The Synthesis Research On The Key Intermediate Of The Carbapenem Antibiotics-Trinems

(3-lactam antibiotics have a wide range of antibacterial activity for both Gram-positive and Gram-negative bacteria. However, in recent years, the appearance of resistant strains has become a serious problem in clinical practice. It is necessary to modify the structure of theβ-lactam antibiotics in order to find out the new effective antibiotics.Carbapenem antibiotics is a kind of P-lactam antibiotics, which has the novelty structure and developed from 1970s. The new kind of carbapenem antibiotics-Trinems which has three rings was discovered by scientists at Glaxo Wellcome Laboratories. Sanfetrinem sodium (GV104326) and its orally active easter pro-drug Sanfetrinem cilexetil (GV118819) have been the subject of considerable study due to their broad spectrum antibacterial activity against a wide range of bacteria including producing strain, resistance to P-lactamase and stability to renal dehydropeptidases and they are currently in phaseⅡclinical studies.The compound ompound Allyl(4S,8S,9S,10S)-4-methoxy-11-oxo-azatricyclo [7.2.0.03,8] undec-2-ene-2-carboxylate (1) is the key intermediate for the synthesis of Sanfetrinem cilexeti (GV118819). The condition of opening cycle reaction of the 7-oxa-bicyclo[4.1.0]heptane is discussed. The reaction temperature is 67℃, the quantity of catalyst N-bromobutanimide is 7mmol% and the reaction time is 2 hous. The yield of 2-methoxycyclohexanol is 93.0%. L-valine with 4-methylbenzenesulfonic acid is chosen as the split reagent of racemic 2-methoxycyclohexanol. The molar ratio of (1S, 2S)-2-methoxycyclohexanol, L-valine and 4-methylbenzenesulfonic acid is 1:0.78:1. The yield is 25.0%. Tetrabutylammonium hydrogen sulfate is chosen as the catalyst to catalyze the hydrolyzation of the easter.The yield is 92.6% and the polarized light [α]D25 =+76°. (1S,2S)-2-methoxycyclohexanol is converted to (S)-2-methoxycyclohexanone through Sarret Oxidation, the yield is 67.5% and the polarized light [α]D25=-110°. (S)-2-methoxycyclohexanone can be produced at low cost with high yield through this method. Titanium (Ⅳ) chloride is used as Lewis acid catalyst to synthesize S-MCA 25, the yield is 60% and the polarized light [α]D25=+34°. Then the S-MCA 25 reacts with allyl 2-chloro-2-oxoacetate to afford 51 with the yield 60.1%, the polarized light [α]D25 =-50°and the compound 51 is refluxed in the xylene to obtain the intermediate 1 with the yield 60.3% and the polarized light [α]D25=+76°. The method to synthesize intermediate 1 is discussed in this paper, which provides the probility of producing GV-118819 on a large scale.The lasted research indicated that when the substituent group of C-4 on cyclohexyl ring is a nitrogen atom, such as amino and guanidino groups, the compounds have good antibacterial activities. (R)-2-hydroxycyclohexanone is key intermediate for those compounds. D-proline is used as the symmetric organocatalysis to synthesize this intermediate with 99% e.e. But when it is connectted with proctecing group of tert-butyldimethylsilyloxymethyl, the polarized light of the compound can not reach the standad. The reason is that the catalyst 4-Dimethylaminopyridine of this reaction is basic, when (R)-2-hydroxycyclohexanone is under the base condition, its polarized light will disappear. The original method is modified, (R)-2-hydroxycyclohexanone is reduced by sodium borohydride, then connects with the protecting group selectively and is oxided to obtain the chiral segment 2 and the polarized light [α]D25=36.8°. The method above is a new way to synthesize the intermediate 2.