Grantville Gazette 38

MedLine Plus: Tuberculosis. Web.

http://en.wikipedia.org/wiki/Tuberculosis

Wikipedia: Tuberculosis. Web.

http://en.wikipedia.org/wiki/History_of_tuberculosis

Wikipedia: History of Tuberculosis. Web.

http://en.wikipedia.org/wiki/Tuberculosis_treatment

Wikipedia: Tuberculosis Treatment. Web.

http://en.wikipedia.org/wiki/Isoniazid

Wikipedia: Isoniazid .Web.

http://en.wikipedia.org/wiki/Bacillus_Calmette-Gu%C3%A9rin

Wikipedia: Bacillus Calmette-Guerin. Web.

http://tuberculosis.emedtv.com/tuberculosis/tuberculosis.html

EmedTV: Tuberculosis. Web.

http://www.emedicinehealth.com/tuberculosis/article_em.htm

Emedicinehealth: Tuberculosis. Web.

The New Royal Touch: Synthesis of Anti-TB Drugs

Iver P. Cooper

This 'mini-article' is intended to supplement Brad Banner's 'The White Plague' article by providing some hopefully informed speculation as to how, and how soon, various anti-tuberculosis drugs might become available in the 1632 universe.

The chemists in Grantville have access to only a minute fraction of modern chemical literature. I have tried to reconstruct what can be figured out from 'Grantville Literature' alone; sources that I deem to be so available are marked with *, and maybes with **.

Mycobacteria are nasty; a cure usually requires treating the subject for several months. If you try to eke out a limited supply by using a short drug course, you will be breeding drug-resistant strains, not curing your patients. Moreover, since the critters are quick to develop drug resistance, it's de rigeur to treat with a combination of two structurally unrelated pharmaceuticals.

My proposed availability is based on a subjective evaluation of synthetic difficulty relative to the canonical DDT (June 1633), chloramphenicol (September 1633), sulfanilamide (winter 1633-34), hexachlorobenzene (same), and coal tar dyes (1634), given the limitations of Grantville Literature. See Cooper, Industrial Alchemy, part 3 (Grantville Gazette 26).

Production of Selected Drugs

Isoniazid. This was first synthesized in 1912, by two young chemists pursing dissertation research (Ryan 359). Isoniazid is a derivative of pyridine. Pyridines make up about 0.01% of coal tar (KO 20:661) and the coal tar pyridine derivatives include the 2-, 3- and 4-methyl picolines (*M amp;B 1083). A chemist would know that pyridines are bases (*M amp;B 1087) and would therefore consider purifying them from coal tar by acid extraction, neutralization of the acid with inorganic base, and fractional distillation or crystallization. Limited characterizing data (melting point, boiling point, refractive index, optical rotation, solubility) is available (*MI, *CRC).

Isoniazid is derived from gamma-picoline (*CCD 484). 4-methyl (gamma) picoline may be oxidized with potassium permanganate to yield pyridine carboxylic acid (isonicotinic acid), which has COOH in the 4-position. (*M amp;B 1083). If you convert COOH to CONHNH₂, you get isoniazid, a.k.a. isonicotinic acid hydrazide. (*M amp;B 1084).

So how can you do that? Isoniazid was first made from the methyl ester of isonicotinic acid (*G amp;G 1186). It may also be made from (a) isonicotinic acid ethyl ester and hydrazine (NH₂NH₂), or (b) 4-cyanopyridine and hydrazine. (*MI 586).

A chemist would know that a carboxylic acid can be esterified by heating it with the corresponding alcohol (methyl, ethyl) in the presence of concentrated sulfuric acid or hydrogen chloride. (*M amp;B 601). This is a reversible reaction, so if you want a good yield, you supply the alcohol in great excess, or find a way to remove one of the products, to force it forward. Alternatively, you convert the acid to the acid chloride and then the latter to the ester.

