4-Methylmorpholine → 3-(2-{[(2,5-Dichloro-thiophene-3-carbonyl)-amino]-methyl}-4-hydroxy-phenyl)-propionic acid tert-butyl ester

HRID 1181045Notes

Reaction equation

HRID 1181045 reaction equation
[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](O)=[O:8].CN1CCOCC1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:33]([O:37][C:38](=[O:50])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=1[CH2:48][NH2:49])([CH3:36])([CH3:35])[CH3:34]>C1COCC1.CN(C=O)C>[C:33]([O:37][C:38](=[O:50])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=1[CH2:48][NH:49][C:7]([C:6]1[CH:5]=[C:4]([Cl:10])[S:3][C:2]=1[Cl:1])=[O:8])([CH3:36])([CH3:34])[CH3:35]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 2254382,5-Dichlorothiophene-3-carboxylic acidHCID 17984622Tert-butyl-3-[2-(aminomethyl)-4-hydroxyphenyl]propanoate

Product 1

HCID 589791033-(2-{[(2,5-Dichloro-thiophene-3-carbonyl)-amino]-methyl}-4-hydroxy-phenyl)-propionic acid tert-butyl esterYield 79.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of the 2,5-dichloro-thiophene-3-carboxylic acid (12.9 g, 65.5 mmol) and 4-methylmorpholine (7.17 mL, 65.2 mmol) in dry THF (400 mL) was cooled to −15° C. Isobutyl chloroformate (8.46 mL, 65.2 mmol) was added. The mixture was stirred 3 min and triethylamine (9.1 mL, 65 mmol) was added. A solution of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (16.4 g, 65.3 mmol) in DMF (130 mL) pre-cooled to −15° C. was added via cannula over 15 min. After stirring 1 h, TLC indicated complete reaction. The reaction mixture was allowed to warm to ambient temperature. Solids were removed by filtration and washed with THF (100 mL). The filtrate was diluted with Et2O (500 mL) and washed with water (250 mL) then brine (150 mL). The organic layer was dried (Na2SO4) and concentrated. The crude brown oil was purified by silica gel chromatography (hexanes/EtOAc 2/1) and recrystallization (toluene) to afford the title compound as a white crystalline solid (22.3 g, 79.6%). MS (ES+) m/z 430.1 [M+H]+.

Workup

  1. additionwas added via cannula over 15 min
  2. stirringAfter stirring 1 h
  3. customreaction
  4. customSolids were removed by filtration
  5. washwashed with THF (100 mL)
  6. additionThe filtrate was diluted with Et2O (500 mL)
  7. washwashed with water (250 mL)
  8. dry with materialThe organic layer was dried (Na2SO4)
  9. concentrationconcentrated
  10. customThe crude brown oil was purified by silica gel chromatography (hexanes/EtOAc 2/1) and recrystallization (toluene)

Sources & evidence

ORD record
ord-2ba3f4d74f7e411da211d19ed2748e8d
Source dataset
uspto-grants-2007_10
Patent number
US07282501B2

Reaction notes

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