The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

Abstract

The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

Keywords: Curtius rearrangement; amine synthesis; carbamates; carboxylic acids; drug discovery; medicinal chemistry.

Figure 1.

Examples of applications of Curtius rearrangement for the synthesis of medicinally relevant compounds. The pink frames highlight the functionalities built by using Curtius rearrangement.

Scheme 1.

The Curtius rearrangement and its applications for the synthesis of amines and amine derivatives.

Scheme 2.

Mechanism of acyl azide formation using DPPA.

Scheme 3.

Use of DPPA for the preparation of inhibitor 13.

Scheme 4.

Use of oxalyl chloride and sodium azide protocol for the Curtius rearrangement involved in the synthesis of oseltamivir (19).

Scheme 5.

Use of thionyl chloride and sodium azide protocol in the synthesis of PTP4A3 inhibitor 22.

Scheme 6.

Use of trimethylsilyl azide in the Curtius rearrangement for the synthesis of cisplatin derivative 26.

Scheme 7.

Use of a mixed anhydride and sodium azide for the Curtius rearrangement in the synthesis of dihydrexidine (29).

Scheme 8.

Synthesis of fluoroquinolone compound 33.

Scheme 9.

Synthesis of fluoroquinolone derivative 36.

Scheme 10.

Synthesis of the antibacterial agent linezolid (41).

Scheme 11.

Synthesis of podophyllotoxin analogue 45.

Scheme 12.

Synthesis of novel colchicine derivative 49.

Scheme 13.

Synthesis of HDAC inhibitors.

Scheme 14.

Synthesis of LSD1 inhibitors.

Scheme 15.

Synthesis of sorafenib derivatives.

Scheme 16.

Synthesis of GSK3b inhibitor 63.

Scheme 17.

Synthesis of compound 66.

Scheme 18.

Synthesis of PTP4A3 inhibitor 22.

Scheme 19.

Synthesis of AR antagonist 72.

Scheme 20.

Synthesis of AR antagonist 73.

Scheme 21.

Synthesis of congeners of cisplatin.

Scheme 22.

Synthesis of Tamiflu (9).

Scheme 23.

Synthesis of oseltamivir (19).

Scheme 24.

Synthesis of influenza virus replication inhibitor 87.

Scheme 25.

Synthesis of diamino alcohol core 94 for HIV protease inhibitors.

Scheme 26.

Synthesis of HIV protease inhibitor core 96.

Scheme 27.

Synthesis of key epoxides 98 and 99 for HIV protease inhibitors.

Scheme 28.

Synthesis of key difluoroepoxide 106.

Scheme 29.

Synthesis of HIV protease inhibitor 110.

Scheme 30.

Synthesis of HIV integrase inhibitor 114.

Scheme 31.

Synthesis of Narlaprevir (118).

Scheme 32.

Synthesis of nucleoside analogue 122.

Scheme 33.

Synthesis of nucleoside analogue 125.

Scheme 34.

Synthesis of renin inhibitor 129.

Scheme 35.

Synthesis of renin inhibitor 133.

Scheme 36.

Synthesis of aliskiren (136).

Scheme 37.

A recent route to aliskiren (136).

Scheme 38.

Synthesis of β1 partial agonists 142a,b.

Scheme 39.

Synthesis of PDEIII inhibitor 146.

Scheme 40.

Synthesis of dopamine receptor agonist 149.

Scheme 41.

Synthesis of NMDA antagonist 151.

Scheme 42.

Synthesis of noncompetitive inhibitor of NMDA receptor complex 154.

Scheme 43.

Synthesis of benzodiazepine receptor ligands.

Scheme 44.

Synthesis of melatonin receptor ligands.

Scheme 45.

Synthesis of GABA receptor ligand 167.

Scheme 46.

Synthesis of glycine agonist 169.

Scheme 47.

Synthesis of spirocyclic sugar derivatives.

Scheme 48.

Synthesis of glycopeptides.

Scheme 49.

Synthesis of pseudo-sugar disaccharides.

Scheme 50.

Synthesis of DPP-4 inhibitor 185.

Scheme 51.

Synthesis of ACC inhibitor 189.

Scheme 52.

Synthesis of cathepsin K inhibitor 192.

Scheme 53.

Synthesis of γ-secretase modulator 196.

Scheme 54.

Synthesis of PNMT inhibitors 199.

Scheme 55.

Synthesis of unsymmetrical ureas.

Scheme 56.

Synthesis of macrocyclic compounds.

Scheme 57.

Synthesis of peptidomimetics.

Scheme 58.

Synthesis of N-(indol-2-yl)amides.

Scheme 59.

Continuous-flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQA, 217).

Scheme 60.

Continuous-flow synthesis of CCR1 antagonist 221.

Scheme 61.

Continuous-flow synthesis of key building block 224.