Diisopropylethylamine → Meropenem

HRID 420873Notes

Reaction equation

HRID 420873 reaction equation
O(P(O[C:18]1[C@H:24]([CH3:25])[C@H:23]2[N:20]([C:21](=[O:29])[C@@H:22]2[C@H:26]([OH:28])[CH3:27])[C:19]=1[C:30]([O:32]CC1C=CC([N+]([O-])=O)=CC=1)=[O:31])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:43][N:44]([CH3:66])[C:45]([C@@H:47]1[CH2:51][C@H:50]([SH:52])[CH2:49][N:48]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:46].C(N(C(C)C)CC)(C)C.CC(C([O-])=O)=CCCCC>C(#N)C.C(OCC)(=O)C.CC(N(C)C)=O>[CH3:25][C@H:24]1[C:18]([S:52][C@@H:50]2[CH2:49][NH:48][C@H:47]([C:45]([N:44]([CH3:66])[CH3:43])=[O:46])[CH2:51]2)=[C:19]([C:30]([OH:32])=[O:31])[N:20]2[C@H:23]1[C@@H:22]([C@H:26]([OH:28])[CH3:27])[C:21]2=[O:29]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 10304013(4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateHCID 10871907(2S,4S)-2-(dimethylaminocarbonyl)-4-mercapto-1-(p-nitrobenzyloxycarbonyl)-1-pyrrolidineHCID 53411096HCID 53411096, compound

Product 1

HCID 441130Meropenem

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
-10 °C

Procedure

4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10 gm) Formula-A and 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-1-carboxylate (6.122 gm) Formula-B was dissolved in 60 ml acetonitrile and 3 ml dimethyl acetamide at ambient temperature. The solution was stirred under same condition for 10 minutes to get clear solution and cool to a temperature of minus −10° C. Di-isopropylethyl amine (9.15 ml) was added dropwise under stirring conditions to the above solution at −10° C. and continued the reaction for 90 minutes at the same reaction parameters. After completion of the reaction, 150 ml ethyl acetate was added in said reaction mass, the ethyl acetate layer was extracted by acidic water till to get pH 6-7 of the extracted acidic water, then dried over sodium sulphate and distilled off up to free solid. Next a 1:1 mixture of 50 ml methyl ethyl ketone and acetone was added and allowed to keep for 14 hours for crystallization at 0-5° C., finally 30 ml cold water with a small amount of seeding was added for complete crystallization. The solid was filtered and washed with 10 ml mixture of diethyl ether and ethyl acetate to obtain pure 4-Nitrobenzyl (4R,5S,6S)-3-({(3S,5S)-5-[(dimethylamino)carbonyl]-1-[(4-nitrophenoxy)carbonxyl]pyrrolidin-3-yl}thio)-6-[(1R)-1-hydorxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0].hept-2-ene-2-carboxylate (referred as protected meropenem)

Workup

  1. customat ambient temperature
  2. customto get clear solution
  3. customthe reaction for 90 minutes
  4. customat the same reaction parameters
  5. additionwas added in said reaction mass
  6. extractionthe ethyl acetate layer was extracted by acidic water till
  7. customto get pH 6-7 of the extracted acidic water
  8. dry with materialdried over sodium sulphate
  9. distillationdistilled off up to free solid
  10. additionNext a 1:1 mixture of 50 ml methyl ethyl ketone and acetone
  11. additionwas added
  12. customto keep for 14 hours for crystallization at 0-5° C.
  13. additionfinally 30 ml cold water with a small amount of seeding was added for complete crystallization
  14. filtrationThe solid was filtered
  15. washwashed with 10 ml mixture of diethyl ether and ethyl acetate
  16. customto obtain pure 4-Nitrobenzyl (4R,5S,6S)-3-({(3S,5S)-5-[(dimethylamino)carbonyl]-1-[(4-nitrophenoxy)carbonxyl]pyrrolidin-3-yl}thio)-6-[(1R)-1-hydorxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]

Sources & evidence

ORD record
ord-c69ea10e6c3e47539919ac9a185722ac
Source dataset
uspto-grants-2012_01
Patent number
US08097719B2

Reaction notes

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