Dichloromethane → 5-Fluoro-3-((4-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride

HRID 920246Notes

Reaction equation

HRID 920246 reaction equation
COC1C=C(OC)C=CC=1C[N:6]([C:40]1[S:44][N:43]=[CH:42][N:41]=1)[S:7]([C:10]1[C:38]([F:39])=[CH:37][C:13]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]4[F:36])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:59]>>[ClH:59].[F:39][C:38]1[C:10]([S:7]([NH:6][C:40]2[S:44][N:43]=[CH:42][N:41]=2)(=[O:9])=[O:8])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[CH2:27][NH:26][CH2:25][CH:24]4[F:36])[C:13]=2[CH:37]=1

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 89526063tert-Butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

Product 1

HCID 895247795-Fluoro-3-((4-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride

Procedure

To a flask containing tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-8) (48 mg, 0.066 mmol) in DCM (3 ml) was added TFA (0.5 ml, 6.49 mmol). The reaction mixture was then stirred at room temperature. Followed by LC/MS . . . after ˜20 minutes the reaction mixture was diluted/quenched with DMSO, then MeOH, then filtered (syringe filter) then concentrated (to remove DCM), then diluted with MeOH/DMSO & purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & added saturated HCl in EtOAc (˜4N) & concentrated to yield 5-fluoro-3-((4-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (24-9). HRMS [M+H]: calculated; 480.0606, observed; 480.0587. 1H NMR (400 MHz, CD3 OD): δ 8.22 (s, 1H); 7.80 (d, J=5.5 Hz, 1H); 7.63-7.57 (m, 1H); 7.57-7.48 (m, 2H); 7.11 (d, J=9.3 Hz, 1H); 5.81 (d, J=48.5 Hz, 1H); 5.16-5.10 (m, 2H); 4.74-4.66 (m, 1H); 4.47-4.39 (m, 1H); 4.02-3.92 (m, 1H); 3.71-3.55 (m, 1H);

Workup

  1. customafter ˜20 minutes the reaction mixture was diluted/quenched with DMSO
  2. filtrationMeOH, then filtered
  3. filtration(syringe filter)
  4. concentrationthen concentrated
  5. custom(to remove DCM)
  6. additiondiluted with MeOH/DMSO
  7. custompurified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column)
  8. concentrationdesired fractions concentrated (GENEVAC)
  9. dissolutiondissolved in MeOH/DCM
  10. additionadded saturated HCl in EtOAc (˜4N)
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-ed8644f4006c49efaee230ac8e284acb
Source dataset
uspto-grants-2016_03
Patent number
US09273040B2

Reaction notes

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