(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester → 3-[[N-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-methoxybenzyloxy)ethyl]-1-piperidinyl]pyridine

HRID 2095456

反応式

HRID 2095456 の反応式
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH2:28][O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:33][CH2:34]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]

参加物

7

反応物 3

HCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 23676156Sodium t-butoxideHCID 568305684-[2-(4-Methoxybenzyloxy)ethyl]piperidine

生成物 1

HCID 593716743-[[N-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-methoxybenzyloxy)ethyl]-1-piperidinyl]pyridine収率 84.1%

試薬・触媒・溶媒 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)触媒HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 1140Toluene溶媒

反応条件

温度
99 °C

実験手順

To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (112 mg, 0.31 mmol) and 4-[2-(4-methoxybenzyloxy)ethyl]piperidine (86 mg, 0.34 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (45 mg, 0.47 mmol, 1.5 equiv.), Pd2dba3 (5.7 mg, 6.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 10.8 mg, 19 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2, then 1:2. The product (137 mg, 84%) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.23-7.30 (m, 3H), 7.24 (d, 2H, J=8.4 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.41 (s, 2H), 4.10 (m, 2H), 3.90-3.80 (m, 1H), 3.78 (s, 3H), 3.65 (m, 2H), 3.49 (t, 2H, J=6.0 Hz), 3.39 (m, 2H), 2.72 (m, 2H), 2.02 (m, 3H), 1.84 (m, 1H), 1.75 (d, 2H, J=12.4 Hz), 1.55 (m, 3H), 1.45 (s, 9H), 1.31 (m, 2H).

後処理

  1. customThe mixture was degassed
  2. custompurged with Ar (3 cycles)
  3. temperatureAfter cooling to room temperature
  4. additionthe mixture was diluted with EtOAc
  5. washthe solution was washed with brine
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customThe residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2

出典と根拠

ORDレコード
ord-89ef7848fffa44cc971abd2a19361f41
出典データセット
uspto-grants-2013_05
特許番号
US08445684B2

関連ノート

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