Triethylamine → (4-methoxyphenyl)methyl (6R)-7-[[(2Z)-2-[(1S)-2-benzhydryloxy-1-(3,4-dihydroxyphenyl)-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

HRID 1653854Notes

Reaction equation

HRID 1653854 reaction equation
[CH:1]([O:14][C:15]([C@@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH:36]=1)\[C:29](O)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>O1CCCC1.CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.O>[CH:1]([O:14][C:15]([C@@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[S:35][CH:36]=1)\[C:29]([NH:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1

Participants

9

Reactant 4

HCID 8471Triethylamine2×HCID 24813Phosphorus oxychlorideHCID 140320224-Methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylateHCID 15780329(2Z)-2-[(1S)-2-benzhydryloxy-1-(3,4-dihydroxyphenyl)-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid

Product 1

HCID 16183829(4-methoxyphenyl)methyl (6R)-7-[[(2Z)-2-[(1S)-2-benzhydryloxy-1-(3,4-dihydroxyphenyl)-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateYield 50%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

60.5 g (0.0794 mol) of (Z)-2-[[(S)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid and 32.2 g (0.0794 mol) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were suspended in 600 ml of tetrahydrofuran, and 22.1 ml (0.158 mol) of triethylamine was added thereto at -5° C. The mixture was stirred at the same temperature for 30 minutes. Then, 18.5 ml (0.198 mol) of phosphorus oxychloride was dropwise added thereto at a temperature of from -10° to -5° C. over a period of 15 minutes. After stirring for 10 minutes, 27.6 ml (0.198 mol) of triethylamine was added thereto at a temperature of at most -5° C., and the mixture was stirred at a temperature of at most 5° C. for 1.5 hours. The reaction mixture was added to a mixed solution of 500 ml of water and 300 ml of ethyl acetate and subjected to liquid separation. The aqueous layer was further extracted with 100 ml of ethyl acetate, and the extract was put together with the organic layer. 120 ml of a saturated sodium hydrogencarbonate aqueous solution was gradually added to the organic layer, and the mixture was stirred for one hour. Then, the organic layer was washed with 400 ml of a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a foam-like solid. The foam-like solid thereby obtained was subjected to silica gel column chromatography (Wakogel® C-300, hexane/ethyl acetate=10/3→10/9). The desired fractions were put together and concentrated under reduced pressure to obtain 44.0 g (yield: 50%) of p-methoxybenzyl 7-[(Z)-2-[[(S)-a-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate as a foam-like solid.

Workup

  1. customat -5° C
  2. waitat a temperature of from -10° to -5° C. over a period of 15 minutes
  3. stirringAfter stirring for 10 minutes
  4. stirringat a temperature of at most -5° C., and the mixture was stirred at a temperature of at most 5° C. for 1.5 hours
  5. customsubjected to liquid separation
  6. extractionThe aqueous layer was further extracted with 100 ml of ethyl acetate
  7. addition120 ml of a saturated sodium hydrogencarbonate aqueous solution was gradually added to the organic layer
  8. stirringthe mixture was stirred for one hour
  9. washThen, the organic layer was washed with 400 ml of a saturated sodium chloride aqueous solution
  10. dry with materialdried over anhydrous magnesium sulfate
  11. concentrationconcentrated under reduced pressure
  12. customto obtain a foam-like solid
  13. customThe foam-like solid thereby obtained
  14. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-886356429f274ceab8ad63865be207c4
Source dataset
uspto-grants-1995_04
Patent number
US05403835

Reaction notes

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