Industrial-scale Synthesis

As a class, these compounds are related to indigo, which is the oldest of all vat dyes. Indigo itself, during its comparatively short history as a commercial pigment, was used especially in rubber. Its structure was first described in 1883 by A.V. Bayer. Knowledge of this structure, together with the development of an industrial scale synthesis, facilitated the development of a series of indigo-based colorants. 

The synthetic route to tetrachlorothioindigo may serve as an example for an industrial scale synthesis. Starting material is 2,5-dichlorothiophenol, which is obtained by reduction of 2,5-dichlorobenzene sulfochloride or by reaction of the 2,5-dichlorobenzene diazonium salt with potassium-o-ethyldithiocarbonate and hydrolysis or with disodium sulfide and subsequent reduction ... 

Asymmetric catalytic hydrogenation is unquestionably one of the most significant transformations for academic and industrial-scale synthesis. The development of tunable chiral phosphorous ligands, and of their ability to control enantioselectivity and reactivity, has allowed asymmetric catalytic hydrogenation to become a reaction of unparalleled versatility and synthetic utility. This is exemplified in the ability to prepare en-antiomerically enriched intermediates from prochiral olefins, ketones, and imines through asymmetric hydrogenation, which has been exploited in industry for the synthesis of enantiomerically enriched drugs and fine chemicals. 

Substrates include benzyl (2 g) and cinnamyl (2.7 g) alcohols to acids cyclopentanol (1 g), benzhydrol (3.9 g), benzoin (4 g), pantolactone (2.6 g) to ketones (RuCy TCCA/( Bu N)Br/aq. Kj(C03)/CH3CN) (Fig. 2.14) [25] [[2-[2-hydroxypropyl) amino]-l,2-dioxoethyl]amino]acetic acid ethyl ester (6.21 kg) to [(l,2-dioxo-2-oxopropyl)amino]ethyl)amino] acetic acid ethyl ester, part of the industrial-scale synthesis of thrombin inhibitor (RuCyaq. Na(BrOj)/CH3CN) [166] (H-)-dihydroc-holesterol (8 g) to cholest-3-one (RuO /aq. K(10 )/(BTEAC)/CHCl3) [308] ... 

A more efficient and convergent industrial-scale synthesis that avoids toxic methyl iodide and sodium cyanide was developed (Scheme 15.2). Condensation of N,N-dimethyl-2,2-dimethoxyacetamide with imidazopyridine 7 under acidic conditions afforded hydroxy derivative 12. Conversion of the hydroxyl group to a chloride with thionyl chloride followed by reductive removal of the chloride with sodium borohydride provided zolpidem. 

The advantages of this industry scale synthesis are the use of non-halogenated solvents, formation of inert inorganic salts as waste products, recycling of valuable side products, ambient temperatures, relinquishment of protecting groups and purification by crystallization or filtration. 

Scheme 17. DoM of N-tritylphenyltetrazole applied to industrial scale synthesis of losartan.

The utility of the sequence has recently been shown by the industrial-scale synthesis of a nonpeptidic angiotensin II receptor antagonist (Scheme 2-46) [121]. 

In Section 9-4-3, we mentioned that cationic Ir catalysts (sometimes called Crabtree catalysts) are quite active for hydrogenation of highly substituted C=C bonds. Moreover, asymmetric Ir-catalyzed hydrogenation of an imine is a key step in the industrial-scale synthesis of the herbicide (S)-metolachlor (Section 9-7-2). In addition to these applications, relatively recent work has shown that cationic Ir(I) complexes bonded to chiral ligands can catalyze asymmetric hydrogenation of unfunctionalized C=C bonds (i.e., C=C bonds to which no polar functional groups, such as C=0, are attached). 

