4-Methylmorpholine → 4-O-tert-butyl 1-O-[(4-methoxyphenyl)methyl] (2S)-2-[(Z)-[2-[[(6R,7R)-2-benzhydryloxycarbonyl-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]amino]-1-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-oxoethylidene]amino]oxybutanedioate

HRID 525912Notes

Reaction equation

HRID 525912 reaction equation
[C:1]([O:5][C:6](=[O:41])[CH2:7][C@H:8]([O:21]/[N:22]=[C:23](/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])\[C:24](O)=[O:25])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:43][C@@H:44]1[C:51](=[O:52])[N:50]2[C@@H:45]1[S:46][CH2:47][C:48]([CH2:69][Cl:70])=[C:49]2[C:53]([O:55][CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[CH:56]([O:55][C:53]([C:49]1[N:50]2[C@H:45]([S:46][CH2:47][C:48]=1[CH2:69][Cl:70])[C@H:44]([NH:43][C:24](=[O:25])/[C:23](=[N:22]\[O:21][C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])[C:51]2=[O:52])=[O:54])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 13038Phosphorodichloridic acid, phenyl esterHCID 132396287-Amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochlorideHCID 90373537(2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[(2S)-1-[(4-methoxyphenyl)methoxy]-4-[(2-methylpropan-2-yl)oxy]-1,4-dioxobutan-2-yl]oxyiminoacetic acid

Product 1

HCID 894886674-O-tert-butyl 1-O-[(4-methoxyphenyl)methyl] (2S)-2-[(Z)-[2-[[(6R,7R)-2-benzhydryloxycarbonyl-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]amino]-1-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-oxoethylidene]amino]oxybutanedioateYield 95%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (16.7 g, 27.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (12.89 g, 28.6 mmol) in Dichloromethane (DCM) (210 mL) at −30° C. was added phenyl phosphorodichloridate (4.95 mL, 32.6 mmol), followed by dropwise N-methylmorpholine (8.97 mL, 82 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (85 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (26 g, 25.7 mmol, 95% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1010.6

Workup

  1. customcompletion of the reaction
  2. customThe reaction was quenched by addition of 10% aq. citric acid (85 mL)
  3. customthe organic solution was separated
  4. washwashed with 5% NaHCO3, brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-1514fab74c4b4f428927a7c19f5a084b
Source dataset
uspto-grants-2016_05
Patent number
US09340556B2

Reaction notes

Loading…