Ethyl chloroformate → 3-[4-(6-Amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester

HRID 1926338Notes

Reaction equation

HRID 1926338 reaction equation
[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:30])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:27][CH:26]4[N:28](C)[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1(C)C=CC=CC=1.O>[CH2:41]([O:40][C:38]([N:28]1[CH:26]2[CH2:25][CH2:24][CH:23]1[CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:14]3[CH:13]=[N:12][C:11]([NH2:30])=[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=3)[CH:17]=[N:18]1)[CH2:27]2)=[O:39])[CH3:42]

Participants

6

Reactant 3

HCID 10928Ethyl chloroformateHCID 11430Potassium CarbonateHCID 441601393-benzothiazol-2-yl-5-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine

Product 1

HCID 675211043-[4-(6-Amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
110 °C

Procedure

To a solution of 3-benzothiazol-2-yl-5-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (50.8 mg, 0.122 mmol; 1 eq) and K2CO3 (1.2 mg, 0.0087 mmol, 7 mol %) in toluene (3 mL), ethyl chloroformate (67.0 mg, 0.617 mmol, 5 eq) in toluene (1 mL) was added. The solution was heated to reflux for a total of 10 h (temp=110° C.). The residue was dissolved in water. The aqueous mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel [0.5″×10″ column, eluting with CH2Cl2:EtOAc 1:0→2:1→1:1→1:2→0:1]. Fractions containing product were combined and concentrated in vacuo to give the title compound. MS (ES+): m/z=475.13 (100) [MH+]. HPLC: tR=3.41 min (ZQ2, polar—5 min).

Workup

  1. temperatureThe solution was heated
  2. extractionThe aqueous mixture was extracted with CH2Cl2 (3×)
  3. dry with materialthe combined organic layers were dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude was purified by column chromatography on silica gel [0.5″×10″ column
  7. washeluting with CH2Cl2:EtOAc 1:0→2:1→1:1→1:2→0:1]
  8. additionFractions containing product
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-b1af2357e5154a05a07289e8d5452b6c
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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