1,4-Dioxane → 1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

HRID 60651ノート

反応式

HRID 60651 の反応式
[C:1]([C:5]1[CH:6]=[C:7]([NH2:38])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:12]([O:28][CH2:29][CH2:30][O:31]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@H:40]1[CH2:45][CH2:44][CH2:43][C@@H:42]([CH3:46])[N:41]1[C:47]1[N:51]2[CH:52]=[C:53]([O:56][C@H:57]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[C@@H:60]([NH2:67])[CH2:59][CH2:58]3)[CH:54]=[CH:55][C:50]2=[N:49][N:48]=1.CCN(C(C)C)C(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:94]1CCOC[CH2:95]1>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:38][C:95]([NH:67][C@@H:60]2[C:61]3[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:57]([O:56][C:53]3[CH:54]=[CH:55][C:50]4[N:51]([C:47]([N:41]5[C@H:40]([CH3:39])[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH3:46])=[N:48][N:49]=4)[CH:52]=3)[CH2:58][CH2:59]2)=[O:94])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:20])[CH3:21])[CH:25]([CH3:27])[CH3:26])=[C:12]([O:28][CH2:29][CH2:30][OH:31])[CH:11]=2)[N:9]=1)([CH3:2])([CH3:4])[CH3:3]

参加物

7

反応物 5

HCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 89624184(1S,4R)-4-[3-(cis-2,6-Dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCID 1238832895-tert-Butyl-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-4-triisopropylsilanyloxymethyl-phenyl}-2H-pyrazol-3-ylamine

生成物 1

HCID 1234602741-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea収率 40%

試薬・触媒・溶媒 1

HCID 887Methanol溶媒

反応条件

温度
45 °C

実験手順

A solution of Intermediate 55e (710 mg, 2.17 mmol), Intermediate C (385 mg, 2.17 mmol) and DIPEA (250 μL, 3.25 mmol) in 1,4-dioxane (10 mL) was stirred at 60° C. overnight. After cooling, the mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a gum (1.25 g, quantitative) that was used without further purification in the next step. TLC [DCM/MeOH (9:1) Rf=0.4]. A solution of the above product (1.25 g, 1.30 mmol) in MeOH (30 mL) was treated with pyridinium p-toluenesulfonate (978 mg, 3.90 mmol) and the resulting mixture was heated at 45° C. overnight. The volatiles were removed under reduced pressure and the residue was taken up in DCM (80 mL) and washed with water (20 mL). The organic phase was separated using a phase separating cartridge and the organic layer was evaporated in vacuo. The product was purified by FCC, eluting with 0-10% MeOH in DCM, to give the title compound (430 mg, 40%). LCMS (Method 3): Rt 5.41 min, m/z 879,880 [MH+].

後処理

  1. temperatureAfter cooling
  2. customthe mixture was partitioned between EtOAc and water
  3. extractionThe aqueous layer was then extracted with EtOAc (3×10 mL)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customto give a gum (1.25 g, quantitative) that
  9. customwas used without further purification in the next step
  10. customThe volatiles were removed under reduced pressure
  11. washwashed with water (20 mL)
  12. customThe organic phase was separated
  13. customseparating cartridge
  14. customthe organic layer was evaporated in vacuo
  15. customThe product was purified by FCC
  16. washeluting with 0-10% MeOH in DCM

出典と根拠

ORDレコード
ord-6fd2235ea9fb467bbe723e046296f69f
出典データセット
uspto-grants-2016_09
特許番号
US09440974B2

反応ノート

読み込み中…