Hydrochloric Acid → (R,R)-N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropanecarboxamide

HRID 2079743Notes

Reaction equation

HRID 2079743 reaction equation
[Br:1]Br.[OH-].[Na+].C([C:8]1[C:9]([Br:20])=[N:10][S:11][C:12]=1[NH:13][C:14]([C@@H:16]1[CH2:18][C@H:17]1[CH3:19])=[O:15])(=O)C.S(=O)(O)[O-].[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[Br:20][C:9]1[C:8]([Br:1])=[C:12]([NH:13][C:14]([C@@H:16]2[CH2:18][C@H:17]2[CH3:19])=[O:15])[S:11][N:10]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 24408BromineHCID 23665763Sodium BisulfiteHCID 67103555HCID 67103555, compound

Product 1

HCID 67103560(R,R)-N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropanecarboxamideYield 55%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
10 °C

Procedure

Add bromine (114; mL, 2.2; mol) dropwise over 45; min to a cooled aqueous solution of sodium hydroxide (4.6M, 3.84; L, 17.8; mol) at −10° C. and stir for 0.5; hour to give a yellow solution. Add this solution dropwise to a pre-cooled −5° C. solution of (1R,2R)-2-methyl-cyclopropanecarboxylic acid (4-acetyl-3-bromo-isothiazol-5-yl)-amide (150; g, 495; mmol) in 1,4-dioxane (2; L) and stir 45; min at 5-10° C. Maintain cooling at 10° C. whilst adding a 40% (wt/wt) aqueous solution of sodium bisulfite (47.5; mL) over 5 min, stir 5; min and add slowly 12; M hydrochloric acid (approximately 500; mL) over 15 min until acidic (pH=2). Dilute with ethyl acetate (2; L) and separate the layers. Extract the aqueous layer twice with ethyl acetate (1; L). Combine the organic phases, dry over magnesium sulfate, filter and concentrate. Dissolve the residue in dichloromethane (600 mL), dilute with n-hexane (3; L), and cool to 5° C. overnight. Filter and wash the recovered solid with four portions of n-hexane (125; mL) to give the title compound as a white solid (92.6; g, 55%). If desired a second crop of the title compound (50.97; g, 30%) can be harvested from the mother liquors. MS (m/z): 339, 341, 343; (M+1).

Workup

  1. customhour to give a yellow solution
  2. customat 5-10° C
  3. temperatureMaintain
  4. stirringstir 5
  5. additionmin and add slowly 12
  6. customseparate the layers
  7. extractionExtract the aqueous layer twice with ethyl acetate (1; L)
  8. dry with materialCombine the organic phases, dry over magnesium sulfate
  9. filtrationfilter
  10. concentrationconcentrate
  11. dissolutionDissolve the residue in dichloromethane (600 mL)
  12. additiondilute with n-hexane (3; L)
  13. temperaturecool to 5° C. overnight
  14. filtrationFilter
  15. washwash the recovered solid with four portions of n-hexane (125; mL)

Sources & evidence

ORD record
ord-1bd4cbcc57ec4afe8fb225717808f751
Source dataset
uspto-grants-2011_04
Patent number
US07932274B2

Reaction notes

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