Cesium carbonate → (R)-N-(6-(methylthio)thiazolo[5,4-b]pyrazin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 1875965Notes

Reaction equation

HRID 1875965 reaction equation
Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][S-:37].[Na+]>CN(C=O)C.O>[CH3:36][S:37][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]3)[CH2:22]4)=[N:10][C:5]2=[N:4][CH:3]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 4378561Sodium methanethiolateHCID 58088150Dimethyl (6-bromothiazolo[4,5-b]pyrazin-2-yl)carbonimidodithioateHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58087968(R)-N-(6-(methylthio)thiazolo[5,4-b]pyrazin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 48.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate from Step A of Example 263 (100 mg, 0.298 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (68 mg, 0.298 mmol) and cesium carbonate (100 mg, 0.60 mmol) in DMF (1.5 mL) was placed in a 1 dram vial and heated on a 100° C. oil bath for 1 hour, at which time, sodium thiomethoxide (100 mg, 1.43 mmol) was added and the mixture was heated overnight. The mixture was cooled to ambient temperature and poured into water (20 mL) and the resulting solids were collected by filtration and then purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(6-(methylthio)thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (52 mg, 46% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.39 (br. s., 1H) 8.31 (s, 1H) 4.03 (d, J=9.77 Hz, 1H) 3.70 (d, J=9.77 Hz, 1H) 3.41 (dd, J=14.95, 1.83 Hz, 1H) 2.73-3.10 (m, 5H) 2.63 (s, 3H) 2.10-2.25 (m, 2H) 1.47-1.86 (m, 3H). MS (LC/MS) R.T.=1.04; [M+H]+=363.04.

Workup

  1. temperaturethe mixture was heated overnight
  2. temperatureThe mixture was cooled to ambient temperature
  3. filtrationthe resulting solids were collected by filtration
  4. custompurified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform)
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-774ac7bcd9ac4fbe81fe37223431b880
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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