Biapenem

Biapenem

Systematic (IUPAC) name
(4R,5S,6S)-3-(6,7-dihydro-5H- pyrazolo[1,2-a][1,2,4]triazol-8- ium-6-ylsulfanyl)- 6-(1-hydroxyethyl)- 4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2- ene-2-carboxylate
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	℞ (Prescription only)
Routes of administration	IV
Identifiers
CAS Number	120410-24-4 Y
ATC code	J01DH05 (WHO)
PubChem	CID: 71339
ChemSpider	64442 Y
UNII	YR5U3L9ZH1 Y
ChEBI	CHEBI:3089 Y
ChEMBL	CHEMBL285347 Y
Chemical data
Formula	C15H18N4O4S
Molecular mass	350.39 g/mol
SMILES CC1C2C(C(=O)N2C(=C1SC3CN4C=NC=[N+]4C3)C(=O)[O-])C(C)O
InChI InChI=1S/C15H18N4O4S/c1-7-11-10(8(2)20)14(21)19(11)12(15(22)23)13(7)24-9-3-17-5-16-6-18(17)4-9/h5-11,20H,3-4H2,1-2H3/t7-,8-,10-,11-/m1/s1 Y Key:MRMBZHPJVKCOMA-YJFSRANCSA-N Y
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Biapenem (INN) is a carbapenem antibiotic. It has in vitro activity against anaerobes. 1-β-methyl-carbapenem antibiotic. Approved in Japan in 2001.

Synthesis

Binapenam synthesis: Total synthesis:

The tin enolate of N-propionyl (4R)-4-Methyl-1,3-thiazolidine-2-thione is prepared by reaction with tin triflate; the chiral heterocyclic ring determines the stereochemical outcome of the next step. Thus condensation of the enolate with the azetidone (3) gives the product from the formal dispalcement of the acetoxy group in the azetidone. This net retention of configuration probably results from the circumstance that the reaction proceeds via the elimination product of 3 or a carbocation equivalent. Treatment of the product 4 with the magnesium salt from the half-ester of malonic acid leads to displacement of the thiazolidine amide by the malonate to give the intermediate acylation product. Hydrochloric acid causes the tricarbonyl compound to decarboxylate; the silyl ether of the side chain is cleaved in the process to give 5. Reaction of the beta-keto ester with 4-n-dodecylphenylsulfonyl azide leads to the transfer of a diazo grouping and formation of the diazoketone (6). Treatment with a rhodium salt results in loss of nitrogen and formation of the corresponding carbene. The very reactive function then inserts in the adjacent N-H bond, forming the fused five-membered ring (7). Diphenyl chlorophosphate then converts the beta-keto ester in 7 to the relatively stable enol phosphate derivative (8).

A key reaction in the synthesis of imipenem consists of displacement of the enol phosphate from an intermediate such as 8 by sulfur. In the present case, reaction of 8 with the protected Pyrazolidine thiol leads to the thioenol ether (9), probably by an addition-elimination sequence. Hydrogenation of the product over palladium leads to reductive cleavage of the protection groups and formation of the amino acid (10). Treatment of that product with Ethyl formimidate leads to conversion of the hydrazine function to a 1,2,4-triazolium ring. The crude product is then passed over an ion-exchange column to convert it to a betaine.

External links

• (Japanese) Omegacin