Synthesis of Sulfanilamide

Purpose To demonstrate principles of multistep synthesis, protecting groups, and 

---

What would happen in the synthesis of sulfanilamide if the amino group were not protected as an amide in the chlorosulfonation step ... 

This experiment is a multistep synthesis of sulfanilamide starting with nitrobenzene. Nitrobenzene is reduced with tin and hydrochloric acid to... 

If each step in the synthesis of sulfanilamide from nitrobenzene proceeded in 90% yield, how much nitrobenzene would be needed to obtain 1.0 kg of sulfanilamide according to the sequence of reactions in Scheme 21.2 ... 

Some related antibacteiials are also included with the sulfonamides. The azo dye, Piontosil (3) is metabolized to sulfanilamide in and was the piogenitoi of the sulfa dmgs. Also, the antibacteiial sulfones, eg, dapsone (4), are believed to act in a similai fashion on enzymes involved with synthesis of fohc acid, leading to bacterial growth inhibition. 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

A sulfanilamide drug of prolonged action, 2-p-aminobenzenesulfamido-4-methylpyiimidine (sulfomerazine 162), first prepared by Japanese chemists from acetacetic aldehyde in 82% yield (49JPJ447), ranks among practically valuable 2-amino-4-methylpyrimidine derivatives. Later, a synthesis of this product directly from l-methoxybut-l-en-3-yne (100°C, AcONa, AcOH, 3 h) in 64% yield has been developed (76MI1). 

Possibly the most significant discovery in the metabolism of aromatic azo compounds had implications that heralded the age of modem chemotherapy. It was shown that the bactericidal effect of the azo dye Prontosil in vivo was in fact due to the action of its transformation product, sulfanilamide, which is an antagonist of 4-aminobenzoate that is required for the synthesis of the vitamin folic acid. Indeed, this reduction is the typical reaction involved in the first stage of the biodegradation of aromatic azo compounds. 

Another observation on oxalate formation is that other a-keto acids, such as oxalosuccinic acid (74) and a-ketoglutaric acid (106) do not seem to yield oxalate directly but indirectly (123). This appears to be due to the fact that only oxaloacetic acid can function as an acetate donor. In this connection the intervention of Coenzyme A may be considered, since it is reported to function in the acetylation of sulfanilamide and choline (73) and recently was shown to take part in the enzymatic synthesis of citric acid. This concept may be illustrated as follows ... 

The structure of sulfa drug molecules, however, is very similar to that of the PABA molecule. Compare the structure of sulfanilamide, in part 2 of the diagram, with that of PABA. Notice how easily the sulfanilamide molecule can substitute for the PABA molecule in the synthesis of the bacterium s folic acid. The problem for the bacterium, however, is that folic acid produced from a sulfa drug molecule is... 

Similar success was achieved in the synthesis of analogs of prontosil and sulfanilamide. A number of these analogs were prepared and tested and found to he effective against a variety of infectious diseases. 

Sulfanilamide and its derivatives competitively inhibit the synthesis of folic acid in micro-orgenisms and, thereby, decrease the synthesis of nucleotides needed for the replication. 

Sulfa drugs have a close structural resemblance to PABA. When taken by a person suffering from a bacterial infection, a sulfa drug is transformed by the body to the compound sulfanilamide, which attaches to the bacterial receptor sites designed for PABA, as shown in Figure 14.7, thereby preventing the synthesis of folic acid. Without folic acid, the bacteria soon die. The patient, however, because he or she receives folic acid from the diet, lives on. 

The sulfonamides, or sulfa drugs, date back to the early 1900s but were not systematically studied until the 1930s. Sulfanilamide (A.17), a key reagent in the synthesis of certain dyes, was the first widely marketed sulfonamide (Figure A.5). Sulfonamides are antimetabolites and competitively inhibit a bacterial enzyme, dihydropteroate synthetase (DHPS) (see Chapter 1 and Chapter 6). DHPS plays a role in the synthesis of tetrahydrofolic acid (THF), an important compound in the preparation of thymidine. Because they limit the... 

Figure 1.12. Stractures of the sulfonamide drag prontosil rubrum , its antibacterially active metabolite sulfanilamide, and the bacterial metabolite p-Aminobenzoic acid. Sulfanilamide acts as an antimetabolite (i.e., competitive inhibitor) in the synthesis of folic acid, of which aminobenzoic acid is a component...

There is a deficiency of N lO-formyltetrahydrofolate. Sulfanilamide inhibits the synthesis of folate by acting as an analog of />-aminobenzoate, one of the precursors of folate. 

Unlike that of most drugs, the mode of action of the sulfa drugs is now completely understood. Bacteria must synthesize folic acid in order to grow. Higher animals, like man, do not synthesize this vitamin and hence must acquire it in their food. Sulfanilamide inhibits the formation of folic acid, stopping the growth of bacteria and because the synthesis of folic acid does not occur in man, only the bacteria are affected. 

Sulfanilamide (77) is a useful intermediate in the synthesis of 2,6-disubstituted anilines (Scheme 48). The last step is the hydrolytic removal of the sulfamoyl group, which occurs as a result of the reversibility of the sulfonation reaction (see p. 97). 

---