1-Hydroxybenzotriazole → N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester

HRID 2270843Notes

Reaction equation

HRID 2270843 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:21])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:23][O:24][C:25](=[O:37])[C@H:26]([CH2:28][NH:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31])[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:21])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C@H:26]([C:25]([O:24][CH3:23])=[O:37])[CH2:28][NH:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31])=[O:6]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 226613772-Chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acidHCID 688207093-(thiophene-2-carbonyl)amino-L-alanine methyl ester hydrochloride

Product 1

HCID 131723034N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl esterYield 98%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid (Example 41; 75.8 mg, 0.25 mmol), 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 73 mg, 0.28 mmol), HBTU (113 mg, 0.30 mmol), HOBT (41 mg, 0.27 mmol) and diisopropylethylamine (0.22 mL, 1.26 mmol) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The solvent was evaporated. Ethyl acetate (30 mL) was added and the solution was washed with sodium hydrogen carbonate solution and 0.5 M HCl. Each of the aqueous layers was extracted with ethyl acetate (10 mL) and the combined organic layers were dried (Na2SO4), filtered, evaporated, and chromatographed (10-100% ethyl acetate/hexanes) to give N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (125 mg, 98%).

Workup

  1. customThe solvent was evaporated
  2. additionEthyl acetate (30 mL) was added
  3. washthe solution was washed with sodium hydrogen carbonate solution and 0.5 M HCl
  4. extractionEach of the aqueous layers was extracted with ethyl acetate (10 mL)
  5. dry with materialthe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated
  8. customchromatographed (10-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-7b3b42c0723043a4a13991dbbc04d915
Source dataset
uspto-grants-2001_12
Patent number
US06331640B1

Reaction notes

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