Sodium Carbonate → (3R,4R)-4-[(R)-7-(2,6-difluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

HRID 519189ノート

反応式

HRID 519189 の反応式
[CH3:1][C@@H:2]1[C@H:7]([C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][C:21]=2B2OC(C)(C)C(C)(C)O2)[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:32])[C:13](=[O:31])[NH:14][N:15]=2)[CH2:6][CH2:5][N:4]([C:33]([OH:35])=[O:34])[CH2:3]1.Br[C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44].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].C(Cl)Cl>[C:2]([O:35][C:33]([N:4]1[CH2:5][CH2:6][C@@H:7]([C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][C:21]=2[C:37]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=2[F:44])[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:32])[C:13](=[O:31])[NH:14][N:15]=2)[C@@H:2]([CH3:1])[CH2:3]1)=[O:34])([CH3:7])([CH3:3])[CH3:1]

参加物

7

反応物 3

HCID 10340Sodium CarbonateHCID 1235571-Bromo-2,6-difluorobenzeneHCID 86727604(3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid

生成物 1

HCID 86727603(3R,4R)-4-[(R)-7-(2,6-difluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester収率 36.5%

試薬・触媒・溶媒 3

HCID 178418807HCID 178418807、化合物触媒HCID 962Water溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
90 °C

実験手順

To a mixture of (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid (0.028 g, 0.052 mmol), 2-bromo-1,3-difluoro-benzene (0.015 g, 0.078 mmol) and sodium carbonate (0.018 g, 0.130 mmol) in 1,4-dioxane (3.0 mL) and water (0.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.008 g, 0.010 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between EtOAc (20 mL) and water (20 mL). The organic portion was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 36) to give (3R,4R)-4-[(R)-7-(2,6-difluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.005 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41-7.51 (m, 1H), 7.08 (m, 2H), 6.95 (s, 1H), 6.82 (s, 1H), 4.57-4.65 (m, 5H), 4.25 (m, 1H), 3.83 (m, 1H), 2.80 (m, 1H), 2.43-2.74 (m, 2H), 2.15-2.30 (m, 1H), 1.40-1.51 (m, 12H), 1.29 (s, 3H). LC/MS (Table 1, Method 25) Rt=0.930 min; MS (ESI): m/z 527 [M+H]+.

後処理

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. filtrationfiltered
  3. customThe filtrate was partitioned between EtOAc (20 mL) and water (20 mL)
  4. customThe organic portion was separated
  5. extractionthe aqueous layer was extracted with EtOAc (3×50 mL)
  6. dry with materialThe combined organic phase was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by preparative HPLC (Table 3, Method 36)

出典と根拠

ORDレコード
ord-39cf722f777246e0a802db1f7b3b8200
出典データセット
uspto-grants-2015_08
特許番号
US09115151B2

反応ノート

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