Potassium Phosphate, Tribasic → (3S,6R)-1-[6-(4-Cyano-3,5-difluorophenyl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide

HRID 2367313ノート

反応式

HRID 2367313 の反応式
Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:39])#[N:28].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:31][C:30]=1[F:39])#[N:28]

参加物

8

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 55252910(4-Cyano-3,5-difluorophenyl)boronic acidHCID 58504823(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide

生成物 1

HCID 58504827(3S,6R)-1-[6-(4-Cyano-3,5-difluorophenyl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide収率 73.6%

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (500 mg, 1.34 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (318 mg, 1.74 mmol, 1.3 equiv), Pd2(dba)3 (92 mg, 0.10 mmol, 0.075 equiv), tricyclohexylphosphine (56 mg, 0.20 mmol, 0.15 equiv), and K3PO4 (483 mg, 2.27 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (10 mL) and water (3.3 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc afforded the title compound (470 mg) as a yellow/greenish gum. LC-MS (ES) m/z=477 [M+H]+.

後処理

  1. customThe mixture was bubbled with argon for 10 minutes
  2. temperatureAfter cooling to room temperature
  3. filtrationthe mixture was filtered through celite
  4. concentrationthe filtrate was concentrated in vacuo
  5. customThe resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL)
  6. dry with materialthe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification by silica gel column chromatography
  10. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

出典と根拠

ORDレコード
ord-df69de36e8c947978248fcda78605f2c
出典データセット
uspto-grants-2014_04
特許番号
US08697685B2

反応ノート

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