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 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 100oC 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.