Hydrochloric Acid → 4-Hydroxy-1-(3-methylbutyl)-3-(8-methyl-1,1-dioxido-4h-[1,3]oxazolo[5,4-h][1,2,4]benzothiadiazin-3-yl)-1,8-naphthyridin-2(1h)-one

HRID 601339Notes

Reaction equation

HRID 601339 reaction equation
[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16].[CH3:18][C:19]1[O:20][C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([CH2:31]C(OCC)=O)=[N:27][S:28](=[O:30])(=[O:29])[C:23]=3[C:22]=2[N:39]=1.[H-].[Na+].Cl>O1CCCC1.O.C(O)(=O)C>[OH:15][C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[C:6](=[O:16])[C:31]=1[C:26]1[NH:25][C:24]2[CH:37]=[CH:38][C:21]3[O:20][C:19]([CH3:18])=[N:39][C:22]=3[C:23]=2[S:28](=[O:30])(=[O:29])[N:27]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 102361501-(3-Methylbutyl)-2H-pyrido[2,3-d][1,3]oxazine-2,4(1H)-dioneHCID 86594016ethyl (8-methyl-1,1-dioxido-4H-[1,3]oxazolo[5,4-h][1,2,4]benzothiadiazin-3-yl)acetate

Product 1

HCID 1363473614-Hydroxy-1-(3-methylbutyl)-3-(8-methyl-1,1-dioxido-4h-[1,3]oxazolo[5,4-h][1,2,4]benzothiadiazin-3-yl)-1,8-naphthyridin-2(1h)-oneYield 60%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of the product of Example 12A (16.7 mg, 0.0714 mmol) and the product of Example 352F (23.1 mg, 0.0714 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (60%, 11.4 mg, 0.286 mmol) under a nitrogen atmosphere. The reaction was heated at reflux for 3 hours, cooled to 0° C., and treated with glacial acetic acid (0.165 mL). The resulting yellow solution was heated at reflux for 2 hours, cooled to 0° C., diluted with water (5 mL), and acidified with 1N aqueous hydrochloric acid to pH 3. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a yellow solid (20 mg, 60%). MS (ESI−) m/z 466 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.71 (m, 1 H) 2.73 (s, 3H) 4.50 (m, 2 H) 7.50 (dd, J=7.72, 4.41 Hz, 1 H) 7.64 (d, J=8.82 Hz, 1 H) 8.10 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=7.91, 2.02 Hz, 1 H) 8.89 (dd, J=4.60, 2.02 Hz, 1 H) 14.18 (s, 1 H). A suspension of the product of Example 352G (14.6 mg, 0.0312 mmol) in anhydrous tetrahydrofuran (3 mL) and distilled water (1 mL) was treated with 0.998 N aqueous sodium hydroxide (0.0313 mL, 0.0312 mmol) and the yellow solution mixed for 15 minutes. The solvent was removed under reduced pressure and the residue dried to afford the sodium salt of Example 352G (15 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.48 (m, 2 H) 1.65 (m, 1 H) 2.67 (s, 3 H) 4.30 (m, J=8.82, 6.25 Hz, 2 H) 7.13 (dd, J=7.91, 4.60 Hz, 1 H) 7.21 (d, J=8.82 Hz, 1 H) 7.86 (d, J=8.82 Hz, 1 H) 8.38 (dd, J=8.09, 1.47 Hz, 1 H) 8.53 (m, J=2.94 Hz, 1 H) 16.09 (s, 1 H).

Workup

  1. temperatureThe reaction was heated
  2. temperatureat reflux for 3 hours
  3. temperatureThe resulting yellow solution was heated
  4. temperatureat reflux for 2 hours
  5. temperaturecooled to 0° C.
  6. filtrationThe resulting precipitate was collected by filtration
  7. washwashed with water
  8. customdried

Sources & evidence

ORD record
ord-0c8e5dd1990d4be8a98d3ce4990c5959
Source dataset
uspto-grants-2011_03
Patent number
US07902203B2

Reaction notes

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