg, 1.2 mmol) in toluene (10 mL) was added thionyl chloride (0.22 mL, 3.0 mmol). The reaction was heated to 110° C. for 1 h and allowed to cool to room temperature. The solvents were removed by rotary evaporation, and the crude product was re-dissolved in toluene and treated with 2-fluoroaniline (0.11 mL, 1.2 mmol), diisopropylethylamine (0.6 mL, 3.6 mmol), and catalytic DMAP. The reaction was then heated to 110° C. for 1 hour, at which point TLC analysis indicated that the reaction was complete. The reaction was cooled to room temperature and preloaded on silica. The desired product, {4-[3-(2-fluoro-phenylcarbamoyl)-5-isopropoxy-phenoxy]-phenyl}-phosphonic acid diisopropyl ester, (350 mg, 54%) was obtained after chromatography on silica gel eluting with ethyl acetate in hexanes. LC-MS m/z=530 [C28H33FNO6P+H]+.

Workup

  1. temperatureto cool to room temperature
  2. customThe solvents were removed by rotary evaporation
  3. dissolutionthe crude product was re-dissolved in toluene
  4. temperatureThe reaction was then heated to 110° C. for 1 hour, at which point TLC analysis
  5. temperatureThe reaction was cooled to room temperature

Sources & evidence

ORD record
ord-e8450b7008cb4518b1d2ba966723b61e
Source dataset
uspto-grants-2015_01
Patent number
US08940927B2

Reaction notes

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