碳酸氢铯 → (1R,2R)-2-({4'-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-3'-fluoro-1,1'-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid

HRID 9610

反应方程式

HRID 9610 反应方程式
I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:19])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:44]1[CH:59]=[CH:58][C:47]([C:48]([C@@H:50]2[CH2:54][CH2:53][CH2:52][C@H:51]2[C:55]([OH:57])=[O:56])=[O:49])=[CH:46][CH:45]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:44]4[CH:45]=[CH:46][C:47]([C:48]([C@@H:50]5[CH2:54][CH2:53][CH2:52][C@H:51]5[C:55]([OH:57])=[O:56])=[O:49])=[CH:58][CH:59]=4)=[CH:3][C:4]=3[F:19])[S:10][C:11]=2[CH:17]=1

参与物

9

反应物 5

HCID 10796碳酸氢铯HCID 517044乙酸钾HCID 2733548联硼酸频那醇酯HCID 23549251(1R,2R)-2-(4-溴苯甲酰基)环戊基甲酸HCID 23549325N-(4-Iodo-2-fluorophenyl)-6-chloro-1,3-benzothiazol-2-amine

产物 1

HCID 11466071(1R,2R)-2-({4'-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-3'-fluoro-1,1'-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid收率 60%

试剂、催化剂与溶剂 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)催化剂2 次HCID 962聚[6-[4-(4-氰基苯基)苯氧基]己基甲基丙烯酸酯]溶剂HCID 6228N,N-二甲基甲酰胺溶剂

反应条件

温度
85 °C

实验过程

A suspension of N-(4-iodo-2-fluorophenyl)-6-chloro-1,3-benzothiazol-2-amine (200 mg, 0.49 mmol), bis(pinacolato)diboron (130 mg, 0.52 mmol), KOAc (150 mg, 1.48 mmol), and PdCl2(dppf) (30 mg, 0.04 mmol) in DMF (5.0 mL) was degassed by bubbling a flow of nitrogen for 30 minutes. The reaction mixture was heated under nitrogen at 85° C. for 3 h. After the mixture was cooled to rt, (1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylic acid (140 mg, 0.49 mmol, >99% ee), Cs2CO3 (400 mg, 1.23 mmol) and PdCl2(dppf) (30 mg, 0.04 mmol) were added, and the reaction mixture was heated at 85° C. under nitrogen for 3 h. TLC analysis showed little starting materials remaining. The reaction mixture was cooled to rt, and diluted with water (50 mL). After the mixture was filtered through a pad of Celite®, 1 N HCl was added to the filtrate to adjust the acidity to pH<3. The solid that formed was collected by filtration, then dissolved in EtOAc (50 mL), and the resulting solution was dried over Na2SO4. Removal of solvent and drying in vacuo provided the desired product (120 mg, 60%, >99% ee). LC-MS m/z 495.3 (MH+), retention time 4.01 min.

后处理

  1. customwas degassed
  2. customby bubbling a flow of nitrogen for 30 minutes
  3. temperatureAfter the mixture was cooled to rt
  4. temperaturethe reaction mixture was heated at 85° C. under nitrogen for 3 h
  5. temperatureThe reaction mixture was cooled to rt
  6. filtrationAfter the mixture was filtered through a pad of Celite®, 1 N HCl
  7. additionwas added to the filtrate
  8. customThe solid that formed
  9. filtrationwas collected by filtration
  10. dissolutiondissolved in EtOAc (50 mL)
  11. dry with materialthe resulting solution was dried over Na2SO4
  12. customRemoval of solvent
  13. customdrying in vacuo

来源与证据

ORD记录
ord-947301e8b5bd42b680eea3d2d619713c
来源数据集
uspto-grants-2006_08
专利号
US07091228B2

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