The development of a safe process for the industrial generation of diazomethane is described. Diazomethane is produced and consumed in a continuous process capable of generating between 50 and 60 tonnes per year whilst the maximum inventory is maintained at less than 80 g. The diazomethane production unit is part of an integrated multistage continuous process that produces key intermediates for the latest generation of HIV protease inhibitor drugs. The use of diazomethane in this role has facilitated a direct cost-effective route to compounds such as (2S,3R)-3-(N-benzyloxycarbonyl)-amino-1chloro-4-phenylthiobutan-2-ol that can be produced in 82% yield from N-benzyloxycarbonyl-S-phenyl-L-cysteine.

5AG'H NMR spectra of the title imine in solution indicate the presence of three stereoisomers due to € / Z isomerism about the imino bond and atropisomerism about the 1 -naphthyl imino bond in the Zisomer. The most abundant Z-isomer, which was isolated in crystalline form, exhibits a highly unusual NMR signal at 6 5.9 assigned to a naphthyl proton cc to the imino group. The X-ray crystal structure reveals that this hydrogen atom is situated only 2.7 a above the face of the phenyl ring of the N-I -phenyl-2-propyl moiety and hence experiences a large diamagnetic ring current shielding effect. An attractive edge-to-face ring interaction involving this naphthyl proton and the n-electrons of the proximate phenyl group could account for this observation. The marked temperature dependence of this NMR signal is quantitatively analysed in terms of a fast equilibrium in solution between the conformation favoured in the solid state and a second conformation which lacks the ring current effect.

IntroductionAs the fi ne chemical and pharmaceutical industries progress into the 21st century there is an ever -increasing necessity to improve the sustainability of their manufacturing processes. In 2006 James Clark stated ' The three cornerstones of sustainable development -economic, environmental, and social benefi t -each provide drivers for change that should help to push the application of green chemistry forward ' [1] . The responsibility, therefore, is on the manufacturer to develop and operate sustainable processes, for example, by (i) reducing waste or treating waste to render it nonhazardous. (ii) improving process effi ciency by using less raw materials and by recycling and re -using solvents whenever appropriate, and (iii) developing cleaner, more energy -effi cient processes and by reducing emissions through effective abatement management.One useful measure of a process ' s sustainability is the E factor [2] . As defi ned by Roger Sheldon, the E factor is the ratio (by weight) of the by -products to the desired product(s). The pharmaceutical and fi ne chemical industries routinely operate processes with E factors one to two orders of magnitude higher than their petrochemical counterparts. There are many reasons for this, including the high level of chemical complexity in pharmaceutical products and the high quality standards in the pharmaceutical industry, but another circumstance contributing to this difference between the E factors is the type of manufacturing technology employed. The petrochemical industry tends to operate continuous processes, whereas the fi ne chemical and pharmaceutical industries predominantly use less effi cient batch manufacturing methods. It could be argued that the different production techniques simply refl ect the volume and complexity of the materials manufactured. Is it correct, however, that relatively simple petrochemical products are produced using modern continuous -based manufacturing technologies whereas pharmaceutical products and intermediates are produced using older batch methods?In the fi eld of organic chemistry, new synthetic strategies and methodologies are developed at an astonishing rate to access a diverse range of molecules.

The reaction of liquid (gamma-) SO3 with CH2Cl2 at room temperature leads to SO3 insertion into the C-Cl bonds, giving the useful chloromethylating agent chloromethyl chlorosulfate (CMCS). The process is very slow but becomes rapid on addition of catalytic quantities of trimethyl borate. The product mixture consists almost entirely of CMCS and the product of further sulfation, methylene bis(chlorosulfate)(MBCS), in a ratio of ca. 2 : 1, but typical yields of CMCS, isolated by distillation, are only 30-35%. The catalysed reaction in the homogeneous liquid phase at -45 degrees C has been followed as a function of time and of reactant concentration by 1H nmr spectroscopy. It is observed that, besides CMCS and MBCS, three additional, transient products (designated A, B and C) are formed. Products A, B and C decompose slowly at -45 degrees C but much more rapidly if the reaction mixture is raised to room temperature, giving additional CMCS and MBCS. From an analysis of the SO3 balance, it is inferred that products A, B and C arise from the reaction of one molecule of CH2Cl2 with respectively two, three and four molecules of SO3; they are suggested to be chloromethyl chloropolysulfates. By measuring initial rates of CMCS formation or total CH2Cl2 consumption, it is shown that the reaction is first order in the catalyst and roughly third order in SO3. A mechanistic scheme is proposed in which SO3 forms equilibrating zwitterionic molecular complexes with CH2Cl2. of 1 : 1, 2 : 1 and higher stoichiometries. The boron-containing catalyst can activate these complexes towards nucleophilic attack at carbon by the negatively charged oxygen of another zwitterion. An analogous mechanism can be written for the conversion of CMCS into MBCS by SO3 in the presence of trimethyl borate. CMCS reacts rapidly with anionic nucleophiles, such as halide or acetate ions (X-), in homogeneous solution of their tetrabutylammonium salts in CD3CN, or in a two-phase system (CDCl3/H2O) using alkali-metal salts in conjunction with a phase-transfer catalyst. In both situations the products (ClCH2X) arise by rapid nucleophilic displacement of the chlorosulfate moiety; this then more slowly liberates chloride ion, which converts further CMCS into CH2Cl2. The reactivity of CMCS has been compared with that of MBCS and methyl chlorosulfate (MCS) in competitive experiments; the reactivity order is MCS > MBCS > CMCS >> CH2Cl2. Evidence is also presented suggesting that, in contrast to the halide nucleophiles, reaction of CMCS with sodium phenoxide in tetrahydrofuran solution leads to nucleophilic displacement of the sulfur-bound chloride.

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