Grantville Gazette 38

from 1,2-dicarbonyl (i.e., glyoxal) and o-phenylenediamine.

A synthesis is set forth in Vardanyan (528), which is not available in Grantville. The first step is making quinoxaline per *Eagleson and then we oxidize with potassium permanganate, remove one carboxylic acid group with a radical initiator, esterify the other, and then ammonolyze. Even if we had Vardanyan to consult, the tricky part is coming up with the radical initiator.

**Remington advises preparation by 'thermal decarboxylation of 2,3-pyrazinedicarboxylic acid to form the monocarboxylic acid, which is esterified with methanol and then subjected to controlled ammonolysis.' (1663) This suggests that perhaps heat will do in place of the radical initiator; Sriram (490) implies that's correct! So, if we have Eagleson and Remington, we can rough out the synthesis, and we might have some product by 1636.

Thicetazone. This is a chemical of moderate complexity, a disubstituted benzene. Treat para-acetamidobenzaldehyde (I) with thiosemicarbazide (II) in alcohol (*MI 1036).

I) Para-acetamidobenzaldehyde: There's no derivation in Grantville Literature.

You can't just combine acetamide with benzaldehyde, you will get benzylidene-diacetamide (Watts 4). I have two plans to propose.

Plan A. First, we make p-acetamidotoluene. We start with toluene (methylbenzene), a coal tar component, and react it with nitric acid in presence of sulfuric acid to make p-nitrotoluene. (*M amp;B777). We reduce this with iron and hydrochloric acid to p-aminotoluene; reduction of aromatic nitros to amines is standard. (*M amp;B 728ff). We then acetylate the amine with acetyl chloride (*M amp;B 751). This shouldn't affect the ring since iron chloride is needed for Friedel-Craft acylation (*M amp;B 342). Actually, I know that this all works (**Johnson 423) but I figured it out before I looked it up! Acetyl chloride is made by reacting acetic acid (vinegar) with any of SOCl₂ (thionyl chloride), PCl₃, and PCl₅; for availability of these chlorinating agents see Cooper, Industrial Alchemy, part 2 (Grantville Gazette 25).

Next, I take the p-acetamidotoluene and add chlorine and heat, hopefully converting the methyl (- CH₃) group to -CHCl₂, and then hydrolyze with water at 100^oC to get the formyl (-CHO) of benzaldehyde. The -CH₃ to -CHO conversion works for toluene (*M amp;B 619) and I think it would work for p-acetamidotoluene, too.

Plan B. First, we make acetanilide (phenylacetamide). This was once used as an analgesic; the body metabolizes it into acetaminophen (Tylenol^R). It's derivable as follows: (coal tar -› nitrobenzene -› aminobenzene (aniline) -› acetanilide, the last step requiring acetyl chloride (*MI 5) or acetic anhydride (*M amp;B 742). Acetanilide is already, implictly, in canon, because it's an intermediate in the standard (undergraduate lab) synthesis of the antibiotic sulfanilamide.

Now, here's the trick. We use the 'Duff Reaction' (*MI 1160), in which an aromatic amine is formylated at the para position by hexamethylenetetramine (hexamine, an oligomer of formaldehyde and ammonia) in the presence of an acidic catalyst. While MI assumes that the aromatic amine is a dialkylamine, I am guardedly hopeful that acetanilide (a monoacylamine) will react properly.

Does hexamine sound familiar? Dr. Phil made it back in 1633. (Offord and Boatright, 'Dr. Phil's Amazing Essence of Fire Tablets,' Grantville Gazette 7.) The preferred acid used to be boric or acetic acid (Ahluwalia 315); it's now trifluoracetic acid if yields of the para product are low. (**March 490).

II) Thiosemicarbazide. Made from potassium thiocyanate and hydrazine (*CCD 868). The 'thiocyanate' is made by reacting sulfur with alkali cyanide (*C amp;W 301).

I think that we are looking at first availability in 1634-5.

Para-aminosalicylic acid. Heat meta-aminophenol with ammonium carbonate or potassium bicarbonate under pressure (*MI 62, *CCD 48).

