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 920234ノート

反応式

HRID 920234 の反応式
[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

参加物

10

反応物 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

生成物 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

試薬・触媒・溶媒 4

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒HCID 6422Trifluoroacetic acid溶媒HCID 22036561Dimethyl sulfoxide methanol溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-3ede0ec5312b45ca8c5b61805be6884b
出典データセット
uspto-grants-2016_03
特許番号
US09273040B2

反応ノート

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