Cesium carbonate → HCID 86708567, compound

HRID 921694Notes

Reaction equation

HRID 921694 reaction equation
Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[O:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[C:29]([O:31][CH3:32])=[O:30])[CH2:20]1.CN1CCNCC1C(OC)=O.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.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1(C)C=CC=CC=1>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH:21]3[CH2:22][O:19][CH2:20]3)[CH:24]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 18404484Methyl 1-methylpiperazine-2-carboxylateHCID 86708481Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamateHCID 86708568HCID 86708568, compound

Product 1

HCID 86708567HCID 86708567, compoundYield 18.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

(+/−) Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (1.52 g, 4.58 mmol), a 3:1 mixture of methyl 1-(oxetan-3-yl)piperazine-2-carboxylate (0.688 g, 3.44 mmol) and methyl 1-methylpiperazine-2-carboxylate (0.181 g, 1.144 mmol), Pd2(dba)3 (0.420 g, 0.458 mmol), BINAP (0.285 g, 0.458 mmol), Cs2CO3 (2.240 g, 6.88 mmol), and Toluene (40 mL) were combined in a round bottom flask. The flask was evacuated and backfilled with N2 3×, and the reaction was heated at 105° C. for 18 h. The reaction was cooled to room temperature and an additional 0.05 eq. each of catalyst and ligand were added. The reaction vial was resealed, evacuated and backfilled with N2 3×, then heated at 105° C. for 2 h. The reaction was cooled to room temperature and diluted with EtOAc. The solution was filtered through celite and the filtrate concentrated in vacuo. The crude material was purified by flash column chromatography 0-5% MeOH/DCM, and then repurified with 0-20% Acetone/DCM. 292 mg of pure methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate was obtained, along with 592 mg of a 3:1.7 mixture of methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate and methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methylpiperazine-2-carboxylate. Estimated yields based on 1H NMR: methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate (683 mg) and methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methylpiperazine-2-carboxylate (201 mg).

Workup

  1. customwere combined in a round bottom flask
  2. customThe flask was evacuated
  3. temperatureThe reaction was cooled to room temperature
  4. customThe reaction
  5. customevacuated
  6. temperatureheated at 105° C. for 2 h
  7. temperatureThe reaction was cooled to room temperature
  8. additiondiluted with EtOAc
  9. filtrationThe solution was filtered through celite
  10. concentrationthe filtrate concentrated in vacuo
  11. customThe crude material was purified by flash column chromatography 0-5% MeOH/DCM
  12. customrepurified with 0-20% Acetone/DCM

Sources & evidence

ORD record
ord-dc8b5ab4bfd0464daeaa69ec3c014573
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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