(R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide → (R)-8-fluorochroman-4-amine

HRID 1363191노트

반응식

HRID 1363191 반응식
[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH:12]C(=O)COC>Cl.CCO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH2:12]

참가 물질

4

반응물 1

HCID 59799572(R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide

생성물 1

HCID 46911919(R)-8-fluorochroman-4-amine수율 88.1%

시약·촉매·용매 2

HCID 313Hydrochloric Acid용매HCID 702Ethanol용매

실험 절차

Resolution of 8-fluorochroman-4-amine. (Procedure based on US published application 2004/0157739). A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was heated at reflux under argon for 2 hours (at which time the ratio of acylated to unacylated product was 1:1 by HPLC). The solid that formed upon cooling was collected via filtration and dissolved in EtOAc. The mixture was filtered to remove the biocatalyst and washed once with 0.5M HCl to remove any lingering (S)-amine. The solvent was evaporated and the product was recrystallized from tert-butyl methyl ether to yield (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g). The reaction solvent and recrystallization mother liquor was washed 3 times with 0.5 M HCl and concentrated to yield additional (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.83 g). The combined acidic aqueous layers were made basic by NaOH and extracted with DCM to yield (S)-8-fluorochroman-4-amine (1.6 g). A solution of (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) was heated at reflux for 4 hours. The solvents were removed from the cooled reaction mixture, the resulting solid was taken up in 50 mL of 0.5M NaOH, salted out with NaCl(S), and extracted 4 times with DCM to yield (R)-8-fluorochroman-4-amine (0.48 g (87%)). The % ee was checked via chiral HPLC: Chiralcel OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) method: isocratic 5% (0.05% TFA/EtOH) 95% (0.05% TFA/Hex), Rt=7.2 min (S)-enantiomer, Rt=9.2 min (R)-enantiomer.

후처리

  1. temperatureat reflux for 4 hours
  2. customThe solvents were removed from the cooled reaction mixture
  3. extractionextracted 4 times with DCM

출처 및 근거

ORD 기록
ord-d5f75005e6a44787887a272ee824da10
출처 데이터셋
uspto-grants-2011_02
특허 번호
US07884109B2

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