The former may be obtained by reduction of meta-nitrophenol (*MI 89); I would reduce with iron and dilute hydrochloric acid (*M amp;B 725). To make m-nitrophenol, it's standard to boil diazotized meta-nitroaniline with sulfuric acid and water (*CCD 624; *MI 741, **Eagleson 700); treating phenol with nitric acid won't work as you get the para- and ortho isomers. Derivatizing nitrobenzene at the meta position is difficult because nitrobenzene is about 100,000 times less reactive than benzene.

You can make meta-nitroaniline from meta-nitrobenzoic acid (*MI 736). Or from aniline, by acetylation, nitration, and then removal of the acetyl group by hydrolysis. (*CCD 619). Note that the reagents aren't spelled out. Diazotization (*M amp;B 773) is standard in dyemaking and Stoner has certainly introduced it by 1634.

An alternative route to meta-aminophenol is 'by reaction of alkali hydroxides with 3-aminobenzene sulfonic acid or from resorcinol and ammonia in the presence of catalysts'. (**Eagelson 62). If we have Eagleson to consult, then we might have PASA by 1635.

Streptomycin. This was isolated in 1943 from a strain of Streptomyces griseus, a microbial fungus found is soil. Re-isolating it in the new universe is essentially a matter of chance; and the more samples, from diverse sources, are screened for the presence of antibiotic-producing fungi, the more likely it is that we will find one that produces streptomycin.

To give you an idea of what the odds are like, in 1946 Waksman noted that 'the production of streptomycin . . . is characteristic of only a few strains of S. griseus,' and that in a recent screen of 40 griseus cultures, none produced streptomycin and only one produced an interesting antibiotic.

While the chemical structure is known (Merck Index), devising a synthesis will likely be extremely difficult. It's an aminoglycoside, which is a chemical class several orders of magnitude more complex than anything reported to have been synthesized in canon. It has three rings, each heavily substituted. The first total synthesis of streptomycin was achieved in 1974 by Umezawa. It is unlikely that the chemical synthesis is described in Grantville Literature.

Conclusion

In medieval and even premodern times, it was believed that the 'royal touch' could cure the skin disease scrofula, a swelling of the lymph nodes caused by tuberculosis. On one Easter Sunday, Louis XIV touched 1600 sufferers (White). But the chemistry of Grantville offers a surer solution to the 'white plague.'

Bibliography:

Grantville Literature:

(The specified edition is merely the one I consulted.)

[MI] Merck Index (8th ed. 1968).

[M amp;B] Morrison amp; Boyd, Organic Chemistry (2d ed. 1966).

[CCD] Hawley, Condensed Chemical Dictionary (8th ed. 1971).

[G amp;G] Goodman amp; Gilman, The Pharmacological Basis of Therapeutics (8th ed. 1993).

Solomons, Organic Chemistry (6th ed. 1996).

[C amp;W] Cotton amp; Wilkinson, Advanced Inorganic Chemistry (1972).

Maybe:

Eagleson, Concise Encyclopedia of Chemistry (1994).

Remington, The Science and Practice of Pharmacy (21st ed., 2005)(need to check pre-RoF edition!)

Johnson, Invitation to Organic Chemistry (1999)

March, Advanced Organic Chemistry (3d. ed. 1985).

Other:

Waksman, Isolation of streptomycin-producing strains of Streptomyces griseus', J. bacteriol., 52:393-7 (1946)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC518198/pdf/jbacter00673-0139.pdf

Umezawa, Total Synthesis of Streptomycin, J. Antibiotics, 27: 997-9 (1974)

http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=antibiotics1968 amp;cdvol=27 amp;noissue=12 amp;startpage=997 amp;lang=en amp;from=jnlabstract

Ryan, Tuberculosis: the greatest story never told (1992)

Vardanyan, Synthesis of Essential Drugs (2006).

Sriram, Medicinal Chemistry (2010).

Ahluwalia, Organic Reaction Mechanisms (2005).

Watt's Dictionary of Chemistry, Vol. 1 (1888).

White, A History of the Warfare of Science with Theology in Christendom (1896), chapter XIII

http://cscs.umich.edu/~crshalizi/White/medicine/fetich.html