Lithium Hydroxide → N-[(4aR,7aS)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride

HRID 470291ノート

反応式

HRID 470291 の反応式
Cl.[C:2]1([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[N:32]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[C:30]([F:37])=[CH:29][N:28]=1.[CH:38](N(C(C)C)CC)(C)C.[OH-].[Li+]>O1CCOCC1>[ClH:26].[F:37][C:30]1[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])=[N:32][C:27]([N:15]2[CH2:14][C@@H:13]3[C@@:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([N:9]=[C:10]([NH:17][C:18](=[O:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:11][CH2:12]3)[CH2:16]2)=[N:28][C:29]=1[CH3:38]

参加物

6

反応物 4

HCID 3939Lithium HydroxideHCID 81531DiisopropylethylamineHCID 866978842-(2-Chloro-5-fluoropyrimidin-4-yl)propan-2-olHCID 86762232N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride

生成物 1

HCID 86762251N-[(4aR,7aS)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride

試薬・触媒・溶媒 1

HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To a solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride (95 mg, 0.25 mmol) and 2-(2-chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (195 mg, 0.57 mmol) in 1,4-dioxane (5.0 mL) is added diisopropylethylamine (150 μL, 0.86 mmol). The resulting solution is heated at 100° C. for 23 hours, cooled to room temperature, and concentrated. The residue is dissolved in methanol (5.0 mL), followed by the addition of lithium hydroxide (100 mg, 4.11 mmol). The resulting solution is heated at 55° C. for 16 hrs and then cooled to room temperature and concentrated. The residue is purified with a 5 g SCX column, eluting first with MeOH/DCM (¼, 50 mL), followed by elution with ammonia in MeOH (7.0 N)/DCM (¼, 50 mL). The basic filtrate is concentrated, and further purified by silica gel flash chromatography, eluting with a gradient of ammonia in MeOH (2.0 M) in dichloromethane (0% to 10%) to give the free base form of the title compound as a colorless oil. EI/MS (m/e): 402.00 (M+H). 19F-NMR (CDCl3): δ (ppm) −154.62. 1H-NMR (CDCl3): δ (ppm) 7.38 (m, 5H), 4.11 (d, 1H), 4.01 (d, 1H), 3.83 (m, 2H), 3.05 (dd, 1H), 2.92 (dd, 1H), 2.81 (m, 1H), 2.37 (s, 3H), 1.53 (s, 6H). The purified material is dissolved in dichloromethane (2 mL), followed by the addition of HCl (1.0 M in diethyl ether, 60 μL, 0.06 mmol) and then concentrated to give the title compound as a white solid (22 mg, 20%).

後処理

  1. temperaturecooled to room temperature
  2. concentrationconcentrated
  3. dissolutionThe residue is dissolved in methanol (5.0 mL)
  4. temperatureThe resulting solution is heated at 55° C. for 16 hrs
  5. temperaturecooled to room temperature
  6. concentrationconcentrated
  7. customThe residue is purified with a 5 g SCX column
  8. washeluting first with MeOH/DCM (¼, 50 mL)
  9. washfollowed by elution with ammonia in MeOH (7.0 N)/DCM (¼, 50 mL)
  10. concentrationThe basic filtrate is concentrated
  11. customfurther purified by silica gel flash chromatography
  12. washeluting with a gradient of ammonia in MeOH (2.0 M) in dichloromethane (0% to 10%)

出典と根拠

ORDレコード
ord-22127afe546b45689b3aa2f9fbe4b02a
出典データセット
uspto-grants-2014_01
特許番号
US08629270B2

反応ノート

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