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

HRID 1247769Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1247769
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]

Komponenten

9

Edukt 4

HCID 24813Phosphorus oxychlorideHCID 25989Acetamide, N-(trimethylsilyl)-HCID 132396287-Amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochlorideHCID 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 acid

Produkt 1

HCID 87787063benzhydryl (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-carboxylateAusbeute 87,1 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8028TetrahydrofuranLösungsmittel2×HCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

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).

Aufarbeitung

  1. stirringthe reaction mixture was stirred at room temperature for 1 hour
  2. temperaturewas warmed
  3. temperatureThe solution was then cooled to −20° C.
  4. additionadded to the activated acid solution
  5. customobtained above
  6. stirringThe reaction mixture was stirred at a temperature of −10° C. to 0° C. for 1 hour
  7. customThe aqueous layer was separated
  8. washthe organic layer was washed with brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. filtrationfiltered
  11. concentrationThe filtrate was concentrated in vacuo
  12. custompurified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:2)

Quellen und Nachweise

ORD-Eintrag
ord-847f1f08c904413282bb64aa78bfbb65
Quelldatensatz
uspto-grants-2006_10
Patentnummer
US07129232B2

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