Sodium Carbonate → n1-{[1,6-Diethyl-4-(tetrahydro-2h-pyran-4-ylamino)-1h-pyrazolo[3,4-b]pyridin-5-yl]methyl}-n1-({6-(methyloxy)-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide

HRID 657408ノート

反応式

HRID 657408 の反応式
Br[C:2]1[CH:3]=[C:4]([CH2:10][N:11]([CH2:20][C:21]2[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:23]3[CH:31]=[N:30][N:29]([CH2:32][CH3:33])[C:24]3=[N:25][C:26]=2[CH2:27][CH3:28])[C:12]([C:14]2([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)[CH2:44][CH2:43]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[CH2:32]([N:29]1[C:24]2=[N:25][C:26]([CH2:27][CH3:28])=[C:21]([CH2:20][N:11]([CH2:10][C:4]3[CH:3]=[C:2]([C:53]4[CH:52]=[CH:51][CH:50]=[C:49]([CH2:48][CH:45]5[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]5)[CH:54]=4)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=3)[C:12]([C:14]3([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15]3)=[O:13])[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]

参加物

7

反応物 3

HCID 10340Sodium CarbonateHCID 578134541-Methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidineHCID 68636994N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide

生成物 1

HCID 69014751n1-{[1,6-Diethyl-4-(tetrahydro-2h-pyran-4-ylamino)-1h-pyrazolo[3,4-b]pyridin-5-yl]methyl}-n1-({6-(methyloxy)-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide収率 29.1%

試薬・触媒・溶媒 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 962Water溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

A mixture of N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (50 mg, 0.081 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (32.7 mg, 0.081 mmol), Na2CO3 (25.9 mg, 0.244 mmol) and PdCl2(dppf) (5.96 mg, 8.15 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 min and was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-(methyloxy)-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (17 mg, 28.9%). LC-MS m/z 723 (M+H)+, 0.82 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.24 (m, 5H) 1.29-1.36 (m, 7H) 1.41-1.67 (m, 5H) 1.84-1.92 (m, 3H) 2.18 (br. s., 2H) 2.50-2.57 (m, 4H) 2.73-2.94 (m, 4H) 3.49-3.56 (m, 2H) 3.71 (s, 3H) 3.78-3.88 (m, 2H) 3.97-4.10 (m, 1H) 4.24 (d, J=5.77 Hz, 2H) 4.31 (q, J=7.28 Hz, 2H) 4.36-4.40 (m, 2H) 6.73-6.77 (m, 1H) 7.00 (d, J=8.53 Hz, 1H) 7.05-7.34 (m, 6H) 7.99 (s, 1H) 8.42 (t, J=5.77 Hz, 1H) 9.03 (t, J=5.77 Hz, 1H).

後処理

  1. customThe mixture was degassed
  2. customby bubbling argon through it for 5 min
  3. filtrationThe crude mixture was filtered through a PL-Thiol MP SPE+
  4. washwas then washed with ethyl acetate and water
  5. concentrationThe organic layer was concentrated under vacuum
  6. customto obtain the crude residue
  7. customIt was purified by reverse phase hplc with a Gilson HPLC (acidic conditions
  8. wash0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  9. washwashed with saturated NaHCO3
  10. extractionextracted with ethyl acetate twice
  11. washThe combined organic layers were washed with brine
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated under vacuum

出典と根拠

ORDレコード
ord-16d497beabfd40059f9ffce799794aa8
出典データセット
uspto-grants-2011_12
特許番号
US08071588B2

反応ノート

読み込み中…