Acetic Acid → 3-((7-(3,3-Difluoroazetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride

HRID 920234노트

반응식

HRID 920234 반응식
[F:1][C:2]1[C:3]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[C:21]4[CH2:20][C:19](=O)[CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:23]=1.[ClH:33].[F:34][C:35]1([F:39])[CH2:38][NH:37][CH2:36]1.CCN(C(C)C)C(C)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.CS(C)=O.C(O)(C(F)(F)F)=O.O.CN(C=O)C>[ClH:33].[F:34][C:35]1([F:39])[CH2:38][N:37]([CH:19]2[CH2:20][C:21]3[C:12]([CH2:11][N:7]4[C:6]5[CH:23]=[C:2]([F:1])[C:3]([S:24]([NH:27][C:28]6[S:32][N:31]=[CH:30][N:29]=6)(=[O:25])=[O:26])=[CH:4][C:5]=5[O:9][C:8]4=[O:10])=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18]2)[CH2:36]1

참가 물질

10

반응물 5

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 5003444Sodium cyanoborohydrideHCID 895260585-Fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide

생성물 1

HCID 895259493-((7-(3,3-Difluoroazetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride

시약·촉매·용매 4

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 6422Trifluoroacetic acid용매HCID 22036561Dimethyl sulfoxide methanol용매

실험 절차

To a vial was added 5-fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-5) (41 mg, 0.086 mmol), then DMF (0.6 mL) followed by 3,3-DIFLUOROAZETIDINE HYDROCHLORIDE (38 mg, 0.293 mmol), then DIPEA (100 μL, 0.573 mmol). The reaction mixture was then permitted to stir at room temperature for 20 minutes, then added ACETIC ACID (150 μL, 2.62 mmol). The reaction mixture was then permitted to stir at room temperature for 2 hrs (capped, but not under N2). Followed by LC/MS. After 2 hours at room temperature added SODIUM CYANOBOROHYDRIDE (33 mg, 0.525 mmol) in one portion to the reaction mixture at room temperature. After another hour at room temperature; the reaction mixture was diluted with MeOH/DMSO/drops TFA/drops H2O, stirred for ˜10 minutes, then filtered (syringe filter), then purified (without workup) by reverse phase chromatography (5-65% 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 a saturated solution of HCl in EtOAc (˜4N) & concentrated to yield 3-((7-(3,3-difluoroazetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (19-6). HRMS [M+H] calculated; 552.0982, observed; 552.0982. 1H NMR (400 MHz, CD3 OD): δ 8.21 (s, 1H); 7.79 (d, J=5.5 Hz, 1H); 7.24-7.18 (m, 3H); 7.01 (d, J=9.3 Hz, 1H); 5.18-5.01 (m, 2H); 4.99-4.88 (m, 4H); 3.83-3.74 (m, 1H); 3.44-3.40 (m, 1H); 3.03-2.94 (m, 2H); 2.69-2.59 (m, 1H); 2.29-2.22 (m, 1H); 1.79-1.67 (m, 1H).

후처리

  1. stirringto stir at room temperature for 2 hrs (
  2. customcapped
  3. waitAfter another hour at room temperature
  4. stirringstirred for ˜10 minutes
  5. filtrationfiltered
  6. filtration(syringe filter)
  7. custompurified (without workup) by reverse phase chromatography (5-65% 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 a saturated solution of HCl in EtOAc (˜4N)
  11. concentrationconcentrated

출처 및 근거

ORD 기록
ord-3ede0ec5312b45ca8c5b61805be6884b
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09273040B2

반응 노트

불러오는 중…