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 338170Notes

Reaction equation

HRID 338170 reaction equation
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]

Participants

6

Reactant 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

Product 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

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

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%).

Workup

  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%)

Sources & evidence

ORD record
ord-fa309da2e2ff4d68aa6835d03bae8c3f
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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