Acetic Acid → N-Cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-4-{[(3R)-3-(hydroxymethyl)piperazin-1-yl]sulfonyl}-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide

HRID 906453Notes

Reaction equation

HRID 906453 reaction equation
[OH-].[Na+].[CH:3]1([NH:6][C:7](=[O:46])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:18]=[C:17]4[S:31]([N:34]3[CH2:39][CH2:38][N:37]4C(=O)[O:41][CH2:42][C@H:36]4[CH2:35]3)(=[O:33])=[O:32])[C:11]([CH3:44])=[C:10]([F:45])[CH:9]=2)[CH2:5][CH2:4]1.C(O)(=O)C>CO>[CH:3]1([NH:6][C:7](=[O:46])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:18]=[C:17]4[S:31]([N:34]3[CH2:39][CH2:38][NH:37][C@@H:36]([CH2:42][OH:41])[CH2:35]3)(=[O:33])=[O:32])[C:11]([CH3:44])=[C:10]([F:45])[CH:9]=2)[CH2:4][CH2:5]1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 67389817N-Cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-4-{[(8aR)-3-oxotetrahydro[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl]sulfonyl}-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide

Product 1

HCID 59285296N-Cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-4-{[(3R)-3-(hydroxymethyl)piperazin-1-yl]sulfonyl}-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamideYield 21.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
90 °C

Procedure

2 N aqueous NaOH solution (2 mL) was added to a solution of N-cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-4-{[(8aR)-3-oxotetrahydro[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl]sulfonyl}-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide (Example 49d, 0.291 g) in methanol (2 mL) and the mixture stirred at 90° C. for 45 min. The reaction was neutralised with acetic acid and the volatiles removed under reduced pressure before partitioning between water and DCM. The organic layer was separated and the aqueous extracted further (2×) and the combined organics dried (MgSO4), filtered and evaporated. The residue was purified by SCX (eluting with methanol to remove impurities, then flushing with methanolic ammonia to elute product). Further purification by preparative HPLC (Xbridge column using a 95-5% gradient of 0.3% aqueous ammonia in acetonitrile), solvent evaporation under reduced pressure and trituration with diethyl ether gave the title compound (0.059 g).

Workup

  1. customthe volatiles removed under reduced pressure
  2. custombefore partitioning between water and DCM
  3. customThe organic layer was separated
  4. extractionthe aqueous extracted further (2×)
  5. dry with materialthe combined organics dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified by SCX (
  9. washeluting with methanol
  10. customto remove impurities
  11. customflushing with methanolic ammonia
  12. washto elute product)
  13. customFurther purification by preparative HPLC (Xbridge column
  14. customsolvent evaporation under reduced pressure and trituration with diethyl ether

Sources & evidence

ORD record
ord-8cf9c51c8566425ea33e755605f60a03
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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