Phosphorus oxychloride → benzhydryl (6R,7R)-3-(chloromethyl)-7-[[(2Z)-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyimino-2-[5-[(2-methylpropan-2-yl)oxycarbonylamino]-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
Reaction equation
P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[S:18][N:17]=[C:16](/[C:19](=[N:23]/[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:20](O)=[O:21])[N:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:36][C@@H:37]1[C:62](=[O:63])[N:39]2[C:40]([C:46]([O:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])=[C:41]([CH2:44][Cl:45])[CH2:42][S:43][C@H:38]12.C[Si](C)(C)NC(=O)C>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[C:6]([O:10][C:11]([NH:13][C:14]1[S:18][N:17]=[C:16](/[C:19](=[N:23]/[O:24][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:33])[CH3:34])/[C:20]([NH:36][C@@H:37]2[C:62](=[O:63])[N:39]3[C:40]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:47])=[C:41]([CH2:44][Cl:45])[CH2:42][S:43][C@H:38]23)=[O:21])[N:15]=1)=[O:12])([CH3:7])([CH3:9])[CH3:8]Participants
Reactant 4
HCID 24813Phosphorus oxychloride
HCID 25989Acetamide, N-(trimethylsilyl)-
HCID 132396287-Amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride
HCID 21904557(2Z)-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyimino-2-[5-[(2-methylpropan-2-yl)oxycarbonylamino]-1,2,4-thiadiazol-3-yl]acetic acidProduct 1
Reagents, catalysts & solvents 4
Procedure
A mixture of N,N-dimethylformamide (0.648 ml) and phosphoryl chloride (0.781 ml) was stirred at room temperature for 30 minutes. To the mixture were added tetrahydrofuran (4 ml) and (Z)-2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}[(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)imino]ethanoic acid (3 g) at 4° C., and the reaction mixture was stirred at room temperature for 1 hour. Meanwhile, a mixture of benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (3 g) and N-(trimethylsilyl)acetamide (8.72 g) in tetrahydrofuran (15 ml) was warmed to make a clear solution. The solution was then cooled to −20° C. and added to the activated acid solution obtained above. The reaction mixture was stirred at a temperature of −10° C. to 0° C. for 1 hour and poured into a mixture of ethyl acetate and water. The aqueous layer was separated, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:2) to give benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (4.79 g).
Workup
- stirringthe reaction mixture was stirred at room temperature for 1 hour
- temperaturewas warmed
- temperatureThe solution was then cooled to −20° C.
- additionadded to the activated acid solution
- customobtained above
- stirringThe reaction mixture was stirred at a temperature of −10° C. to 0° C. for 1 hour
- customThe aqueous layer was separated
- washthe organic layer was washed with brine
- dry with materialdried over anhydrous magnesium sulfate
- filtrationfiltered
- concentrationThe filtrate was concentrated in vacuo
- custompurified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:2)
Sources & evidence
- ORD record
- ord-847f1f08c904413282bb64aa78bfbb65
- Source dataset
- uspto-grants-2006_10
- Patent number
- US07129232B2
Reaction notes
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