The Larock synthesis was used by Chen and co-workers to synthesize the 5-(triazolyl-methyl)tryptamme MK-0462, a potent 5-HTjn receptor agonist, as well as a metabohte [366], Larock employed his methodology to prepare tetrahydroindoles [367], and Maassarani used this method for the synthesis of /V-(2-pyridyl)indoles [368]. The latter study features the isolation of cyclopalladated Y-phenyl-2-pyridylammes. Rosso and coworkers have employed this method for the industrial-scale synthesis of an antimigraine drug candidate 331. In this paper removal of spent palladium was best effected by trimer-captotriazine (332) although many techniques were explored [369]. 

Scheme 13.7 Industrial-scale synthesis of acrylamide and 6-APA by immobilized enzymes.

So far, much research has gone into finding new synthetic routes, new products and novel selective syntheses, and in the analysis of important factors affecting yield and in some cases selectivity. However, other practical constraints relevant to process development for industrial-scale synthesis have to be tackled. For example, new insights are needed to develop cost-effective, stable, and selective PT catalysts (especially effective immobilized triphase catalysts). Other relevant factors include the recovery and recycle of the PT catalyst, catalyst decomposition, environmental issues such as catalyst toxicity, and ease of product recovery. Catalyst costs are not very high when quats are used, as against the more expensive crown ethers or cryptands. In most cases, the overall process is more than cost-effective since PTC allows the use of cheap alternative raw materials, prevents the use of costly dipolar solvents, is less energy intensive (due to lower temperatures) than alternative methods, alleviates the need... 

Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. One notable exception, however, was the first industrial-scale synthesis of optically active steroids performed by workers at Roussel-UCLAF. The linear synthesis began with a suitable B—C-ring synfhon, 6-methoxy-l-tetralone (186). In a series of steps, tetralone (186) was converted to 2-methyl-2-cyanotetralone (270). Condensation of (270) with dimethyl succinate followed by carbonyl reduction, saponification, and resolution produced the optically active tricyclic acid (271). A series of reductions, a decarboxylation, and a hydrolysis produced (272). Appendage of the A-ring functionality by alkylation produced intermediate (273). Compound (273) was used as a common intermediate for the synthesis of 19-norsteroids, estrogens, and corticosteroids (230). 

The modern industrial-scale synthesis of ibuprofen has very high atom efficiency, and it has been modified from the original synthesis to be both more environmentally friendly and more cost effective. The original method involved six synthetic steps but used stoichiometric (as opposed to catalytic) quantities of reagents, had lower atom efficiency, and produced undesirable quantities of waste. The modern alternative, on the other hand, requires just three steps, each of which is catalytic in nature. The first step employs a recyclable catalyst (hydrogen fluoride, HF) and produces almost no waste. The second and third steps each achieve 100% atom efficiency (wow ). This process truly represents an idetd benchmark for excellence in green synthesis on the industrial scale. 

Rosso and co-workers have employed this method for the industrial-scale synthesis of an anti-migraine drug candidate. The triethylsilyl masked protective group was removed under strong acidic conditions to reveal the C2-H. The removal of spent palladium was best effected by trimercapto-triazine (TMT) although many techniques were explored. ... 

From the thousands of CD derivatives described in hundreds of scientific papers and patents, only a few can be taken into consideration for industrial-scale synthesis and utilization. Complicated muitistep reactions, using expensive, toxic, environment-polluting reagents, and purification of the products by chromatography are feasible for preparing derivatives only on laboratory scale. To produce tons, at an acceptable price, only about a dozen of the known CD derivatives can be taken into consideration. 

Standard plastic soft drink bottles are made of poly(ethylene terephthalate), or PET. In the industrial-scale synthesis of PET, the usual starting materials are dimethyl terephthalate and ethylene glycol (Eigure 10.1). These compounds react to form bis-(2-hydroxyethyl) terephthalate (BHET) and methanol. The methanol boils off at the reaction temperature (typically around 210°C), leaving fairly pure BHET. Then, the BHET is heated further to around 270°C, where it undergoes a condensation reaction to form PET polymer. Ethylene glycol is a byproduct in this second step and can thus be reused within the plant to produce more BHET. 

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