1-Pyrrolidinamine → 1-((3R,4R)-3-(4-dimethylamino-6-methylthieno[3,2-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666630ノート

反応式

HRID 1666630 の反応式
NN1CCCC1.Cl[C:8]1[N:9]=[C:10]([N:18]([CH3:20])[CH3:19])[C:11]2[S:16][C:15]([CH3:17])=[CH:14][C:12]=2[N:13]=1.[NH2:21][C@H:22]1[C@H:26]([OH:27])[CH2:25][N:24]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:23]1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.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].O1CCOCC1>[CH3:19][N:18]([CH3:20])[C:10]1[C:11]2[S:16][C:15]([CH3:17])=[CH:14][C:12]=2[N:13]=[C:8]([NH:21][C@H:22]2[C@H:26]([OH:27])[CH2:25][N:24]([C:28](=[O:41])[CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=3)[CH2:23]2)[N:9]=1

参加物

9

反応物 4

HCID 279461-PyrrolidinamineHCID 23676156Sodium t-butoxideHCID 579700892-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amineHCID 579701111-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

生成物 1

HCID 579701861-((3R,4R)-3-(4-dimethylamino-6-methylthieno[3,2-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone収率 29.7%

試薬・触媒・溶媒 4

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
60 °C

実験手順

To a solution of 50% aqueous dimethyl amine (0.15 g) in ethanol (5 mL) were added 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (0.25 g) and triethylamine (0.12 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine and then dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure and crystallized with diethyl ether to obtain 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.150 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.067 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.26 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylamino-6-methylthieno[3,2-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.097 g).

後処理

  1. customthe interlayer was removed by Celite filtration
  2. washthe organic layer was washed with saturated brine
  3. dry with materialThe organic layer was dried with anhydrous magnesium sulfate
  4. customthe desiccant was removed by filtration
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customthe residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate)

出典と根拠

ORDレコード
ord-75507d9fee7d4c08b5ce24243a418dc0
出典データセット
uspto-grants-2011_10
特許番号
US08044068B2

反応ノート

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