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1-Hydroxybenzotriazole → Rac.-n-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester

HRID 1058409
Notes
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Reaction equation

HRID 1058409 reaction equation
C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:40][CH3:41])([O:38][CH3:39])=[O:37])[NH2:35].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:38][CH3:39])([O:40][CH3:41])=[O:37])[NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([C:20](=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][C:11]=1[Cl:10]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 2734718Methyl 2-{[(benzyloxy)carbonyl]amino}-2-(dimethyl phosphono)acetateHCID 11084793Methyl 2-amino-2-(dimethoxyphosphoryl)acetate
HCID 22661377
2-Chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid

Product 1

HCID 23560746Rac.-n-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl esterYield 62%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21584119Ethylacetate methanolSolvent

Procedure

Diisopropylethylamine (1.05 mL, 6 mmol) was added to a solution of 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid (Example 94; 457 mg, 1.5 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (662.5 mg, 2.0 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (597 mg, 1.6 mmol) and 1-hydroxybenzotriazole (223 mg, 1.65 mmol) in N,N-dimethylformamide (12 mL). The solution was stirred at room temperature for 17 h and then it was evaporated in vacuo to remove N,N-dimethylformamide. A solution of the residue in ethyl acetate (40 mL) was washed in turn with 0.5N hydrochloric acid solution (20 mL), brine (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL). Each of the aqueous layers was extracted with ethyl acetate (20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting oil was chromatographed over silica gel (75% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to give rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (450 mg, 62% yield) as an oil.

Workup

  1. customit was evaporated in vacuo
  2. customto remove N,N-dimethylformamide
  3. washA solution of the residue in ethyl acetate (40 mL) was washed in turn with 0.5N hydrochloric acid solution (20 mL), brine (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL)
  4. extractionEach of the aqueous layers was extracted with ethyl acetate (20 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customThe resulting oil was chromatographed over silica gel (75% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-1861df910da8432b99573e16d5fe4f88
Source dataset
uspto-grants-2003_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06515124B2

Reaction notes

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