An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Abstract

This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

Keywords: five-membered rings; heterocycles; medicinal chemistry; pharmaceuticals; synthesis.

Figure 1

Structures of atorvastatin and other commercial statins.

Figure 2

Structure of compactin.

Scheme 1

Synthesis of pentasubstituted pyrroles.

Scheme 2

[3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.

Scheme 3

Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.

Scheme 4

Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.

Scheme 5

Formation of pyrrole 33 via the Paal–Knorr reaction.

Scheme 6

Convergent synthesis towards atorvastatin.

Figure 3

Binding pocket of sunitinib in the TRK KIT.

Scheme 7

Synthesis of sunitinib.

Scheme 8

Alternative synthesis of sunitinib.

Scheme 9

Key steps in the syntheses of sumatriptan and zolmitriptan.

Scheme 10

Introduction of the N,N-dimethylaminoethyl side chain.

Scheme 11

Japp–Klingemann reaction in the synthesis of sumatriptan.

Scheme 12

Synthesis of the intermediate sulfonyl chlorides 62 and 63.

Scheme 13

Alternative introduction of the sulfonamide.

Scheme 14

Negishi-type coupling to benzylic sulfonamides.

Scheme 15

Heck reaction used to introduce the sulfonamide side chain of naratriptan.

Scheme 16

Synthesis of the oxazolinone appendage of zolmitriptan.

Scheme 17

Grandberg indole synthesis used in the preparation of rizatriptan.

Scheme 18

Improved synthesis of rizatriptan.

Scheme 19

Larock-type synthesis of rizatriptan.

Scheme 20

Synthesis of eletriptan.

Scheme 21

Heck coupling for the indole system in eletriptan.

Scheme 22

Attempted Fischer indole synthesis of elatriptan.

Scheme 23

Successful Fischer indole synthesis for eletriptan.

Scheme 24

Mechanistic rationale for the Bischler–Möhlau reaction.

Scheme 25

Bischler-type indole synthesis used in the fluvastatin sodium synthesis.

Scheme 26

Palladium-mediated synthesis of ondansetron.

Scheme 27

Fischer indole synthesis of ondansetron.

Scheme 28

Optimised Pictet–Spengler reaction towards tadalafil.

Figure 4

Structures of carvedilol 136 and propranolol 137.

Scheme 29

Synthesis of the carbazole core of carvedilol.

Scheme 30

Alternative syntheses of 4-hydroxy-9H-carbazole.

Scheme 31

Convergent synthesis of etodolac.

Scheme 32

Alternative synthesis of etodolac.

Figure 5

Structures of imidazole-containing drugs.

Scheme 33

Synthesis of functionalised imidazoles towards losartan.

Scheme 34

Direct synthesis of the chlorinated imidazole in losartan.

Scheme 35

Synthesis of trisubstituted imidazoles.

Scheme 36

Preparation of the imidazole ring in olmesartan.

Scheme 37

Synthesis of ondansetron.

Scheme 38

Alternative route to ondansetron and its analogues.

Scheme 39

Proton pump inhibitors and synthesis of esomeprazole.

Scheme 40

Synthesis of benzimidazole core pantoprazole.

Figure 6

Structure of rabeprazole 194.

Scheme 41

Synthesis of candesartan.

Scheme 42

Alternative access to the candesartan key intermediate 216.

Scheme 43

.Medicinal chemistry route to telmisartan.

Scheme 44

Improved synthesis of telmisartan.

Scheme 45

Synthesis of zolpidem.

Scheme 46

Copper-catalysed 3-component coupling towards zolpidem.

Figure 7

Structure of celecoxib.

Scheme 47

Preparation of celecoxib.

Scheme 48

Alternative synthesis of celecoxib.

Scheme 49

Regioselective access to celecoxib.

Scheme 50

Synthesis of pazopanib.

Scheme 51

Syntheses of anastrozole, rizatriptan and letrozole.

Scheme 52

Regioselective synthesis of anastrozole.

Scheme 53

Triazine-mediated triazole formation towards anastrozole.

Scheme 54

Alternative routes to 1,2,4-triazoles.

Scheme 55

Initial synthetic route to sitagliptin.

Figure 8

Binding of sitagliptin within DPP-IV.

Scheme 56

The process route to sitagliptin key intermediate 280.

Scheme 57

Synthesis of maraviroc.

Scheme 58

Synthesis of alprazolam.

Scheme 59

The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.

Figure 9

Structures of itraconazole, ravuconazole and voriconazole.

Scheme 60

Synthesis of itraconazole.

Scheme 61

Synthesis of rufinamide.

Scheme 62

Representative tetrazole formation in valsartan.

Figure 10

Structure of tetrazole containing olmesartan, candesartan and irbesartan.

Scheme 63

Early stage introduction of the tetrazole in losartan.

Scheme 64

Synthesis of cilostazol.

Figure 11

Structure of cefdinir.

Scheme 65

Semi-synthesis of cefdinir.

Scheme 66

Thiazole syntheses towards ritonavir.

Scheme 67

Synthesis towards pramipexole.

Scheme 68

Alternative route to pramipexole.

Scheme 69

Synthesis of famotidine.

Scheme 70

Efficient synthesis of the hyperuricemic febuxostat.

Scheme 71

Synthesis of ziprasidone.

Figure 12

Structure of mometasone.

Scheme 72

Industrial access to 2-furoic acid present in mometasone.

Scheme 73

Synthesis of ranitidine from furfuryl alcohol.

Scheme 74

Synthesis of nitrofurantoin.

Scheme 75

Synthesis of benzofuran.

Scheme 76

Synthesis of amiodarone.

Scheme 77

Synthesis of raloxifene.

Scheme 78

Alternative access to the benzo[b]thiophene core of raloxifene.

Scheme 79

Gewald reaction in the synthesis of olanzapine.

Scheme 80

Alternative synthesis of olanzapine.

Figure 13

Access to simple thiophene-containing drugs.

Scheme 81

Synthesis of clopidogrel.

Scheme 82

Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).

Scheme 83

Alternative synthesis of key intermediate 422.

Figure 14

Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.

Scheme 84

Synthesis of timolol.

Scheme 85

Synthesis of tizanidine 440.

Scheme 86

Synthesis of leflunomide.

Scheme 87

Synthesis of sulfamethoxazole.

Scheme 88

Synthesis of risperidone.

Figure 15

Relative abundance of selected transformations.

Figure 16

The abundance of heterocycles within top 200 drugs (5-membered rings).