Boron trifluoride etherate → (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester

HRID 1266700Notes

Reaction equation

HRID 1266700 reaction equation
[CH2:1]([O:3][C:4]1[C:5]([O:13][CH2:14][CH2:15][OH:16])=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=O)[CH3:2].[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[O:26]1[CH2:31]CN(CC[N+]#[C-])[CH2:28][CH2:27]1.B(F)(F)F.CC[O:42]CC>C(O)C.O>[CH2:27]([O:26][C:31](=[O:42])[CH:9]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:8]1[CH:11]=[C:4]([O:3][CH2:1][CH3:2])[C:5]([O:13][CH2:14][CH2:15][OH:16])=[CH:6][C:7]=1[F:12])[CH3:28]

Participants

7

Reactant 4

HCID 8000Boron trifluoride etherateHCID 133964-AminobenzonitrileHCID 27594344-(2-Isocyanoethyl)morpholineHCID 219055785-Ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-benzaldehyde

Product 1

HCID 70001799(RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Procedure

The 5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-benzaldehyde (10.34 g) described in example 1.4 was dissolved in ethanol (160 ml). 4-Aminobenzonitrile (4.87 g) was added and stirred at room temperature. After 1 hour, 5.68 ml of morpholinoethyl isonitrile was added. The solution obtained was cooled to 0° C., then treated dropwise with 15.53 ml of boron trifluoride etherate in a manner such that the temperature did not exceed 5° C. The reaction mixture was stirred at 0° C. for 15 min and at room temperature for 1.5 h. Water (20 ml) was added and stirred overnight at room temperature. The crude product was isolated by extraction and purified by chromatography on silica gel and yielded 11.13 g of (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester as a yellowish solid. MS: 425 ([M+Na]+).

Workup

  1. customThe solution obtained
  2. temperaturewas cooled to 0° C.
  3. customdid not exceed 5° C
  4. stirringThe reaction mixture was stirred at 0° C. for 15 min and at room temperature for 1.5 h
  5. stirringstirred overnight at room temperature
  6. customThe crude product was isolated by extraction
  7. custompurified by chromatography on silica gel

Sources & evidence

ORD record
ord-d35fbc7eabb54d28b7ce4080eb5de13d
Source dataset
uspto-grants-2003_04
Patent number
US06548694B2

Reaction notes

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