Cesium carbonate → (S)-2-benzyl 3-ethyl 8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

HRID 1499213Notes

Reaction equation

HRID 1499213 reaction equation
Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[CH:7]=1.ClC1C=C(O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=NC=1.[CH2:53]1[C:57]2([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH:55]([C:63]([O:65][CH2:66][CH3:67])=[O:64])[N:54]1[C:68]([O:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)=[O:69].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[CH:7]=[C:2]([N:60]3[CH2:59][CH2:58][C:57]4([CH2:53][N:54]([C:68]([O:70][CH2:71][C:72]5[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=5)=[O:69])[C@H:55]([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:56]4)[CH2:62][CH2:61]3)[N:3]=[N:4][CH:5]=2)[C:10]([F:12])([F:11])[F:13])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 1179417662-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylateHCID 131734251(R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine (R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine

Product 1

HCID 117951939(S)-2-benzyl 3-ethyl 8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of the (R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine/(R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine mixture from step 1 in 1,4-dioxane (19 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (980 mg, 2.83 mmol), Cs2CO3 (2.30 g, 7.07 mmol), Pd2(dba)3 (432 mg, 0.471 mmol), and rac-BINAP (587 mg, 0.940 mmol), and the reaction mixture was heated to 60° C. for 60 h. Then the reaction mixture was cooled to RT, filtered through celite, washed with EtOAc, and the filtrate concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Workup

  1. temperatureThen the reaction mixture was cooled to RT
  2. filtrationfiltered through celite
  3. washwashed with EtOAc
  4. concentrationthe filtrate concentrated in vacuo
  5. customPurification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane)

Sources & evidence

ORD record
ord-2839d2bffbbb4c9a83b446a703994153
Source dataset
uspto-grants-2015_12
Patent number
US09199994B2

Reaction notes

Loading…