Lithium Hydroxide → 3-[3-(Hydroxymethyl)-4-[1-methyl-5-[(5-methylisoxazol-3-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-4-one

HRID 1022148Notes

Reaction equation

HRID 1022148 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([N:27]2[C:39](=[O:40])[C:38]3[S:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]=3[CH:29]=[N:28]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[C:39](=[O:40])[C:38]3[S:37][C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]=3[CH:29]=[N:28]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1

Participants

4

Reactant 2

HCID 3939Lithium HydroxideHCID 86684535(4-{1-Methyl-5-[(5-methyl-1,2-oxazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridin-3-yl)methyl Acetate

Product 1

HCID 866845373-[3-(Hydroxymethyl)-4-[1-methyl-5-[(5-methylisoxazol-3-yl)amino]-6-oxo-3-pyridyl]-2-pyridyl]-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-4-oneYield 60.2%

Reagents, catalysts & solvents 1

HCID 22722550Tetrahydrofuran water isopropanolSolvent

Procedure

To a solution of 291a (100 mg, 0.18 mmol) in THF/i-propanol/water (10/5/5 mL) was added lithium hydroxide (43 mg, 1.8 mmol) at room temperature. After being stirred for 1 h, MS indicated the reaction was complete. Then the mixture was concentrated under reduced pressure and the residue was partitioned between water (10 mL) and dichloromethane (15 mL). The water phase was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 291 (56 mg, 60%) as white solid. MS-ESI: [M+H]+ 517.2. 1H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 6.25 (s, 1H), 4.87-4.85 (m, 1H), 4.42-4.36 (m, 2H), 3.61 (s, 3H), 2.98-2.85 (m, 4H), 2.32 (s, 3H), 1.92-1.86 (m, 4H).

Workup

  1. concentrationThen the mixture was concentrated under reduced pressure
  2. customthe residue was partitioned between water (10 mL) and dichloromethane (15 mL)
  3. extractionThe water phase was extracted with dichloromethane (3×10 mL)
  4. washThe combined organic layer was washed with brine (30 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-5148fc5e042d4b71bc1850817c16bf99
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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