Hydrochloric Acid → 4-{4-(3-Chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-morpholine

HRID 230935

反応式

HRID 230935 の反応式
Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46].Cl>>[Cl:39][C:40]1[CH:41]=[C:42]([C:2]2[CH:7]=[C:6]([N:26]3[CH2:25][CH2:24][N:23]([C:18]4[C:17]([C:16]([F:15])([F:29])[F:30])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:28][CH2:27]3)[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[CH:43]=[CH:44][C:45]=1[F:46]

参加物

6

反応物 5

HCID 313Hydrochloric AcidHCID 62657Potassium Phosphate, Tribasic2 回HCID 27346603-Chloro-4-fluorophenylboronic Acid (contains varying amounts of Anhydride)HCID 27720684-(4,6-Dichloropyrimidin-2-yl)morpholineHCID 27777861-[3-(Trifluoromethyl)pyridin-2-yl]piperazine

生成物 1

HCID 117527744-{4-(3-Chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-morpholine

反応条件

温度
90 °C

実験手順

To a rubber-septum-capped vial containing 4,6-dichloro-2-morpholinopyrimidine (0.2 M in dioxane, 0.25 mL) and 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (0.2 M in dioxane, 0.28 mL) (Oakwood Products, Inc., West Columbia, S.C.) add aqueous K3PO4 (0.5 M, 0.125 mL). Heat the mixture at 90° C. for 24 hours. After cooling, add 3-chloro-4-fluorophenylboronic acid (0.2 M in dioxane, 0.35 mL) and K3PO4 (0.5 M in water, 0.10 mL) and flush the vial with argon. Add Pd(PPh3)4 (0.01 M in toluene, 0.125 mL). Heat the mixture at 80° C. overnight, add EtOAc(0.5 mL), separate the organic phase and load onto a 6-mL cartridge containing 1 g of SCX (a sulfonic acid-pregnated silica gel strong cation exchanger). Wash the SCX cartridge with 5 mL of MeOH and elute the product with 10% Et3N in EtOAc (5 mL). Concentrate the eluent to give the pure product which can be converted to the HCl salt: LCMS (m/e); 523, 1H NMR (CDCl3); d 3.4 (br s, 4 H), 3.8 (br s, 4 H), 4.0 (br s, 8 H), 6.4 (br s, 1H), 7.1 (br s, 1H), 7.2 (br s, 1H), 7.9 (m, 3 H), 8.5 (s, 1H).

後処理

  1. temperatureAfter cooling
  2. customflush the vial with argon
  3. temperatureHeat the mixture at 80° C. overnight
  4. additionadd EtOAc(0.5 mL)
  5. customseparate the organic phase and load onto a 6-mL cartridge
  6. additioncontaining 1 g of SCX (a sulfonic acid-pregnated silica gel strong cation exchanger)
  7. washWash the SCX cartridge with 5 mL of MeOH
  8. washelute the product with 10% Et3N in EtOAc (5 mL)
  9. concentrationConcentrate the eluent
  10. customto give the pure product which

出典と根拠

ORDレコード
ord-fcd57aa7cccf4c14a2d434fd2da1819d
出典データセット
uspto-grants-2009_07
特許番号
US07566712B2

関連ノート

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