Nobuyoshi Hayashi

Computer-assisted automatic synthesis II. Development of a fully automated apparatus for preparing substituted N-(carboxyalkyl)amino acids.

A versatile automated apparatus, equipped with an artificial intelligence has been developed which may be used to prepare and isolate a wide variety of compounds. The prediction of the optimum reaction conditions and the reaction control in real time, are accomplished using novel kinetic equations and substituent effects in an artificial intelligence software which has already reported [1]. This paper deals with the design and construction of the fully automated system, and its application to the synthesis of a substituted N-(carboxyalkyl)amino acid. The apparatus is composed of units for perfoming various tasks, e.g. reagent supply, reaction, purification and separation, each linked to a control system. All synthetic processes including washing and drying of the apparatus after each synthetic run were automatically performed from the mixing of the reactants to the isolation of the products as powders with purities of greater than 98%. The automated apparatus has been able to run for 24 hours per day, and the average rate of synthesis of substituted N-(carboxyalkyl)amino acids has been three compounds daily. The apparatus is extremely valuable for synthesizing many derivatives of one particular compound structure. Even if the chemical yields are low under the optimum conditions, it is still possible to obtain a sufficient amount of the desired product by repetition of the reaction. Moreover it was possible to greatly reduce the manual involvement of the many syntheses which are a necessary part of pharmaceutical research.

Computer-assisted automated synthesis. III. Synthesis of substituted N-(carboxyalkyl) amino-acid tert-butyl ester derivatives.

A versatile automated synthesis apparatus, equipped with a chemical artificial intelligence, was developed to prepare and isolate a wide variety of compounds. The apparatus was to the synthesis of substituted N-(carboxyalkyl)amino-acids. The apparatus [1,2] is composed of units for performing various tasks,for example reagent supply, reaction, purification and separation, each linked to a control system. All synthetic processes, including washing and drying of the apparatus after each synthetic run, were automatically performed from the mixing of the reactants to the isolation of the products as powders or crystals. The reaction of an amino-acid tertbutyl ester acetic acid salt with a 2-keto acid sodium salt produces an unstable intermediate, Schiff base, which is reduced with sodum cyanoborohydride to give a substituted N-(carboxyalkyl)aminoacid tert-butyl ester sodium salt. The equilibrium and the consecutive reactions were controlled by adding sodium cyanoborohydride using the artificial intelligence software, which contained novel kinetic equations [3] and substituent effects [4]. Substitued N-(carboxyalkyl)amino-acid tert-butyl esters, 90 derivatives, were automatically synthesized using the computerassisted automated synthesis apparatus. The syntheses were performed unattended 24 hours a day, except for supplying the raw materials, reagents and solvents. The apparatus is extremely valuable for synthesizing many derivatives of a particular compound. The configurations of the products were determined by circular dichroism measurements.

Computer-assisted automated synthesis I: computer-controlled reaction of substituted N-(carboxyalkyl)amino acids

Abstract Kinetic equations for controlling the consecutive reactions in the reduction of a Schiff base, formed by the equilibrium reaction of an amino acid with a 2-keto acid, have been developed. These equations have been integrated into a computer control program for automated synthesis of substituted N-(carboxyalkyl)amino acids. The equations were especially useful for obtaining optimum reaction conditions and on-line reaction control.

Automated synthesis ofradiopharmaceuticals for PET: anapparatus for [1-11C]labelled aldoses

This paper describes an instrumentation system for positron emission tomography (PET). A variety of [1-11C]labelled aldoses, such as [1-11C]-D-glucose, and galactose by a modification of the Kiliani-Fischer method have been produced. The instrumentation is fully automatic and consists of a synthesis system and control system. The synthesis system has the following functions: supplying reagents; performing reactions; purifying 11C labelled aldose; and preparing an injectable solution of 11C labelled aldose. These operations are performed by the control system in a remote control room. In a preliminary, hot experiment an injectable solution of [1-11C]-D-glucose was obtained. In addition, the operator is exposed to minimal radiation. The radioactivity of [1-11C]-Dglucose was 47 MBq, and the preparation time was 49 min.

Effect of gamma irradiation on disodium α-sulfobenzylpenicillin in solid state

Abstract The effect of γ irradiation on hydrated crystal of disodium α-sulfobenzylpenicillin (I) in solid state has been studied in relation to the radiation sterilization. From the decomposition products, at least two processes can be recognized during γ radiolysis of (I). One leads to CSO 3 Na scission, giving benzylpenicillin (III), and the second to hydrolysis of the β-lactam in (I), giving α-sulfobenzylpenicilloic acid (II). The studies show that radiation sterilization of (I) is feasible.

Automated synthesis of radiopharmaceuticals for positron emissiontomography: an apparatus for [1-11C] labeled carboxylic acid

A fully automated apparatus for the synthesis and formulation of short-lived 11C (t1/2 = 20 min)-labeled carboxylic acids for positron emission tomograpy (PET) has been developed. Injectable solutions of [1-11C]acetic acid, [1-11C]octanoic acid and [1-11C]palmitic acid wilh radioactivities of 6.36-8.29 GBq, 0.070-1.43 GBq and 0.42-0.89 GBq were obtained. The preparation time was under 40 min after the end of bombardment. An automatic washing function means that labeled compound of the same or different kinds can be produced several times a day without any maintenance of the system. The control system is sited away from the ‘hot laboratory’, so operator exposure to radiation is minimized.

Automated synthesis of radiopharmaceuticals for positron emissiontomography: an apparatus for labelling with [11C] methyl iodide (MIASA)

A fully automated apparatus for the routine synthesis and formulation of short-lived 11C (t1/2 = 20 min) labelled radiopharmaceuticals for positron emission tomography (PET) has been developed. [11C]Carbon dioxide is converted to [11C]methyl iodide, which can be used to label a wide variety of substrates by methylation at C, N, O, or S electron rich centres. The apparatus, MIASA (methyl iodide automated synthesis apparatus), was designed to operate as part of an automated labelling system in a shielded ‘hot’ laboratory. The apparatus was designed without the size constraints of typical instrumentation used in hot cells, although it is compact where necessary. Ample use of indicators and sensors, together with compact design of the reaction flasks for small dead space and efficient evaporation, led to good reliability and performance. The design of the hardware and software is described in this paper, together with a preparation of 3-N-[11C]methylspiperone as a sterile injectable solution in physiological saline.