4-Methylmorpholine → benzhydryl (6R,7R)-3-(chloromethyl)-7-[[(2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

HRID 525918Notes

Reaction equation

HRID 525918 reaction equation
[C:1]([O:5][C:6](=[O:30])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:19][C:20]=1[Cl:21])\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:32][C@@H:33]1[C:40](=[O:41])[N:39]2[C@@H:34]1[S:35][CH2:36][C:37]([CH2:58][Cl:59])=[C:38]2[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:30])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[S:19][C:20]=1[Cl:21])\[C:13]([NH:32][C@@H:33]1[C:40](=[O:41])[N:39]2[C@@H:34]1[S:35][CH2:36][C:37]([CH2:58][Cl:59])=[C:38]2[C:42]([O:44][CH:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:43])=[O:14])([CH3:9])[CH3:8])([CH3:3])([CH3:4])[CH3:2]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 13038Phosphorodichloridic acid, phenyl esterHCID 132396287-Amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochlorideHCID 88534087(2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyiminoacetic acid

Product 1

HCID 90373529benzhydryl (6R,7R)-3-(chloromethyl)-7-[[(2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateYield 89%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (20 g, 39.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (18.59 g, 41.2 mmol) in Dichloromethane (DCM) (300 mL) at −30° C. was added phenyl phosphorodichloridate (7.15 mL, 47.1 mmol), followed by dropwise 4-methylmorpholine (12.94 mL, 118 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 (120 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, 0-45% EtOAc/Hexanes) to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (29.9 g, 34.7 mmol, 89% yield) as a light yellow foaming solid. LCMS: (M+H)+: 860.3

Workup

  1. customcompletion of the reaction
  2. customThe reaction was quenched by addition of 10% aq. citric acid (120 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, 0-45% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-2d6c246ee10f40a7bd1723fbdeed2207
Source dataset
uspto-grants-2016_05
Patent number
US09340556B2

Reaction notes

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