Sulphanilamide was first prepared in 1908 but its therapeutic value was only recognised in 1932.

Numerous derivatives have been synthesised since then. It can be seen as a milestone in the history of chemotherapy because the synthesis of "sulpha" medicines signified the first rational study for the synthesis of organic compounds.

The various steps in the synthesis can be described as follows:

- The reaction starts from aniline, which must be
  sulphonated. To protect the amino-group, without
  losing the para-directing effect, the amino-group is
  first acetylated to acetanilide using acetic anhydride:
  i.e. nucleophilic substitution of the amino group by the
  anhydride.
- By electrophilic substitution of an acid chloride
  (chlorosulphonic acid) into the aromatic ring, an
  aromatic sulphonyl chloride is formed. The N-acetyl-
  group maintains its ortho-para-directing action.
- Organic sulphonyl-chlorides react with ammonia to
  form sulphonamides: i.e. nucleophilic substitution of
  ammonia in the acid chloride.
- All that remains is to unblock the amino group. This
  can be achieved by acid hydrolysis of the protecting
  amide group (nucleophilic substitution).
  The sulphamide group remains stable.
- The amino group, that was protonated in the acidic
  solution, is recovered by an acid-base reaction using a   basic solution of bicarbonate ions.