Dichloromethane → (6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone

HRID 2266682Notes

Reaction equation

HRID 2266682 reaction equation
C(OC(=O)[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[CH2:12]2)(C)(C)C.[Cl:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([Cl:32])[C:26]=1[CH:33]([O:35][C:36]1[C:37]([NH2:51])=[N:38][CH:39]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:41]=1)[CH3:34].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].Cl.O1CCOCC1>COCCOC.C(OCC)(=O)C.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]>[NH2:7][CH:8]1[CH:9]2[CH:13]1[CH2:12][N:11]([C:14]([C:15]1[CH:16]=[CH:17][C:18]([C:40]3[CH:39]=[N:38][C:37]([NH2:51])=[C:36]([O:35][CH:33]([C:26]4[C:27]([Cl:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=4[Cl:24])[CH3:34])[CH:41]=3)=[CH:19][CH:20]=1)=[O:22])[CH2:10]2

Participants

9

Reactant 5

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 204431481,4-Dioxane hydrochlorideHCID 211113943-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineHCID 58886163[3-(4-Iodo-benzoyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-carbamic acid tert-butyl ester

Product 1

HCID 21111335(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanoneYield 26%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of [3-(4-iodo-benzoyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-carbamic acid tert-butyl ester (100 mg, 0.234 mmol) and 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg, 0.234 mmol) in DME (2 mL) was added Pd(dppf)2Cl2.CH2Cl2 (10 mg, 0.012 mmol) and Cs2CO3 (351 mg, 0.702 mmol). The mixture was bubbled with nitrogen for 10 min then microwaved at 150° C. for 30 min. LCMS checked that the reaction was completed. The crude reaction mixture was diluted with ethyl acetate followed by washings with water and brine. The solution was dried over MgSO4. Purification by prep-HPLC afforded a solid. The solid was stirred with 4 N HCl/dioxane (3 mL) for 3 hr at room temperature. Removal of the volatiles led to a residue that was purified by prep-HPLC to afford (6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone (30 mg, yield 26%).

Workup

  1. customThe mixture was bubbled with nitrogen for 10 min
  2. customthen microwaved at 150° C. for 30 min
  3. customThe crude reaction mixture
  4. washfollowed by washings with water and brine
  5. dry with materialThe solution was dried over MgSO4
  6. customPurification
  7. customby prep-HPLC afforded a solid
  8. customRemoval of the volatiles
  9. customwas purified by prep-HPLC

Sources & evidence

ORD record
ord-6a3c87b002b14774bcea8174575ef9f3
Source dataset
uspto-grants-2010_12
Patent number
US07858643B2

Reaction notes

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