N-methyl-2-pyrrolidone → 2-Ethyl-6-methylisonicotinic acid tert-butyl ester

HRID 1908713

반응식

HRID 1908713 반응식
[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:19][CH2:18]1.C([Mg]Br)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:18][CH3:19])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]

참가 물질

5

반응물 3

HCID 13387N-methyl-2-pyrrolidoneHCID 860403662-Chloro-6-methyl-isonicotinic acid tert-butyl esterHCID 178418443HCID 178418443, 화합물

생성물 1

HCID 670269672-Ethyl-6-methylisonicotinic acid tert-butyl ester

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

To a red solution of 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (2.95 g, 13.0 mmol), Fe(acac)3 (512 mg, 1.45 mmol) and NMP (1.58 g, 16.0 mmol) in THF (400 mL), a solution of ethylmagnesium bromide (1.81 g, 13.6 mmol) in THF is slowly added at −77° C. The brown solution turns green-grey. The suspension is warmed to rt, stirred for 30 min before the yellow solution is again cooled to −70° C. and another portion of the Grignard reagent (1.38 g, 10.4 mmol) is added. The reaction mixture is warmed to rt, stirred for 16 h and then carefully quenched with 1 N aq. HCl (100 mL) and diluted with diethyl ether. The org. layer is separated and the aq. phase is extracted with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-ethyl-6-methyl-isonicotinic acid tert.-butyl ester as a yellow oil which is dissolved in 4 N HCl in dioxane (50 mL). The solution is stirred at 50° C. for 16 h before the solvent is evaporated to give 2-ethyl-6-methylisonicotinic acid hydrochloride as a beige powder; LC-MS: tR=0.28 min; [M+1]+=166.25; 1H NMR (CDCl3): δ 8.19 (s, 2H), 3.12 (q; J=7.6 Hz, 2H), 2.84 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).

후처리

  1. temperatureis again cooled to −70° C.
  2. temperatureThe reaction mixture is warmed to rt
  3. stirringstirred for 16 h
  4. customcarefully quenched with 1 N aq. HCl (100 mL)
  5. additiondiluted with diethyl ether
  6. customlayer is separated
  7. extractionthe aq. phase is extracted with diethyl ether
  8. dry with materialextracts are dried over MgSO4
  9. filtrationfiltered
  10. customevaporated
  11. customThe crude product is purified by MPLC on silica gel

출처 및 근거

ORD 기록
ord-d49b1e277b9a4cb18973f72760efeb29
출처 데이터셋
uspto-grants-2013_12
특허 번호
US08598208B2

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