2-Methyltetrahydrofuran → 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

HRID 41877

反応式

HRID 41877 の反応式
Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C.CC1CCCO1>C1COCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)=[CH:6][N:5]([CH3:7])[N:4]=2)=[CH:9][CH:10]=1

参加物

7

反応物 4

HCID 73012-MethyltetrahydrofuranHCID 50177412-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 534214614-Bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazoleHCID 178461733HCID 178461733、化合物

生成物 1

HCID 670738063-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
10 °C

実験手順

A solution of 4-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (700 g, 2.74 mol) in THF (1.4 L) was cooled to 15° C. and isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 3.8 L, 4.94 mol) was added slowly while maintaining the reaction temperature below 25° C. The mixture was stirred for 3 hr at 20° C. and a 10° C. solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (610 g, 3.28 mol) in THF (1.4 L) was added dropwise while maintaining an internal temperature below 20° C. The resulting green/brown hazy solution as stirred for 1 hr between 10° C. and 20° C. after which time it was cooled to 10° C. Water (5.6 L) cooled to 10° C. was added slowly to the reaction mixture so that the reaction temperature stayed below 25° C. Celite (1.4 kg) was added followed by 2-methyltetrahydrofuran (7 L) and the mixture was stirred for 15 min at 20° C. The mixture was filtered through Celite and the filter pad was rinsed with 2-methyltetrahydrofuran (8 L). The organic phase was separated and washed with brine (5.6 L) then concentrated under vacuum to a low stir volume. The material was diluted with EtOH (3 L) and reconcentrated. This material was re-dissolved in EtOH (3.5 L) and water (4.2 L) was added over 30 min with strong stirring. The resulting slurry was stirred at 15° C. for 1 hr, filtered and washed with 4 volumes of water. The resulting cake was blown dry then further dried in a vacuum oven at 40° C. to yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid: APCI MS m/z 303.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J=8.9, 5.6, 2H), 7.70 (s, 1H), 7.03 (dd, J=8.8, 8.8, 2H), 3.90 (s, 3H), 1.29 (s, 12H).

後処理

  1. temperaturewhile maintaining the reaction temperature below 25° C
  2. additionwas added dropwise
  3. temperaturewhile maintaining an internal temperature below 20° C
  4. additionwas added slowly to the reaction mixture so that the reaction temperature
  5. customstayed below 25° C
  6. additionCelite (1.4 kg) was added
  7. stirringthe mixture was stirred for 15 min at 20° C
  8. filtrationThe mixture was filtered through Celite
  9. washthe filter pad was rinsed with 2-methyltetrahydrofuran (8 L)
  10. customThe organic phase was separated
  11. washwashed with brine (5.6 L)
  12. concentrationthen concentrated under vacuum to a low stir volume
  13. additionThe material was diluted with EtOH (3 L)
  14. dissolutionThis material was re-dissolved in EtOH (3.5 L)
  15. additionwater (4.2 L) was added over 30 min with strong stirring
  16. stirringThe resulting slurry was stirred at 15° C. for 1 hr
  17. filtrationfiltered
  18. washwashed with 4 volumes of water
  19. customThe resulting cake was blown dry
  20. customthen further dried in a vacuum oven at 40° C.
  21. customto yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid

出典と根拠

ORDレコード
ord-9555b304ac5e4273943d137a2587a958
出典データセット
uspto-grants-2013_09
特許番号
US08536164B2

関連ノート

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