Indole manufacture

Experiments on the synthesis of 4,5,6,7-tetrahydroindole and 1 -vinyl-4, 5,6,7-tetrahydroindole from cyclohexanone oxime and acetylene on bench reactors of 5 and 25 L performed under a 1.5 atm pressure give positive answers to these questions. Thus, at 100°C and KOH concentration of 0.4 mol/L, the output of 1 L of catalyst solution can amount to 50-100 g of pyrroles per hour. This means that in a small 1 m3 reactor, it is possible to produce up to 400 tons of 4,5,6,7-tetrahydroindoles (1 and/or 2) per year, which is quite acceptable to meet an initial demand for these products. It can initiate, for instance, a cheap indole manufacture by catalytic dehydrogenation of tetrahydroindoles 1 and 2. 

The industrial source of indole has been isolation from coal-tar distillate (7). Several patents for the manufacture of indole have been issued with aniline and ethylene glycol (8), aniline and ethylene oxide (9), 2-ethy1ani1ine (10), and /V-ethy1ani1ine (11) as the starting materials. 

Finally, it is appropriate to close this chapter with an example from the roots of fine chemicals the dyestuff, indigo. Manufacture of indigo involves chemistry (see Fig. 2.15) which has hardly changed from the time of the first commercial synthesis more than a hundred years ago (see earlier). Mitsui Toatsu has developed a two-step process in which indole is produced by vapour-phase reaction of ethylene glycol with aniline over a supported silver catalyst (Inoue et al., 1994). Subsequent liquid-phase oxidation of the indole, with an alkyl hydroperoxide in the presence of a soluble molybdenum catalyst, affords indigo. 

The indole- and benzindole-cyanine dyes illustrated in Scheme 6 are used by many major manufacturers in optical disk recording applications. These types of dye tend to be more light-stable than many other readily synthesized polymethine dyes. To increase the photostability, the dyes are used in combination with various types of stabilizers such as nickel dithiolato complexes and selected tertiary aromatic amine compounds.199 The application of cyanine dyes for optical storage media was primarily developed in Japan203 and several dyes and compatible stabilizers are commercially available in pure form from Japanese suppliers.199... 

Orders for certain chemicals used to make psychedelics (especially large orders in suspect areas) are sometimes checked by narcs. Indole, lithium aluminum hydride, trimethoxybenzaldehyde, phenyl-2-propanol, diethylamine, olivetol and ergotamine are among those watched. The vast majority of the homologs and analogs described here are, however, legal to manufacture and use. 

What kind of business This depends largely on what kind of dope you plan to manufacture. Amine-type precursors go hand in hand with perfumery or dyes. Nitrating-type compounds (nitromethane, nitroethane) are also used as solvents, and rocket fuels. Indole has been used in perfumery. Tyrosine and tryptophan are nutrients added to feeds. Urea is a plant fertilizer and a feed additive. 

Benzofuran is prepared in semicommercial amounts. Its manufacture from o-nitroethylbenzene (as well as that of indole and benzo[fc]thio-phene) has been considered.104 Alkylbenzofurans are prepared in the pharmaceutical industry as basic products.105... 

The observation that fractions of the rosey periwinkle, Catharanthus rosea, produced severe leukopenia, resulted in the isolation and development of two major anticancer drugs, vincristine and vinblastine. These two complex, dimeric indole-indoline alkaloids are important in the treatment of acute childhood leukemia (vincristine), Hodgkin s disease (vinblastine), and metastatic testicular tumors (vinblastine), and continue to be manufactured today by mass cultivation and processing of their natural source. 

U.S. 4,816,470 assigned to Glaxo describes the process for making 3-(2-Aminoethyl)-N-methyl-lH-indole-5-methanesulponamide, which is the API for Imigran . Estimate the cost of production for a generic manufacturer to produce this compound. 

Hypothyroidism is quite common in older adults and may present with an indolent course, or it may induce dramatic mental changes such as coma or pericardial effusion with tamponade. The most conunon etiology is primary hypothyroidism, or failure of the thyroid gland to manufacture and release sufficient thyroid hormone. The diagnosis is estabUshed by an elevated thyroid-stimulating hormone (TSH). The treatment is by thyroxine replacement. 

Four fluids were studied filtrates from the manufacture of (a) basic yellow Cl U805 indole type (b) acid yellow Cl 13906, azo-type (c) acid blue Cl 62055 anthraquinone type and... 

In order to identify the chromophore of a bisindole alkaloid, it is often enough to add the spectra of the two suspected monomers [e.g. the u.v. spectrum of geis-sospermine (105) was obtained by superimposition of the spectra of an indole (cinchonamine) and an indoline (geissoschizoline)]. Steric constraints introduced in the dimerisation process can, of course, result in small differences in actual and manufactured spectra but these do not affect first-order interpretations. In contrast, a decision concerning the position of an auxochrome e.g. 5-methoxy-or 6-methoxy-indoline ) can certainly be jeopardised. Whenever possible such distinctions must be made by examination of the monomeric products of cleavage. 

Indole-3(2f()-one (indoxyl), bright yellow crystals, mp 85°C, is manufactured by a process developed by Heumann and Pfleger (1890, 1898). Aniline and chloroacetic acid yield (phenylamino)acetic acid. On melting with KOH/NaOH/NaNH2, its potassium salt cyclizes to indoxyl ... 

One of the first indole derivatives to find a utilitarian application was the 6,6 -dibromo derivative of indigo, which was extracted from a Mediterranean mollusk to provide the dye Tyrian purple, long known to be a symbol of royalty. The parent compound, indigo, was also one of the first dyes to be manufactured by synthesis. 

A number of reactions relevant to fine chemicals manufacture can be catalyzed by superacids, for example, dehydration of carboxamides to nitriles, Friedel-Crafts alkylation and acylation, Fisher indole synthesis of coumarins, isomerization of limonene, condensation of hydroquinone with aniline, and esterification in general (Hino and Arata, 1980, 1985 Joshi and Rajadhyaksha, 1980 Rajadhyak-sha and Chaudhari, 1987 Kumbhar and Yadav, 1989 Rajadhyaksha and Joshi, 1991 Kumbhar et al., 1994). Two particularly important reactions are described here. 

A further important application of indole is the manufacture of the amino acid tryptophan. Since tryptophan is needed as an essential amino acid in the L-form, it may be produced by biotechnical means. Possible methods include enzyme-catalyzed reaction of indole with L-serine and fermentation of nutrients (carbon source) containing anthranilic acid with mutants of Bacillus subtilis. 

Bianconi, A., and Bianchi, A. 1932. Sui rapporti di indole chimioa fra I acido sulforoso ed i composti a funzione aldeidica e chetonica. Ann. chim. appl. 22, 291-316. Bioletti, F. T. 1906. The manufacture of dry wines in hot countries. Calif. Agr. Expt. Sta. Bull. 167, 1-66. 

All of the established industrial processes which use enzymes are simple. The majority are hydrolyses where one substrate, water, is the solvent. A few reactions of greater complexity, such as the synthesis of L-tryptophan from indole and L-serine, are described in patents, but it is by no means clear that these are viable commercial processes. A few complex reactions have been taken to the scale of a large pilot plant, one of these being the stereospecific synthesis of a few amino acids from racemic a-hydroxyacids. This must complete with other processes for the manufacture of amino acids, but it does already operate at a tonne scale. 

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