Water → HCID 22012207, compound

HRID 1377492Notes

Reaction equation

HRID 1377492 reaction equation
CS(O[CH2:6][CH:7]1[C:11]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8]1)(=O)=O.[C:17]([O:24][CH3:25])(=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].CC(C)([O-])C.[K+].O>CN1C(=O)CCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][CH:7]([CH2:6][CH:18]([C:17]([O:24][CH3:25])=[O:23])[C:19]([O:21][CH3:22])=[O:20])[C:11]=2[CH:12]=1

Participants

6

Reactant 4

HCID 962WaterHCID 7943Dimethyl malonateHCID 22012215HCID 22012215, compound2×HCID 23665647Potassium tert-butoxide

Product 1

HCID 22012207HCID 22012207, compoundYield 90.1%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent2×

Conditions

Temperature
60 °C

Procedure

The oil was dissolved in methanol (1.8 l) and magnesium turnings (7 g) was added. After the reaction had started additional magnesium (80 g) was added portionswise during 1.5 h keeping the reaction temperature at 30°-40° C. The reaction mixture was stirred for 1 h followed by addition of aq. ammonium chloride. Extraction with ether, drying the ether phase over sodium sulfate followed by removal of the solvent in vacuo, left a viscous oil, methyl 2,3-dihydro-5-fluorobenzofuran-3-carboxylate (120 g). The oil was dissolved in 500 ml of dry ether and added dropwise to a suspension of lithium aluminium hydride (32 g) in 600 ml of dry ether. The mixture was refluxed for 3 h followed by hydrolysis with water. Filtration and removal of solvent in vacuo gave 2,3-dihydro-5-fluoro-3-hydroxymethyl-benzofuran (95 g) which was converted to 155 g of 2,3-dihydro-5-fluorobenzofuran-3-ylmethyl methanesulfonate by the method described in EXAMPLE 2. Dimethyl malonate (262 g) was dissolved in NMP (2 l) and potassium tert-butoxide (202 g) was added portionwise keeping the temperature at 15°-20° C. The mixture was heated to 60° C. and a solution of 2,3-dihydro-5-fluorobenzofuran-3-ylmethyl methanesulfonate (155 g) in NMP (150 ml) was added dropwise. The mixture was stirred for 4 h at 70°-75° C. followed by addition of cold water. Extraction with ether, drying the ether phase over magnesium sulfate, followed by removal of solvent in vacuo gave dimethyl 2-(2,3-dihydro-5-fluorobenzofuran-3-ylmethyl)malonate (160 g) as an oil, which was sufficiently pure for the further synthesis. The oil was dissolved in 2 l of ethanol and a mixture of 120 g of solid potassium hydroxide and 200 ml of water was added followed by reflux for 2 h. The reaction mixture was concentrated in vacuo, water was added followed by extraction with ether. The water phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Drying of the organic phase over magnesium sulfate and removal of solvent in vacuo gave a viscous oil which was dissolved in NMP (1 l) and kept at 150° C. for 2 h. Addition of water and extraction with ether gave, after drying over magnesium sulfate and removal of solvent in vacuo, 77 g of 3-(2,3-dihydro-5-fluorobenzofuran-3-yl)-propionic acid. Reduction with lithium aluminium hydride by the method described above yielded 51 g of 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propanol which was converted to 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propyl methanesulfonate by the method described in EXAMPLE 2. The title compound, 11a, was prepared from 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propyl methanesulfonate (4.2 g) and 4-(4-fluorophenyl)piperidine (5.5 g) by the method described in EXAMPLE 2. Yield: 1.8 g, mp: 83°-85° C.

Workup

  1. customat 15°-20° C
  2. extractionExtraction with ether
  3. dry with materialdrying the ether phase over magnesium sulfate
  4. customfollowed by removal of solvent in vacuo

Sources & evidence

ORD record
ord-7c8218c5125c455ab2025b3dcf990eac
Source dataset
uspto-grants-1997_09
Patent number
US05665725

Reaction notes

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