4-(Methoxycarbonyl)-3-methylbenzoic acid → Methyl 4-(hydroxymethyl)-2-methylbenzoate

HRID 633139

반응식

HRID 633139 반응식
[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:14])=[O:4]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([CH3:14])[CH:7]=1

참가 물질

3

반응물 1

HCID 186730034-(Methoxycarbonyl)-3-methylbenzoic acid

생성물 1

HCID 23021531Methyl 4-(hydroxymethyl)-2-methylbenzoate

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL of THF before a solution of 2.6 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction was re-cooled to 0° C. and another 2.6 mL of BH3-THF was added dropwise before the ice bath was removed. Upon completion, the reaction was re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbenzoate. 220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-methylbenzoate. 255 mg of methyl 4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45° C. for 1 hour via Procedure M to give 2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.

후처리

  1. additionwas added dropwise
  2. customThe ice bath was subsequently removed
  3. temperatureThe reaction was re-cooled to 0° C.
  4. additionanother 2.6 mL of BH3-THF was added dropwise before the ice bath
  5. customwas removed
  6. temperatureUpon completion, the reaction was re-cooled to 0° C.
  7. customquenched with 3N HCl dropwise
  8. extractionThe aqueous layer was extracted 2 times with Ethyl Acetate
  9. extractionthe organic layer was then extracted once with bicarbonate solution and brine
  10. dry with materialdried over Magnesium Sulfate
  11. filtrationfiltered
  12. concentrationconcentrated

출처 및 근거

ORD 기록
ord-9b50d0df9acd499fada7464eb55e4666
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09321761B2

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