Water → 1,1-Dimethylethyl 4-{[5'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-2'-(methyloxy)-3-biphenylyl]methyl}-1-piperidinecarboxylate

HRID 657399ノート

反応式

HRID 657399 の反応式
BrC1C=C(C[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])C=CC=1OC.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[C:51]([CH2:55][CH:56]3[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH:52]=[CH:53][CH:54]=2)O1.[C:70](=[O:73])([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([N:29]1[C:24]2=[N:25][C:26]([CH2:27][CH3:28])=[C:21]([CH2:20][NH:11][C:12]([C:14]3([C:17]([NH:19][CH2:55][C:51]4[CH:50]=[CH:49][C:54]([O:73][CH3:70])=[C:53]([C:49]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH:56]6[CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]6)[CH:50]=5)[CH:52]=4)=[O:18])[CH2:15][CH2:16]3)=[O:13])[C:22]([NH:34][CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]

参加物

7

反応物 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 578134461,1-Dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylateHCID 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 578199281,1-Dimethylethyl 4-{[5'-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-2'-(methyloxy)-3-biphenylyl]methyl}-1-piperidinecarboxylate収率 247.5%

試薬・触媒・溶媒 2

HCID 178418397HCID 178418397、化合物触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To 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 (6.75 g, 11.00 mmol) in 1,4-dioxane (120 mL) was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (4.42 g, 11.00 mmol). Then potassium carbonate (4.56 g, 33.0 mmol), water (40.0 mL) and tetrakis(triphenylphosphine)palladium(0) (0.636 g, 0.550 mmol) was added and the reaction was heated at 100° C. for 1 h. HPLC showed a small amount of starting material present therefore the reaction was left for a further hour. HPLC showed no change so the reaction was worked up. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed with EtOAc and the combined organic layers were rinsed with brine, dried over MgSO4, filtered and evaporated to give a light brown foam (˜11 g). The foam was dissolved in DCM and passed through a celite column before combining with a batch from a similar preparation (0.85 g). The combined brown solutions were concentrated and applied to a 330 g silica column using 15-100% EtOAc-DCM over 10 column volumes as the gradient. Product fractions were combined and evaporated to yield a white foam 7.42 g (83%). A second peak containing the product was combined and evaporated to yield as a pale yellow oil, 0.69 g (7%) HPLC 2.61 min (ret time) 96.6%; LC-MS m/z 808 (M+H)+, 3.78 min (ret time).

後処理

  1. waitthe reaction was left for a further hour
  2. customThe reaction mixture was partitioned between EtOAc and water
  3. washThe aqueous layer was washed with EtOAc
  4. washthe combined organic layers were rinsed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated

出典と根拠

ORDレコード
ord-52bffa5653f1446b89c1554ffa4babc4
出典データセット
uspto-grants-2011_12
特許番号
US08071588B2

反応ノート

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