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 349535ノート

反応式

HRID 349535 の反応式
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]

参加物

9

反応物 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

生成物 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-carboxylate収率 87.1%

試薬・触媒・溶媒 4

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒2 回HCID 8857Ethyl Acetate溶媒

実験手順

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-butoxy carbonyl)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-trimethylsilylacetamide (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).

後処理

  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)

出典と根拠

ORDレコード
ord-0782b2f602854216a379d880c56c2106
出典データセット
uspto-grants-2007_02
特許番号
US07179801B2

反応ノート

読み込み中…