Arbekacin, aminoglycoside antibiotic, was synthesized in 1973 by Kondo et al starting from Dibekacin by the acylation of 1-amino group with (S) -4-amino-2-hydroxybutyric acid (AHB), and approved as a chemotherapeutic agent in 1990 limiting to MRSA infection. In the development of industrial large scale synthesis, the main theme was selective protection of four amino groups except 1-amino group. We focused our effort to set up large scale synthetic method by taking advantage of zinc-chelation reaction. By the optimization of reaction conditions and minimization of isolation procedures, final production method was completed. We herein report the development course of high yield and low cost production method by the selective protection of amino group.
Cefotetan (YM09330) is a semi-synthetic injectable antibiotic which was discovered and developed by Yamanouchi Pharmaceutical Co., Ltd. and has been on the market since 1983. This compound shows a strong and wide spectrum of antibacterial activity and high stability against β-lactamase This paper outlines the optimization of the synthetic process, the replacement of the trifluoroacetic acid used for the cleavage method of benzhydryl ester, work on the stability of diphenyldiazomethane, an alternative synthetic route to Cefotetan, the method for synthesizing the isothiazole derivative and the scale-up of Cefotetan synthesis.
Several problems encountered during the kg scale production of such an unstable carbapenem antibiotic “Panipenem” (CS-533) was overcome by scrutinizing the reaction conditions and the factors influencing the reactions. Each item was reviewed from the nostalgic standpoint of a basic organic chemist, and the hard work of isolation technology is described at the same time.
It is well-known that (3R, 4R) -4-acetoxy-3- [(R) -1'- ((t-butyldimethylsilyl) oxy) ethyl] -2-azetidinone (4-AA) and (3S, 4S) - [(R) -1'- (t-butyldimethylsilyl) oxyethyl] -4- (R) -1-carboxyethyl-2-azetidinone (1β-methylcarboxylic acid) are very important intermediates for the synthesis of carbapenems and 1β-methyl carbapenems. We have developed the industrial processes for the syntheses of these intermediates. The synthesis of 4-AA was accomplished by the use of the ruthenium-BINAP complex catalyzed asymmetric hydrogenation of methyl 2-benzamidomethyl-3-oxobutanoate followed by the cyclization to β-lactam and the ruthenium catalyzed acetoxylation of β-lactam as the key technologies. In addition, for the synthesis of 1β-methylcarboxylic acid, we have developed three processes which involve a palladium catalyzed deallyloxycarbonylation, a rhodium catalyzed asymmetric hydroformylation and a magnesium enolate addition reaction as the key reaction, respectively.
An efficient method for preparation of diltiazem hydrochloride, a representive calcium antagonist widely used for the treatment of ischemic heart disease all over the world, is described. In the reaction of 2-nitrothiophenol (1) with trans-3-phenylglycidic esters (2) carrying various substituents on the benzene ring, both reactivity and stereoselectivity of the oxirane ring-opening of the glycidates were markedly influenced by the electronic nature of the substituents. As a result of our investigation on the catalytic effect of various Lewis acids in the reaction of 2a with 1, tin compounds were found to be effective catalysts for the cis-opening and readily produced the threo-nitro ester (3a), a key intermediate for the synthesis of diltiazem. Isolation of the crystalline complex from the reaction of 1 with SnCl4 and its efficient catalytic activity similar to that of SnCl4 suggest that the transition state involves co-cordination of tin derivatives both with 1 and the epoxy oxygen of 2a to result in highly specific cis-opening.
A convenient large-scale preparation of the indoloquinone antitumor agent EO9 has been developed. A Nenitzescu reaction has been used to prepare the indole skeleton having all functional groups necessary for its conversion into a key intermediate in a short synthesis of the indoloquinone EO9. Moreover, the hazardous reagent, Fremy's salt was replaced by safer one, [bis (trifluoroacetoxy) iodo] benzene, for oxidation of the 4-aminoindole to the corresponding indoloquinone, and high quality EO9 was easily obtained by choosing acetonitrile as the solvent in the substitution reaction of the methoxy group with ethylenimine to introduce the aziridinyl group into the precursor.
An efficient and practical synthetic route to OPC-15161 (1), a novel inhibitor of superoxide anion generation, is described. Intensive survey on pyrazine ring manipulation has led to the development of multi-kilo synthetic pathway, in which beneficial use of a nitrogen protecting group is the key to the problematic cyclization and O-methylation process, both being carried out in one-pot operation. Thus, the synthesis proceeds in 40% overall yield in four steps from tryptophan methyl ester with simple operation and without chromatographic purification, which also opens a general route for the preparation of related 5-alkoxypyrazin-2 (1H) -one 4-oxide such as emeheterone.
Vamicamide is a new anticholinergic agent useful for the treatment of urinary incontinence. Vamicamide is synthesized from benzonitrile in 6 steps which include reductive amination and separation of diastereomers as key steps. In this paper, the process development of Vamicamide is described not only from the point of organic synthesis but also from the industrialization standpoints such as scale-up, economy, safety and environmental control.
