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The racemization of N-acetylindoline-2-carboxylic acid in p-xylene revealed beneficial rate enhancements due to microwave effects, by comparing conventional and microwave heating. The magnitude of this effect was governed by the degree of heterogeneity of the reaction system. The amount of catalyst, the temperature and the amount of cosolvent played a decisive role. The microwave effect completely vanished when a homogeneous solution was heated. During the microwave-assisted heterogeneous racemization of N-acetylphenylalanine in p-xylene a comparable microwave effect was observed. The microwave effects could be rationalized by adapting selective heating in the phase boundary region of solid and liquid. Additionally, a straightforward translation was achieved from batchwise operation in a stirred reactor to a batch-loop reactor. The (heterogeneous) racemization of N-acetylindoline-2-carboxylic acid retained its microwave effect in the loop reactor. Our results demonstrated that avoiding plugging of the tubular reactor is a severe challenge in scaling up.

A consistent setup of experiments has been conducted to demonstrate an enhanced reaction rate under microwave irradiation as compared to conventional heating, i.e. a real microwave effect. It was found that addition of a cosolvent, diminishing the heterogeneous character of the reaction mixture, greatly reduced the microwave effect. This was demonstrated by two examples; selective mono-urea formation and racemization of an N-acetylamino acid. Furthermore, formation of a Grignard reagent was accelerated under MW irradiation by electrostatic etching of the metal surface. The microwave effect observed in these reactions seems to rely on heterogeneity and specific interactions on the solid–liquid interface. Basic understanding of these findings is crucial for scaling up microwave assisted processes.

The conventional way of scaling up a contact drying process includes a pilot-scale step. Scaling up from lab scale to production scale without the use of a pilot plant saves time and money. A method has been developed to perform a scale-up from a 200-g bench-scale Rotavap drying process to production scale (approximately 1000 kg). A mathematical model, an improvement on the so-called Schlünder model, has been developed to simulate bench-scale drying processes. This simulation is used to determine the unknown mixing parameters by regression analysis. Besides the heat transfer resistances predicted by Schlünder an additional resistance term was found which is product dependent and can also be determined by regression. Ultimately the model can be used to predict the drying curve on production scale. In five out of eight cases the developed method accurately predicted drying behaviour. In three remaining cases the model did not apply due to extreme stickiness or aggregation during drying.

The objective of this study was the design of a scalable process for the synthesis of 3-4 mol of a-terthienyl from 2,5-dibromothiophene and thienylmagnesium bromide in a 10-L stirred tank reactor. In THF the Grignard reagent, thienylmagnesium bromide, was readily formed from 2-bromothiophene and magnesium. To avoid crystn. the maximal concn. was limited to 1.4 M. Furthermore, the novel combination of THF and NiCl2[bis(diphenylphosphino)benzene] allows for fast double coupling of the Grignard reagent with 2,5-dibromothiophene. The concn. of catalyst could be limited to 0.5 mol% based on the amt. of 2,5-dibromothiophene. An adapted workup procedure was developed, in which n-octane was used to sep. the magnesium salts from the desired product. The reaction was performed in a (semi)batch-wise operated reactor. A global model for the coupling step proved to predict the results at 0.1-, 1-, and 10-L scales very accurately. The heat of reaction evolved in the coupling step was valorized and could be handled easily. Mixing of the feed stream and the reactor content proved to be another important factor in the scaling-up of the a-terthienyl synthesis. [on SciFinder (R)]

The two-step synthesis of (2S)-2-(tetrahydropyran-2-yloxy)propane-1-ol was selected for fine chemical scale-up. The first step, an acid-catalyzed protection of ethyl (S)(−)-lactate with 3,4-dihydro-2H-pyran, could be performed without solvent. The reaction enthalpy was determined to be −48 kJ/mol ethyl (S)(−)-lactate, ensuring safe scale-up. The crude reaction mixture was used in the second step, the hydride reduction. For the reduction of the protected ester a clear solution of 1 M LiAlH4 in THF was used. The reaction enthalpy was determined to be −313 kJ/mol ethyl (2S)-2-(tetrahydropyran-2-yloxy)propionate, and the work-up was optimised with experimental design techniques. Combination of all experimental and theoretical results resulted in a master recipe for a 10-dm3 scale synthesis of (2S)-2-(tetrahydropyran-2-yloxy)propane-1-ol.

The synthesis of tris-O-dodecyl-gallic acid [3,4,5-tris(dodecyloxy)benzoic acid] - a versatile building block for org. liq. cryst. materials - has been selected for fine chem. scale-up. A large-scale procedure of the alkylation of Me gallate with dodecyl bromide was optimized with exptl. design techniques. Apart from the solvent effect, the temp., phase-transfer catalyst, stirring speed, and amt. of base were found to be most significant for the reaction rate. Reaction calorimetry revealed no excessive exothermic reaction steps in the process. Reaction kinetics on the alkylation reaction was studied as a function of particle size distribution of the base, potassium carbonate, and formation of carbon dioxide. Combination of all exptl. results has debouched into a master recipe for kilogram-scale synthesis in a 10 dm3 fully automated (semi)batchwise operated reactor. [on SciFinder (R)]

A scaleable process for the chlorination of 5-amino-2,4,6-triiodoisophthalic acid to the corresponding acid chloride, a building block for the synthesis of iodinated X-ray contrast agents, has been developed. Two dimeric byproducts have been isolated and assigned structures consistent with an amide and an anhydride. Hydrolysis of the N-sulfinyl intermediate and simultaneous crystallisation of the phthalic acid chloride have been optimised by applying fractional factorial design.