We then need to go from the ester to the hydrazide. It turns out that just adding hydrazine to the ester works fine. Elementary organic chemistry texts mention ammonolysis, in which an ester (-CO-O-hydrocarbon) is converted to an amide (-CO-NH₂) by reaction with ammonia (NH₃) (*M amp;B 603). Some texts mention that the reaction can be with other primary or secondary amines (*Solomons 822). Anyway, hydrazonolysis is the analogous reaction with hydrazine (NH2NH2). The reaction produces water so it helps to evaporate it off.

So, where does the hydrazine come from? If you react nitrogen with hydrogen, either nothing happens, or you get ammonia. The standard Raschig process (suggested in 1893 and demonstrated in 1906, KO 13:560) involves reacting ammonia, chlorine and sodium hydroxide, distilling the hydrazine monohydrate, and then eliminating the water by azeotropic distillation with aniline (*CCD 450). The chlorine and sodium hydroxide react to form sodium hypochlorite (13:578), which could be used directly. Aniline (aminobenzene) is a coal tar dye and should be available by nitrating coal tar benzene with nitric acid and then reducing the nitrobenzene. It may take a bit of fiddling to get the process working; it requires pressure and elevated temperature (120-150oC) to get a good reaction rate, and you need to eliminate metal ion impurities that might catalyze a side-reaction. (KO 13:575). **Eagleson (504) suggests carrying the reaction out in the presence of gelatin, which inhibits that side reaction and also catalyzes the desired reaction.

An interesting twist, not in Grantville Literature, is using urea in place of ammonia; capital costs are low and the method found favor in China (KO 13:580).

We could have isoniazid within a year or so after we first isolate gamma-picoline from coal tar. (Pyridines may also be obtained by destructive distillation of bone (CCD 694) but coal tar is a richer source (KO 20:661).) Figure 1634 or a bit later.

It's true that after 1950 it became more common to produce pyridines synthetically (KO 20:642) but I don't see that as a viable option in the 1630s. While the 1906 Chichibabin pyridine synthesis is in Grantville Literature (*MI 1152), it took half a century to commercialize (KO 20:661) and the commercial embodiments involve vapor phase reactions with proprietary catalysts.

Ethambutol. A symmetric aliphatic compound with a ten atom main chain and two types of functional groups. Heat ethylene dichloride with (+)-2-aminobutanol, or reduce 2-aminobutanol and glyoxal with sodium borohydride. (*MI 424).

Ethylene and chlorine react to form ethylene dichloride. 2-aminobutanol is obtainable by reduction or catalytic hydrogenation of 2-nitro-butanol (Merck Index), and nitrobutanol by nitration of butanol with nitric acid. Note the '(+)'; there are three isomers, and what you get is a mixture. The (+) isomer is the most active, and all are equally toxic (**Eagleson 383). **Remington (1663) says to resolve it 'via its tartrate' and then condense with 1,2-dichloroethane (ethylene dichloride) in a dehydrochlorinating environment. Another route, from nitropropane and formaldehyde, is given in Sriram (491).

For glyoxal, oxidize acetaldehyde with nitric acid or hydrolyze dichlorodioxane (*MI 502). For sodium borohydride (a very useful reducing agent), heat methyl borate and sodium hydride (MI 955). For trimethyl borate, react boric acid with methanol (*CCD 896), and sodium hydride, react sodium with hydrogen (*CCD 802).

With two synthetic routes available, ethambutol might be available in R amp;D quantities as early as 1634, although later is more likely.

Pyrazinimide. Heterocyclic compound made by ammonolysis of methyl pyrazinoate, derived in undisclosed manner from quinoxaline (*MI 888). Unfortunately, this isn't a coal tar compound. The Gutknecht pyrazine synthesis is one of the organic name reactions generically described in the Merck Index 8th ed, p 1173, so that offers a clue as to a synthetic strategy. Also, *Eagleson 317 says that quinoxaline is synthesized