Diisopropylamine → 5-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

HRID 1812213ノート

反応式

HRID 1812213 の反応式
C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C@H:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C@@H:23]2[CH3:35])[CH3:21])=[CH:16][CH:15]=1.[B:36](OC(C)C)([O:41]C(C)C)[O:37]C(C)C.[OH-].[Na+]>C1COCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C@@H:20]([C:17]2[CH:16]=[C:15]([B:36]([OH:41])[OH:37])[C:14]([F:13])=[N:19][CH:18]=2)[CH3:21])[C@@H:23]([CH3:35])[CH2:24]1)=[O:29])([CH3:33])([CH3:32])[CH3:34]

参加物

7

反応物 5

HCID 7912DiisopropylamineHCID 14798Sodium HydroxideHCID 21531Triisopropyl borateHCID 68514890tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylateHCID 178418339Butyllithium

生成物 1

HCID 685129855-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid収率 91%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
-40 °C

実験手順

n-Butyllithium (2.5 M in hexanes; 7.23 mL, 18.07 mmol) was added dropwise to a solution of diisopropylamine (2.55 mL, 18.07 mmol) in 8 mL of THF at −40° C. The mixture was stirred for 1 h at −40° C. This solution was cannulated into a 3-necked 250-mL round-bottomed flask that contained a solution of tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (4.87 g, 15.06 mmol) in 60 mL of THF at −78° C. After 15 min at −78° C., triisopropyl borate (Aldrich; 6.92 mL, 30.1 mmol) was added, and the resulting mixture was stirred at −78° C. for 15 min and then allowed to warm to ambient temperature. The reaction mixture was subsequently treated with 1 M NaOH (80 mL) and allowed to stir for 20 min. The aqueous layer was separated and the organic layer was discarded. The aqueous layer was treated with 10% HCl (aq) until a pH of about 5 to 6 was achieved. The resulting mixture was diluted with EtOAc (20 mL) and the mixture was extracted with 8:2 EtOAc/MeOH (200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (5.01 g, 13.64 mmol, 91% yield) as an off-white solid. m/z (ESI, +ve) 368.1 (M+H)−.

後処理

  1. customThis solution was cannulated into a 3-necked 250-mL round-bottomed flask
  2. customat −78° C
  3. waitAfter 15 min at −78° C.
  4. stirringthe resulting mixture was stirred at −78° C. for 15 min
  5. temperatureto warm to ambient temperature
  6. stirringto stir for 20 min
  7. customThe aqueous layer was separated
  8. additionThe aqueous layer was treated with 10% HCl (aq) until a pH of about 5 to 6
  9. additionThe resulting mixture was diluted with EtOAc (20 mL)
  10. extractionthe mixture was extracted with 8:2 EtOAc/MeOH (200 mL)
  11. dry with materialThe combined organic extracts were dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated

出典と根拠

ORDレコード
ord-9090961bc09845d39775644cb672d56c
出典データセット
uspto-grants-2013_01
特許番号
US08362241B2

反応ノート

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