Potassium Carbonate → Ceftolozane Impurity 20

HRID 459603Notes

Reaction equation

HRID 459603 reaction equation
[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(Cl)(=O)=O.Cl.[NH2:35][C@@H:36]1[C:57](=[O:58])[N:38]2[C:39]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)=[O:46])=[C:40]([CH2:43][Cl:44])[CH2:41][S:42][C@H:37]12>CN(C)C(=O)C.O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([NH:35][C@@H:36]2[C:57](=[O:58])[N:38]3[C:39]([C:45]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)=[O:46])=[C:40]([CH2:43][Cl:44])[CH2:41][S:42][C@H:37]23)=[O:10])[N:3]=1

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 13577059(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-methyl-1-((2-methylpropan-2-yl)oxy)-1-oxopropan-2-yl)oxyiminoacetic acidHCID 140320244-methoxybenzyl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride (1:1)

Product 1

HCID 87481325Ceftolozane Impurity 20Yield 98.3%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 8471TriethylamineSolvent2×HCID 8857Ethyl AcetateSolvent2×HCID 31374DimethylacetamideSolvent

Conditions

Temperature
10 °C

Procedure

To a solution of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid (319 g) in N,N-dimethylacetamide (1.5 L) were added potassium carbonate (113 g) and methanesulfonyl chloride (126 ml) under ice-cooling. The mixture was stirred at 10° C. for 2 hours. The reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was washed with water and brine to give an activated acid solution. On the other hand, a suspension of 4-methoxybenzyl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (300 g) in a mixture of water (1 L) and ethyl acetate (1 L) was adjusted to pH 6 with triethylamine under ice-cooling. To the resulting mixture was dropwise added the above obtained activated acid solution at 10° C. under stirring. Stirring was continued at 5–10° C. for 1.5 hours keeping pH of the reaction mixture at 6 with triethylamine. The organic layer was separated, washed with water and brine, and evaporated in vacuo. The concentrate was poured into diisopropyl ether (15 L), and the resulting precipitate was collected by filtration and dried to give 4-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (495.7 g).

Workup

  1. temperaturecooling
  2. washThe organic layer was washed with water and brine
  3. customto give an activated acid solution
  4. temperaturecooling
  5. additionTo the resulting mixture was dropwise added the
  6. customabove obtained
  7. customat 10° C.
  8. stirringunder stirring
  9. stirringStirring
  10. waitwas continued at 5–10° C. for 1.5 hours
  11. customThe organic layer was separated
  12. washwashed with water and brine
  13. customevaporated in vacuo
  14. additionThe concentrate was poured into diisopropyl ether (15 L)
  15. filtrationthe resulting precipitate was collected by filtration
  16. customdried

Sources & evidence

ORD record
ord-dbdd3f1ba6684a32ae7f5179cce43b01
Source dataset
uspto-grants-2007_03
Patent number
US07192943B2

Reaction notes

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