Diisopropylethylamine → (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acid

HRID 1279033Notes

Reaction equation

HRID 1279033 reaction equation
Cl.C([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]([OH:6])=[O:17])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 5627874-Methoxy-2,3,6-trimethylbenzenesulfonyl chlorideHCID 11459563L-Phenylalanine, 1,1-dimethylethyl ester, hydrochloride (1:1)

Product 1

HCID 57314611(2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acidYield 88.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2× s), 2.12 and 2.17 (3H, 2× s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2× s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).

Workup

  1. concentrationwas concentrated
  2. dissolutionthe residue dissolved in ethyl acetate
  3. washThe ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in 16 mL of dichloromethane
  7. addition4 mL of trifluoroacetic acid was added
  8. stirringAfter stirring for 2h at room temperature the reaction mixture
  9. concentrationwas concentrated
  10. additionDichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture
  11. customseparated
  12. washwashed with dichloromethane
  13. extractionextracted with dichloromethane
  14. washThe combined dichloromethane layers were washed with brine
  15. dry with materialdried over magnesium sulfate
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-64bf3ef2de184373ba2cdee5b012a09d
Source dataset
uspto-grants-2002_09
Patent number
US06444672B1

Reaction notes

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