Thionyl Chloride → 1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

HRID 1969898Notes

Reaction equation

HRID 1969898 reaction equation
[CH2:1]([CH:3]1[CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH:4]1[C:12]([NH:14][NH:15][C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1)=O)[CH3:2].O1CCOCC1.CCN(C(C)C)C(C)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH:4]1[C:12]1[N:17]2[C:18]3[CH:24]=[CH:23][N:22]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:27])=[O:26])[C:19]=3[N:20]=[CH:21][C:16]2=[N:15][N:14]=1)[CH3:2]

Participants

6

Reactant 4

HCID 24386Thionyl Chloride2×HCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 585573298-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide

Product 1

HCID 585572181-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineYield 64%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
75 °C

Procedure

A round bottom flask was charged with 8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide (4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To the flask was added DIEA (8.81 mL, 50.5 mmol) followed by the addition of thionyl chloride (0.770 mL, 10.6 mmol). The mixture was heated to about 75° C. for about 90 min. Additional thionyl chloride (0.074 mL, 1.0 mmol) was added and heating was continued for about 1 h. The reaction was cooled to rt and stirred overnight. The solution was diluted with DCM (75 mL) and washed with water (50 mL). The layers were separated and the organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a dark brown oil. The crude product was purified via flash silica gel chromatography eluting with a gradient of 0-60% acetone in heptane. The product containing fractions were combined and concd to give material that was loaded onto a second column eluting with a gradient of 0-60% acetone in heptane. The product containing fractions were combined and concd under reduced pressure to give 1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a tan powder (3.0 g, 64%): LC/MS (Table 1, Method c) Rt=1.44 min; MS m/z: 468 (M+H)+.

Workup

  1. temperatureheating
  2. temperatureThe reaction was cooled to rt
  3. washwashed with water (50 mL)
  4. customThe layers were separated
  5. dry with materialthe organic layer was dried over anhydrous MgSO4
  6. filtrationfiltered
  7. customconcd under reduced pressure to give a dark brown oil
  8. customThe crude product was purified via flash silica gel chromatography
  9. washeluting with a gradient of 0-60% acetone in heptane
  10. additionThe product containing fractions
  11. customto give material that
  12. washeluting with a gradient of 0-60% acetone in heptane
  13. additionThe product containing fractions

Sources & evidence

ORD record
ord-f331d5618139407e91b170801cb889b4
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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