Prescribed drugs containing nitrogen heterocycles: an overview

Abstract

Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic information has been extracted from both scientific journals and the wider patent literature.

Scheme 1. Synthesis of penicilin G 7.

Scheme 2. Synthesis of penicillin V 20.

Scheme 3. Two-step one-pot enzymatic cascade process for industrial synthesis of amoxicillin.

Scheme 4. Synthesis of cephalexin 32.

Scheme 5. Synthesis of ezetimibe 41.

Scheme 6. A pathway for the synthesis of lisinopril 47.

Scheme 7. Synthesis of enalapril 51.

Scheme 8. Synthetic route to ramipril 57.

Scheme 9. Total synthesis of atorvastatin 68.

Scheme 10. Synthesis of sumatriptan 77.

Scheme 11. Preparation of sumatriptan 86via combination of Japp–Klingemann and Fischer-indole.

Scheme 12. Fischer indole synthesis of ondansetron 94.

Scheme 13. Synthetic pathway to tadalafil 99.

Scheme 14. Synthesis of carvedilol 104.

Scheme 15. Preparation of losartan 109.

Scheme 16. Synthesis of clonidine 113.

Scheme 17. Tow routes for the formation of apixaban 123.

Scheme 18. Synthesis of acyclovir 136.

Scheme 19. Synthesis of valacyclovir 140.

Scheme 20. Synthesis of omeprazole 152.

Scheme 21. Asymmetric synthesis of esomeprazole 159.

Scheme 22. Sequence of reactions for the formation of pantoprazole 169.

Scheme 23. Synthesis of zolpidem 177.

Scheme 24. Synthesis of celecoxib 182.

Scheme 25. Synthetic pathway to sitagliptin 187.

Scheme 26. Synthesis of alprazolam 193.

Scheme 27. Synthesis of valsartan 205.

Scheme 28. Synthesis of cefdinir 211.

Scheme 29. Synthesis of famotidine 220.

Scheme 30. Synthesis of nitrofurantoin 227.

Scheme 31. Synthesis of tizanidine 233.

Scheme 32. Synthesis of risperidone 244.

Scheme 33. Synthesis of (−)-levetiracetam 252.

Scheme 34. Synthesis of fluconazole 257.

Scheme 35. Synthesis of allopurinol 262.

Scheme 36. Synthesis of hydroxychloroquine 268.

Scheme 37. Synthesis of pioglitazone 275.

Scheme 38. Synthesis of lansoprazole 283.

Scheme 39. Synthesis of nifedipine 286.

Scheme 40. Synthesis of amlodipine 295.

Scheme 41. Synthesis of rosuvastatin 309.

Scheme 42. Syntheses of azelastine 314.

Scheme 43. Synthesis of hydralazine 319.

Scheme 44. Synthesis of glipizide 323.

Scheme 45. Synthesis of lamotrigine 328.

Scheme 46. Synthesis of lamotrigine 328.

Scheme 47. Synthesis of oxycodone 336.

Scheme 48. Synthesis of Viagra™ (Sildenafil) in accordance of Phizer procedure.

Scheme 49. Synthesis of methylphenidate 354.

Scheme 50. Synthesis of loratadine 362.

Scheme 51. Synthesis of meclizine 367.

Scheme 52. Synthesis of cetirizine 374.

Scheme 53. Synthesis of levofloxacin 384.

Scheme 54. Synthesis of fentanyl 389 and acetylthiofentanyl 390.

Scheme 55. Synthesis of donepezil hydrochloride 394 (Method A).

Scheme 56. Synthesis of donepezil hydrochloride 394 (Method B).

Scheme 57. Synthesis of paroxetine 407.

Scheme 58. Synthesis of optically pure clopidogrel 422.

Scheme 59. Synthesis of ketoconazole 431.

Scheme 60. Synthesis of mirtazapine 437.

Scheme 61. Synthesis of hydroxyzine 440.

Scheme 62. Synthesis of levocetirizine 441.

Scheme 63. Methods for obtaining trazodone 454.

Scheme 64. Preparation of doxazosin mesylate 460.

Scheme 65. Synthesis of aripiprazole 464.

Scheme 66. Synthesis of finasteride 474.

Scheme 67. Synthetic process of ciprofloxacin 480.

Scheme 68. Synthesis of promethazine 483.

Scheme 69. Synthesis of buspirone 489.

Scheme 70. Synthesis of methotrexate 502.

Scheme 71. Synthesis of morphine 521.

Scheme 72. Synthesis of diazepam 526.

Scheme 73. Synthesis of diazepam 526.

Scheme 74. Synthesis of lorazepam 536.

Scheme 75. Synthesis of clonazepam 541.

Scheme 76. Synthesis of temazepam 546.

Scheme 77. Synthesis of quetiapine 555.

Scheme 78. Synthesis of benazepril 565.

Scheme 79. Synthesis of olanzapine 571.