Dichloromethane → HCID 89526046, compound

HRID 920279Notes

Reaction equation

HRID 920279 reaction equation
COC1C=C(OC)C=CC=1C[N:6]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)[S:7]([C:10]1[C:39]([F:40])=[CH:38][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][C:24]4([F:37])[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:60]>>[ClH:60].[F:37][C:24]1([F:36])[C:23]2[C:28](=[C:19]([CH2:18][N:14]3[C:13]4[CH:38]=[C:39]([F:40])[C:10]([S:7]([NH:6][C:41]5[S:42][CH:43]=[CH:44][N:45]=5)(=[O:8])=[O:9])=[CH:11][C:12]=4[O:16][C:15]3=[O:17])[CH:20]=[CH:21][CH:22]=2)[CH2:27][NH:26][CH2:25]1

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 89526552HCID 89526552, compound

Product 1

HCID 89526046HCID 89526046, compound

Procedure

To a flask containing tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (44-4) (45 mg, 0.060 mmol) (prepared from 43-1 by a sequence analogous to that presented herein) in DCM (3 ml) was added TFA (300 μl, 3.89 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 & filtered. The filtrate was 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 3-((4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-fluoro-2-oxo-N-(thiazol-2-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (44-5). HRMS [M+H]: calculated; 497.0560, observed; 497.0556. 1H NMR (499 MHz, DMSO): δ 7.77 (d, J=5.5 Hz, 1H); 7.73 (d, J=7.5 Hz, 1H); 7.58-7.50 (m, 2H); 7.39 (d, J=9.4 Hz, 1H); 7.29 (d, J=4.6 Hz, 1H); 6.88 (d, J=4.6 Hz, 1H); 5.13 (s, 2H); 4.52 (s, 2H); 3.99 (t, J=11.8 Hz, 2H).

Workup

  1. customprepared from 43-1 by a sequence analogous to that
  2. customAfter 20 minutes the reaction mixture was diluted/quenched with DMSO
  3. filtrationMeOH then filtered
  4. filtration(syringe filter)
  5. concentrationthen concentrated
  6. custom(to remove DCM)
  7. additiondiluted with MeOH/DMSO
  8. filtrationfiltered
  9. customThe filtrate was 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)
  10. concentrationdesired fractions concentrated (GENEVAC)
  11. dissolutiondissolved in MeOH/DCM
  12. additionadded saturated HCl in EtOAc (˜4N)
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-e91459f2e1af44d2931023cdc1a454c1
Source dataset
uspto-grants-2016_03
Patent number
US09273040B2

Reaction notes

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