Synthesis of HR 916 K: An Efficient Route to the Pure Diastereomers of the 1‐(Pivaloyloxy)ethyl Esters of Cephalosporins

Abstract

HR 916 K (5), the 1-(S)-(pivaloy1oxy)ethyl prodrug ester of was recycled by acidic saponification or enzymatic cleavage the cephalosporin cefdaloxime, exhibits a significantly to AMCA (7). The amine 10 was acylated with mercaptobenhigher oral bioavailability than the 1-(R) diastereomer HR zothiazole thioesters or mixed anhydrides, prepared from 916 J. An efficient'synthesis of HR 916 K was developed. The carboxylic acids 13 and 14, in almost quantitative yield. Deseparation of the diastereomers was achieved by precipita-protection of the oxime and formation of the tosylate protion of the 1-(R)-hydrochloride 9 followed by crystallization ceeded in one step. Using thioester 18, we obtained HR 916 of the 1-(S)-amine 10 (de > 96%). The 1-(R) diastereomer 9 K (5) from AMCA (7) in 42% yield.Most of the therapeutically useful third-generation cephalosporins are orally not well absorbed. Conversion of the carboxylic acid to prodrug esters, which are cleaved after absorption from the bowl, has been successfully used to obtain orally absorbable cephalosporins. Especially successful are the 1 -acyloxy-and 1 -alkoxycarbonyloxy-substituted methyl and ethyl esters, Typical examples of these types of esters are cefetamed pivoxil 1['] and cefpodoxime proxetil 2F21. In the case of the substituted ethyl esters an additional stereocenter is introduced into the molecule. Cefpodoxime proxetil 2 is on the market as a mixture of diastereomers.,OMe 1: Rf = Me, R2 = CH,OCOCMe, 2: R f = CH,OMe, R2 = CH(Me)OC02CHMe, HR 916 B (3) was selected as a candidate for clinical development, as its active metabolite cefdaloxime . shows broad antibacterial activity against Gram-positive and Gram-negative bacteria"], and the prodrug ester 3 exhibits good oral bioavailability in different animal species [4]. Formation of the toluenesulfonic acid salt increases the stability of the cephalosporin ester15]. The diastereomers could be separated by chromatography of an intermediate. HR 916 J (4) and HR 916 K (5) show comparable bioavailabilities in mice and rats, but in dogs the latter is enterally absorbed to 68%, whereas the former only to 20'Y0 [~]. Phase 1 clinical studies confirmed that HR 916 K (5) is enterally well absorbed [7]. Therefore, the pure diastereomer 5 was chosen as candidate for further clinical development.At that time HR 916 K (5) could be prepared either by separation of the diastereomers by chromatography of an intermediate or by multifold recrystallization[*l of HR 91 6 B (3). For ecological and economical reasons none of these methods was suitable for the large-scale synthesis and therefore, an efficient synthetic access to our compound 5 had to be identified. Results and DiscussionThe most elegant access to the diastereomerically pure prodrug ester would be esterification of the carboxylic acid

Practical Synthesis of Triethylammonium (Z)-2-[2-(Boc-amino)thiazol-4-yl]-2-(trityloxyimino)acetate, the Side Chain of Cefmatilen

“…To reduce the amount of Boc 2 O, the oxime group should be selectively protected before the tert -butoxycarbonylation. According to two examples for the protection of oxime ester 6 with TrCl, which were independently reported by Kamachi and Wollmann,2c the selectivity ( O -tritylester/ N , O -ditritylester = 4:1 5 and 9:1 2c ) and yield (81%) 2c were not satisfied. Since acetic anhydride (Ac 2 O) is cheaper than Boc 2 O, we then tried selective acetylation of oxime ester 6 with Ac 2 O.…”

“…( Z )-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetyl group is significantly useful as a C-7 side chain for cephalosporin antibiotics, for instance, cefdinir, cefdaloxime, and cefmatilen, since this side chain gives a broad antibacterial spectrum and some oral activity. Cefmatilen, which was discovered by Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan, is a new oral cephalosporin antibiotic .…”

Beating the Hydrogen Bond: First Selective and High-YieldingN-Acylation Process for an α,β-Diaminoalcohol

“…Mercaptobenzothiazolyl-2-thioesters of substituted acetic acids have been used very successfully for N -acylations of not only sensitive API intermediates, mostly in the area of β-lactam antibiotics − but also for ACE inhibitors, β-lactones, and quinolone antibiotics . However, thioesters of α,β-unsaturated acids such as N -acylating agents have not been reported, perhaps because it was felt that 1,4-addition of the liberated thiol to the unsaturated carbonyl group would be a side reaction difficult to overcome in those systems…”

“…We wanted to investigate the mercaptobenzothiazolyl-2-thioester of the cinnamic acid 3 as a potentially more selective reaction partner for the aminoalcohol 1 . In the event, synthesis of the desired thioester was best accomplished by reaction of 3 with bis(2-mercaptobenzothiazolyl)disulfide [(BThS) 2 ] in the presence of triphenylphosphine and N -methylmorpholine (Scheme ) 4 Synthesis of cinnamic thioester 5 …”

The Alkylation of Heteroatoms

“…O-Alkylation of unprotected amino acids[131][132][133]. O-Alkylation of unprotected amino acids[131][132][133].…”