Synthetic Approaches to Piperazine-Containing Drugs Approved by FDA in the Period of 2011-2023

Abstract

The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.

Keywords: Buchwald–Hartwig amination; Finkelstein alkylation; amide bond formation; aromatic nucleophilic substitution; kinase inhibitors; receptor modulators; reductive amination.

Scheme 1

Synthesis of Palbociclib (1), Ribociclib (2) and Trilaciclib (6).

Scheme 2

Synthesis of the 2-ketopiperazine derivative 45.

Scheme 3

Synthesis of Vortioxetine (3).

Scheme 4

Synthesis of Avapritinib (4).

Scheme 5

Synthesis of Letermovir (5) from 2-bromo-6-fluoroaniline ((A), discovery (blue) and first process (red) routes) and from compound 65 (B).

Scheme 6

Design of 1-(6-(amino)pyrimidin-4-yl)-3-aryl-urea (A) and synthetic procedure to obtain Infigratinib (7) (B).

Scheme 7

Synthesis of Entrectinib (8).

Scheme 8

Synthesis of Avatrombopag (9). Reaction yields are not indicated in the original patent.

Scheme 9

(A) Synthesis of Netupitant (10) and Fosnetupitant (11); Synthesis of compounds 93 (B) and 97 (C).

Scheme 10

Synthetic procedures to obtain Venetoclax (12) (A) and compound 106 (B).

Scheme 11

Synthesis of Brexpiprazole (13).

Scheme 12

Synthesis of Vilazodone (14).

Scheme 13

Synthesis of Flibanserin (15).

Scheme 14

Synthesis of Aripiprazole Lauroxyl (16) and Cariprazine (17).

Scheme 15

Synthesis of Bosutinib (18).

Scheme 16

Synthesis of Ponatinib (19) and Nintedanib (20).

Scheme 17

Synthesis of Maralixibat (24).

Scheme 18

Synthesis of Abemaciclib (21).

Scheme 19

Synthesis of Gilteritinib (22).

Scheme 20

Synthesis of Brigatinib (23) and its ¹¹C-analog.

Scheme 21

Structure of the PKM2-activator I (A) and synthesis of Mitapivat (25) (B).

Scheme 22

Synthesis of Zavegepant (26).

Scheme 23

Synthesis of Olaparib (27).

Scheme 24

Synthesis of Fostemsavir (28).

Scheme 25

Synthetic procedures to obtain Selpercatinib (29) starting from 181 (A) or from 182 (B).

Scheme 26

Synthesis of Risdiplam (30).

Scheme 27

Synthesis of Sotorasib (31).

Scheme 28

Synthesis of the piperazine building blocks of Adagrasib (32).

Scheme 29

Synthesis of Adagrasib (32) from 213a and 213b (A); Synthesis of intermediate (S,S)-216 from 8-chloronaphthalen-1-amine (B).

Scheme 30

Synthesis of Fezolinetant (33).

Scheme 31

Synthesis of Lumateperone (34) from 3,4-dihydroquinoxalin-2(1H)-one (A), from (2-bromophenyl)hydrazine (B) and from 4a(S),9b(R)-233 (C).

Scheme 32

Synthesis of Fosdenopterin (35).

Scheme 33

(A): Synthesis of Lurbinectedin (36) and Trabectedin (37); (B) Synthesis of lactone 246. TBS = tert-butyldimethylsilyl; All = allyl; Alloc = COOAllyl.

Scheme 34

Synthesis of integrase inhibitors 38–40.