Where does chlorthalidone come from?

Chlorthalidone, or 2-chloro-5-(1-hydroxy-3-oxo-2H-isoindol-1-yl)benzenesulfonamide, is a synthetically made thiazide-like diuretic.¹

Thiazide diuretics originally evolved from sulfanilamide, a derivative of sulfonamides, known to inhibit the enzyme carbonic anhydrase.² Sulfanilamide was first synthesized by Paul Gelmo in 1908 and used as a dye intermediate.³ Sulfanilamide’s antimicrobial properties were later discovered by Gerhard Domagk.⁴

In the mid 1940’s, the antihypertensive effects of sulfanilamide was uncovered through the works of Robert Pitts and William Schwartz.⁵ However, sulfanilamide’s carbonic anhydrase inhibition caused bicarbonate depletion, leading to metabolic acidosis.⁵ In search of an effective antihypertensive that did not cause an electrolyte disturbance, researchers at Merck developed the first thiazide diuretic, chlorothiazide, in 1958.⁶ One year later, the chemical structure of chlorthalidone was first described by Graf et al. of the pharmaceutical company Ciba-Geigy.⁷

There are several methods of synthesizing chlorthalidone.^8-11 Chemists may utilize the diazotization process (nitrosating primary aromatic amines to diazonium salts) by diazotizing 3-amino-4-chlorobenzophenone-2-carboxylic acid.⁸ The diazotized product is reacted with sulfur dioxide followed by thionyl chloride and ammonia to produce chlorthalidone.⁸ An alternative synthesis method involves heating 4-chloro-2’-carboxybenzophenone-3-sulfonyl chloride with thionyl chloride to produce 3-chloro-3-(3’-chlorosulfonyl-4’-chlorophenyl)phthalide.⁹ The product is then dissolved in chloroform, reacted with ammonia via an ethanol solute and treated with hydrochloric acid to yield chlorthalidone.⁹

^References 

1. PubChem Compound Database https://pubchem.ncbi.nlm.nih.gov/compound/2732. Accessed Sept. 14, 2017.
2. Greger R, Better OS, Knauf H, Mutschler E, Palmer LG. Diuretics. Berlin ; New York: Springer; 1995.
3. Gelmo P. Über Sulfamide der p‐Amidobenzolsulfonsäure. Advanced Synthesis & Catalysis. 1908;77(1):369-382.
4. Domagk G. Ein beitrag zur chemotherapie der bakteriellen infektionen. DMW-Deutsche Medizinische Wochenschrift. 1935;61(07):250-253.
5. Pizzi RA. Developing diuretics: From mercurials to the thiazides, these "urine promoters" have proved to be some of the most prescribed therapeutics. American Chemical Society. 2003;6(2).
6. Novello FC, Sprague JM. BENZOTHIADIAZINE DIOXIDES AS NOVEL DIURETICS. Journal of the American Chemical Society. 1957/04/01 1957;79(8):2028-2029.
7. Graf W, Girod E, Schmid E, Stoll WG. Zur Konstitution von Benzophenon-2-carbonsäure-Derivaten. Helvetica Chimica Acta. 1959;42(3):1085-1101.
8. Sriram D. YP. Medicinal Chemistry. Second ed: Dorling Kindersley of Pearson Education; 2007.
9. Osol A, Hoover JE. Reminton's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co.; 1975:871.
10. Budavari S. The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ, USA: Merck and Co., Inc.; 1996:367.
11. Kumar A, Singh D, Jadhav A, Pandya DN. An efficient industrial process for 3-hydroxy-3-(3’-sulfamyl-4’-chlorophenyl)phtalimidine. Google Patents; 2005.