3-Chlorobenzoic Acid → 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzene-sulfonamide

HRID 419037Notes

Reaction equation

HRID 419037 reaction equation
[Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:46]2[C:47]([CH:53]=O)=[N:48][CH:49]=[C:50]([Cl:52])[CH:51]=2)[CH2:43][O:44][CH3:45])(=[O:41])=[O:40])=[CH:35][C:34]=1[C:55]([F:58])([F:57])[F:56]>C1COCC1.CCOCC>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:46]2[C:47]([CH:53]3[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][C:23]=4[Cl:22])[C:26](=[O:28])[O:27]3)=[N:48][CH:49]=[C:50]([Cl:52])[CH:51]=2)[CH2:43][O:44][CH3:45])(=[O:41])=[O:40])=[CH:35][C:34]=1[C:55]([F:56])([F:58])[F:57]

Participants

8

Reactant 5

HCID 4473-Chlorobenzoic AcidHCID 8058HexaneHCID 130352,2,6,6-TetramethylpiperidineHCID 579420984-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideHCID 178418339Butyllithium

Product 1

HCID 579423744-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzene-sulfonamideYield 26.6%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-50 °C

Procedure

To a solution of n-BuLi in hexane (0.69 mL, 1.1 mmol, 1.6 M solution in hexane) under N2 atm at −20° C. was added a solution of 2,2,6,6-tetramethyl piperidine (TMP, 187 μL) in THF (1 mL). The mixture cooled to −50° C. and a solution of 3-chlorobenzoic acid (78.3 mg, 0.5 mmol) in THF (0.5 mL) was added. The resulting reaction mixture was stirred at −50° C. for 4 h and treated slowly with 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (884 mg, 2.0 mmol) in THF (1 mL), warmed to room temperature and stirred for 2 h. The reaction mixture was slowly poured in ice cold water (10 mL), and ether was added. The bilayer was separated and the aqueous portion was washed with diethyl ether (2×25 mL) and separated. The aqueous layer was acidified with 4 N HCl solutions to pH 2 and extracted with diethyl ether (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residual solid was dissolved in CH2Cl2 (5 mL), treated with p-toluenesulfonic acid monohydrate (100 mg), and stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by flash chromatography (25% EtOAc in hexanes) to obtain 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (77 mg) in 26.6% yield. MS m/z: 581 (M+H).

Workup

  1. customThe resulting reaction mixture
  2. temperaturewarmed to room temperature
  3. stirringstirred for 2 h
  4. customThe bilayer was separated
  5. washthe aqueous portion was washed with diethyl ether (2×25 mL)
  6. customseparated
  7. extractionextracted with diethyl ether (2×25 mL)
  8. dry with materialThe combined organic extracts were dried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated
  11. dissolutionThe residual solid was dissolved in CH2Cl2 (5 mL)
  12. additiontreated with p-toluenesulfonic acid monohydrate (100 mg)
  13. stirringstirred at room temperature for 2 h
  14. concentrationThe reaction mixture was concentrated
  15. custompurified by flash chromatography (25% EtOAc in hexanes)

Sources & evidence

ORD record
ord-10164bd3ff3945b1b4f0b0fb068ebd38
Source dataset
uspto-grants-2012_01
Patent number
US08093247B2

Reaction notes

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