tert-Butyl 2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate → tert-Butyl 2-(5-(2-fluoro-6-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 579364Notes

Reaction equation

HRID 579364 reaction equation
C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[C:11]([F:20])[C:10]=1[C:21]1[S:25][C:24]([N:26]2[CH2:29][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:27]2)=[N:23][N:22]=1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[F:20][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:14]=[C:9]([OH:8])[C:10]=1[C:21]1[S:25][C:24]([N:26]2[CH2:27][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:29]2)=[N:23][N:22]=1

Participants

5

Reactant 1

HCID 86727188tert-Butyl 2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Product 1

HCID 136341347tert-Butyl 2-(5-(2-fluoro-6-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 74.5%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

A solution of tert-butyl 2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (86 mg, 0.149 mmol) in a 1:1: mixture MeOH:DCM (3 mL) was added to a nitrogen flushed flask containing 10% Pd/C (8.6 mg). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 18 hours. The reaction mixture was flushed with nitrogen and an additional 8.6 mg of 10% Pd/C was added. The reaction was diluted with 1:1 MeOH:DCM (3 mL), and again placed under a hydrogen atmosphere (balloon) and stirred at room temperature for an additional 5 days. The reaction mixture was flushed with nitrogen, diluted with 10% MeOH in DCM (50 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford a pale brown/off-white solid. The solid was re-dissolved in 25% MeOH in DCM (10 mL) and added to a nitrogen flushed flash containing 10% Pd/C (8.6 mg). The reaction mixture was placed under a hydrogen atmosphere (balloon) and left to stir at room temperature for 18 hours. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product as a brown solid. The crude material was purified by flash chromatography using a 10 g silica cartridge running a MeOH/DCM gradient and collecting by mass to afford an the title compound as a pale brown solid (54 mg, 74% yield). LC-MS: Rt 1.33 min; MS m/z 487.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.92 (s, 1H), 8.36 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.22 (dd, J=12.6, 1.6 Hz, 1H), 7.14-7.19 (m, 1H), 3.92 (s, 4H), 3.28-3.31 (m, 4H), 1.69-1.79 (m, 4H), 1.40 (s, 9H).

Workup

  1. customThe reaction mixture was flushed with nitrogen
  2. additionan additional 8.6 mg of 10% Pd/C was added
  3. additionThe reaction was diluted with 1:1 MeOH
  4. stirringstirred at room temperature for an additional 5 days
  5. customThe reaction mixture was flushed with nitrogen
  6. additiondiluted with 10% MeOH in DCM (50 mL)
  7. filtrationfiltered through celite
  8. concentrationThe filtrate was concentrated in vacuo
  9. customto afford a pale brown/off-white solid
  10. additionadded to a nitrogen
  11. customflushed flash
  12. additioncontaining 10% Pd/C (8.6 mg)
  13. waitleft
  14. stirringto stir at room temperature for 18 hours
  15. additionThe reaction mixture was diluted with 10% MeOH in DCM (50 mL)
  16. filtrationfiltered through celite
  17. concentrationThe filtrate was concentrated in vacuo
  18. customto afford the crude product as a brown solid
  19. customThe crude material was purified by flash chromatography
  20. customcollecting by mass

Sources & evidence

ORD record
ord-0217c8617eee469c8e8f1678d7162169
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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