Dichloromethane → 2,2-dichloro-N-[(1S,2R)-2-(4-{6-[cyano(fluoro)methyl]pyridin-3-yl}phenyl)-1-(fluoromethyl)-2-hydroxyethyl]acetamide

HRID 1500304ノート

反応式

HRID 1500304 の反応式
Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([F:11])[C:9]#[N:10])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.[Cl:38][CH:39]([Cl:55])[C:40]([NH:42][C@H:43]([CH2:53][F:54])[C@H:44]([OH:52])[C:45]1[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=1)=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:38][CH:39]([Cl:55])[C:40]([NH:42][C@H:43]([CH2:53][F:54])[C@@H:44]([C:45]1[CH:46]=[CH:47][C:48]([C:2]2[CH:7]=[N:6][C:5]([CH:8]([C:9]#[N:10])[F:11])=[CH:4][CH:3]=2)=[CH:49][CH:50]=1)[OH:52])=[O:41]

参加物

9

反応物 6

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 683504732,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamideHCID 867131922-(5-Bromopyridin-2-yl)-2-fluoroacetonitrile

生成物 1

HCID 736035732,2-dichloro-N-[(1S,2R)-2-(4-{6-[cyano(fluoro)methyl]pyridin-3-yl}phenyl)-1-(fluoromethyl)-2-hydroxyethyl]acetamide

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 6228Dimethylformamide溶媒

反応条件

温度
80 °C

実験手順

A stirred mixture of the product of step 1, Example 22 (127 mg, 0.591 mmol), bis(pinacolato)diboron (163 mg, 0.640 mmol), and potassium acetate (193 mg, 1.97 mmol) in dry dimethylformamide (4.9 mL) is sparged with nitrogen for 5 min before [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (40.2 mg, 0.0492 mmol) is added. The mixture is sparged with nitrogen for another 5 min, heated to 80° C. under nitrogen and maintained at this temperature. After 4.5 hours, the mixture is cooled to ambient temperature, solid 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (previously described in WO13057619 Preparation 1 page 16, 200 mg, 0.492 mmol) and cesium carbonate (0.562 g, 1.72 mmol) were added under a stream of nitrogen, and the mixture is sparged with nitrogen for 5 min and heated to 80° C. After 2 hours, the mixture is cooled to ambient temperature, diluted with water (25 mL), and extracted with ethylacetate (2×25 mL). The combined organic phase is washed with water (3×20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g, 25-45% ethyl acetate/hexanes) gave the title compound (77 mg): 1H NMR (300 MHz, DMSO-d6) δ 4.28 (m, 1.5H), 4.45 (m, 0.5H), 4.58 (m, 0.5H), 4.72 (m, 0.5H), 4.93 (m, 1H), 6.02 (d, 1H), 6.53 (s, 1H), 6.93 (d, 1H), 7.51 (d, 2H), 7.77 (m, 3H), 8.28 (dd, 1H), 8.62 (bd, 1H), 9.04 (m, 1H). MS (ESI+) m/z 414 [M+H].

後処理

  1. additionis added
  2. customThe mixture is sparged with nitrogen for another 5 min
  3. temperaturemaintained at this temperature
  4. temperaturethe mixture is cooled to ambient temperature
  5. additionwere added under a stream of nitrogen
  6. customthe mixture is sparged with nitrogen for 5 min
  7. temperatureheated to 80° C
  8. waitAfter 2 hours
  9. temperaturethe mixture is cooled to ambient temperature
  10. additiondiluted with water (25 mL)
  11. extractionextracted with ethylacetate (2×25 mL)
  12. washThe combined organic phase is washed with water (3×20 mL), brine (20 mL)
  13. dry with materialdried over anhydrous magnesium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customPurification by silica gel chromatography (40 g, 25-45% ethyl acetate/hexanes)

出典と根拠

ORDレコード
ord-5519892c29c0421ca91df1ebcce26a94
出典データセット
uspto-grants-2015_12
特許番号
US09206126B2

反応ノート

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