Cesium carbonate → (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 242321

反応式

HRID 242321 の反応式
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].CCOC(C)=O.CO.C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([C:30]#[N:31])[CH:32]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

参加物

8

反応物 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 263699225-Bromo-2-methoxynicotinonitrileHCID 57495324Tert-butyl (S)-3-((5,6,7,8-tetrahydropyrido[4,3-D]pyrimidin-4-YL)amino)pyrrolidine-1-carboxylate2 回

生成物 1

HCID 57495326(S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester収率 29.3%

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 6386tert-Butanol溶媒HCID 21584119Ethylacetate methanol溶媒

反応条件

温度
110 °C

実験手順

To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 23) (566 mg, 1.77 mmol), 5-bromo-2-methoxynicotinonitrile (453 mg, 2.13 mmol), cesium carbonate (1155 mg, 3.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (162 mg, 0.18 mmol), X-Phos (287 mg, 0.60 mmol) and anhydrous tert-butanol (5 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 18 h at 110° C. Allowed to cool and partitioned between CH2Cl2 (20 mL) and water (10 mL) and filtered the biphasic mixture through a celite pad. The organic layer was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash column chromatography on silica gel with heptane/EtOAc, 100/0 to 0/100 then EtOAc/MeOH (90/10) to give (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown gum (234 mg, 29% yield). LCMS: [M+H]+=452.1, Rt(4)=0.90 min.

後処理

  1. customThe vial was flushed with a stream of argon for 15 sec
  2. customcapped
  3. temperatureThe mixture was heated
  4. temperatureAllowed to cool
  5. custompartitioned between CH2Cl2 (20 mL) and water (10 mL)
  6. filtrationfiltered the biphasic mixture through a celite pad
  7. customThe organic layer was separated
  8. filtrationby filtering through a phase separation tube
  9. concentrationconcentrated in vacuo
  10. customPurified by flash column chromatography on silica gel with heptane/EtOAc, 100/0 to 0/100

出典と根拠

ORDレコード
ord-322b3749d8794992a2ab3906bd74348e
出典データセット
uspto-grants-2014_02
特許番号
US08653092B2

関連ノート

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