Prostaglandins (PGs), which play an important role in human physiology, have attracted much interest in their pharmacology and therapeutic potential. Development of a general and efficient organic synthesis of PGs is very important for it is the only viable means to supply sufficient quantities and to create more effective compounds. We have succeeded in establishing a two-component coupling synthesis of PGs as an industrially viable process by developing highly efficient and practical syntheses of the following requisite key intermediates ; the endo-enone bearing an α side chain 1, the exo-enone bearing an ω side chain 2, and the ω side chain unit (γ-iodo allylic alcohols). The key features of our synthesis of 1 and 2 are illustrated in equation 7. The key intermediate, enone 9, is prepared efficiently from readily available chiral epoxy alcohol 3. The enone is treated with an organocopper compound derived from the α side chain unit to give 1 via a 1, 4-addition reaction, which is accompanied by the elimination of the alkoxy group. Compound 9 is also converted into 2, which involves the organocuprate conjugate addition of the ω side chain to 10, obtained from 9 by the Michael addition of Et2NH. Optically active γ-iodo allylic alcohols, the ω side chain unit, are prepared by highly efficient kinetic resolution of the corresponding racemic alcohols by the Katsuki-Sharpless asymmetric epoxidation.
In 1959 Sumitomo Chemical Co. invented the low toxic insecticide Fenitrothion (trade name : Sumithion). In 1960s the demand of 2, 6-ditertiary butyl-4-methyl phenol (BHT), a fundamental antioxidant for polymers, was getting bigger and bigger, as the polymer industry in Japan grew up sharply. The starting material of Fenitrothion is m-cresol and the one of BHT is p-cresol. The demand of m, p-cresol for exceeded the supply from the coal and the petroleum industry. The development of the manufacturing process of m, p-cresol turned an important theme for Sumitomo Chemical Co. Sumitomo Chemical Co. studied the several processes and decided to adopt to cymene process that was consisted of the isopropylation, oxidation and cleavage of toluene. The cymene process was studied at a laboratory stage in 1965 and at a pilot plant stage in 1968. The m, p-cresol plant via cymene started in the end of 1969 with an annual production capacity 20, 000 ton at Sumitomo Chemical Co. Ohita work and this was the first cymene process m, p-cresol plant in the world. This plant has met an increasing demand of the insecticide and the antioxidant.
3, 4, 3', 4'-Biphenyltetracarboxylic acid (s-BTC) derivatives are now widely recognized as a useful compound. The anhydride (s-BPDA) is a raw material for polyimide which is the most heatproof resin, and it is known that the carboxylate has unique functions as a plasticizer. Although it is supposed to be difficult to form biphenyl structure on a factory scale, there are two industrial methods. The first method is oxidative dimerization of dimethyl phthalate by palladium catalyst and the second is reductive dimerization of 4-chlorophthalic acid by palladium catalyst. In 1994, the latter process was established in our laboratory and then we started the industrial production on hundreds tons per year according to the process flow diagram (Fig. 2).
A new highly heat-resistant polymer containing silicon, poly [(phenylsilylene) ethynylene-1, 3-phenyleneethynylene] (MSP), was prepared by dehydrogenative coupling polymerization between phenylsilane and 1, 3-diethynylbenzene in the presence of magnesia and other base catalysts. The research and development of preparation process of MSP are described, and the preparation flow chart in a bench test using a magnesia catalyst are shown. The properties and some applications of MSP are also reported.
The progress of the metallocene-based catalysts for syndiotactic polystyrene (SPS) has been reviewed. SPS is an excellent polymer, but the production cost was expensive at the beginning. In this review, the process of the improvement for catalyst system is summarized to show how Idemitsu commercialize SPS. We found electron denotative ligand of metal transition complexes improves the catalyst activity. Trimethylaluminum contaminate in MAO decreases the catalyst activity and there is the optimum molecular weight of MAO for styrene polymerization. The combination of transition metal and borate compounds is also catalyst for syndiospecific polymerization of styrene.
The process of enantiomeric purity improvement in industrial scale resolution is presented. Enantiomeric purity of 1-phenylethylamine (1) obtained from an industrial resolution with enantiomerically pure mandelic acid (2) as resolving agent, was improved by changing the crystal shape of the intermediate, the less-soluble diastereomeric salt [(R) -1 · (R) -2], through coexistence with a chiral secondary amine derived from substrate 1. Mechanism of the crystal habit modification is discussed and its applications to manufacture are described.
Some organic fine chemicals have been developed by a combination of microbial and chemical processes. These combination processes make the production more simple, cost-effective, and environmentally friendly. The process of 6-chloro-3-aminomethylpyridine was established by incorporating the regioselective microbial hydroxylation of 3-cyanopyridine and the improved reduction of 6-chloro-3-cyanopyridine with modified Raney Nickel catalysts. Production of ethyl (R) -β-hydroxy-γ-cyanobutylate has been achieved via microbial asymmetric reduction of chloroacetoacetate. A novel method of 2-cyanopiperazine that includes a Michael addition of ethylenediamine to 2-chloroacrylonitrile, followed by an intramolecular cyclization, was found, and its application for the chiral piperazine derivatives via biotransformation is now under development.
Chiral separation by elution chromatography (EC) with chiral stationary phases (CSPs) is useful for the quick preparation of enantiomers in the developing stage of new drugs. The use of this method is limited to a small separation, less than kilo-gram scale, because of the large solvent consumption. The simulated moving bed (SMB) process is good to separate two components, and it has been developed for the application to chiral separations. As compared to the EC system in our study, the productivity of the SMB process is twenty times better, and the solvent consumption is less than one twentieth. This shows the good possibility that the SMB technology can be applied to the industrial-scale production to supply enantiomers. With improvement of the process, the range of production will be spread from hundred grams to several ten tons.