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

HRID 633139

反応式

HRID 633139 の反応式
[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

参加物

3

反応物 1

HCID 186730034-(Methoxycarbonyl)-3-methylbenzoic acid

生成物 1

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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

実験手順

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)+.

後処理

  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

出典と根拠

ORDレコード
ord-9b50d0df9acd499fada7464eb55e4666
出典データセット
uspto-grants-2016_04
特許番号
US09321761B2

関連ノート

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