Antibiotics intermediates

Utility Amino Acid and j8-Lactam Antibiotic Intermediates... 

S. Torii etal, US Patent 6,197,185 (March 6, 2001) Assignee Otsuka Kagaku Kabushike Kaisha Utility Antibiotic Intermediate... 

An example of a commercial process that uses a hydrolase in the hydrolytic mode is the production of the antibiotic intermediate 6-APA by Gist-brocades [13], discussed above in Section 7.2.1 (Fig. 7.1). The biocatalyst is a penicillin acylase, which generates 6-APA from the starting material penicillin G in one step at a moderate temperature in water. The atom utilization of the enzymic process is much higher than that of the corresponding chemical process [14]. 

Catalysis, whether by noble metals or enzymes, offers an opportimity to reduce environmental loads. Replacing a chemical process with an enzymatic one, Hoechst research lowered the elf value for making the valuable antibiotic intermediate 7-aminocephalosporin. The value fell from 30 to -0.7, a fourfold change Christ, 1996). Despite an increase in waste water, the fall in ELF reduced environmental costs of this step by 90%. 

DSM has succeeded in simplifying considerably the synthesis of the antibiotic intermediate, 6-aminopenicillanic acid cf. Section 5.2). A process using an immobilised enzyme has superseded the costly chemical synthesis. [21 ]... 

The hydrogenation/dynamic kinetic resolution shown in Scheme 32 for the production of a penem antibiotic intermediate is carried out by Takasago [72] on a scale of 50-120 t/year, and recently, it was reported that an optimized segphos ligand [81] can achieve even higher stereoselectivities. Similar results were claimed by Chemi [82] with a Ru/tmbtp catalyst. 

Scheme 32 Hydrogenation/dynamic kinetic resolution for a penem antibiotics intermediate...

The well known valerolactone (115), commonly described as the Prelog-Djerassi lactone, has attracted the attention of many synthetic chemists over the years and another synthesis of this important macrolide antibiotic intermediate has appeared (Scheme 13). The synthesis involves the Hg -induced cycliz-ation of the aldehyde (114) to control the stereochemistry at C(2) and C(3). This was followed by demercuration with sodium trithiocarbonate in methanol at -60 C, hydrolysis, and oxidation to give the lactone (115) and its epimer in a 3.5 1 ratio. Demercuration with sodium borohydride followed by hydrolysis and oxidation gave almost complete inversion. 

Randall J (2004) Preparation of quinoline derivatives as antibiotic intermediates using sUylat-ing agents for cycUzation of ethoxy-substituted aromatic intermediates. WO Patent 13103,14 Mar 2004... 

Hong W, Lee K (2006) BayUs-HiUman route to several quinolone antibiotic intermediates. Synthesis 963-968... 

Dihydioxytetiahydionapthacenedione derivatives, used as intermediates for the anthracycline antibiotics have been prepared by Friedel-Crafts reaction of tetralin derivatives with orthophthaloyl chlotide [88-95-9J in high yields (93). 

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

Pharmaceutical. Ion-exchange resins are useful in both the production of pharmaceuticals (qv) and the oral adrninistration of medicine (32). Antibiotics (qv), such as streptomycin [57-92-17, neomycin [1404-04-2] (33), and cephalosporin C [61-24-5] (34), which are produced by fermentation, are recovered, concentrated, and purified by adsorption on ion-exchange resins, or polymeric adsorbents. Impurities are removed from other types of pharmaceutical products in a similar manner. Resins serve as catalysts in the manufacture of intermediate chemicals. 

Chloroacetoacetic esters are important industrial intermediates used especially for the synthesis of the aniinothia2olylacetic acid side chain of modem cephalosporins (see Antibiotics, P-LACTAMS-cephalosporins). For a review of the chemistry of 4-chloroacetoacetates see Reference 112. 

In a similar way, several cephalosporins have been hydrolyzed to 7-aminodeacetoxycephalosporanic acid (72), and nocardicin C to 6-aminonocardicinic acid (73). Penicillin G amidase from Pscherichia coli has been used in an efficient resolution of a racemic cis intermediate required for a preparation of the synthon required for synthesis of the antibiotic Loracarbef (74). The racemic intermediate (21) underwent selective acylation to yield the cis derivative (22) in 44% yield the product displayed a 97% enantiomeric excess (ee). 

Cyanide Wastes. Ozone is employed as a selective oxidant in laboratory-scale synthesis (7) and in commercial-scale production of specialty organic chemicals and intermediates such as fragrances, perfumes (qv), flavors, antibiotics (qv), hormones (qv), and vitamins (qv). In Japan, several metric tons per day (t/d) of piperonal [120-57-0] (3,4-methylenedioxybenzaldehyde) is manufactured in 87% yield via ozonolysis and reduction of isosafrole [93-16-3], Piperonal (or heHotropine [120-57-0]) has a pleasant odor and is used in perfumery. Oleic acid [112-80-1/, CH3(CH2 )7CH—CH(CH2 ). C02H, from tall oil (qv) is ozonated on a t/d scale to produce pelargonic, GgH2yG02H, and azelaic, H02G(GH2)yG02H, acids. Oleic acid also is ozonated in Japan... 

Monofunctional, cyclohexylamine is used as a polyamide polymerization chain terminator to control polymer molecular weight. 3,3,5-Trimethylcyclohexylamines ate usehil fuel additives, corrosion inhibitors, and biocides (50). Dicyclohexylamine has direct uses as a solvent for cephalosporin antibiotic production, as a corrosion inhibitor, and as a fuel oil additive, in addition to serving as an organic intermediate. Cycloahphatic tertiary amines are used as urethane catalysts (72). Dimethylcyclohexylarnine (DMCHA) is marketed by Air Products as POLYCAT 8 for pour-in-place rigid insulating foam. Methyldicyclohexylamine is POLYCAT 12 used for flexible slabstock and molded foam. DM CHA is also sold as a fuel oil additive, which acts as an antioxidant. StericaHy hindered secondary cycloahphatic amines, specifically dicyclohexylamine, effectively catalyze polycarbonate polymerization (73). 

TicarcHHn [34787-01-4] (SB) (52) is a significant penicillin antibiotic that incorporates the thiophene ring system. A number of routes to the required intermediate, 3-thiophenemalonic acid [21080-92-2] have been used over the years. Those from thiophene-based starting materials have involved 3-methylthiophene and 3-bromothiophene. 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

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