Quinolones nomenclature of organic compounds.pptx

Nomeclature of quinolones

1. Bioactive Quinolines/ Isoquinolines H N Et 2 Me H O N H N H Me O Me O N N quinine chloroquine • Quinine is an anti-malarial natural product isolated from the bark of the Cinchona tree • Chloroquine is a completely synthetic anti-malarial drug that has the quinoline system found in quinine - parasite resistance is now a problem Me O N Me O O Me O Me papaverine • Papaverine is an alkaloid isolated from the opium poppy and is a smooth muscle 45 relaxant and a coronary vasodilator

2. Drugs Containing a Quinoline/Isoquinoline H O 2 C S C O 2 H C O 2 Et N Cl N Ph N H O Name: Singulair Name: Quinapril 2008 Sales: $2.90 billion H O 2008 Sales: $133 million 2008 Ranking: 7 branded 2008 Ranking: 84 generic Company: Merck Company: N/A Disease: Asthma and allergies Disease: Hypertension and heart failure N H N O H Cl N Name: Hydroxychloroquine 2008 Sales: $74 million 2008 Ranking: 146 generic Company: N/A 46 Disease: Malaria, lupus erythematosus, rheumatoid arthritis

3. Malaria • Approximately 500 million cases of malaria each year and 1-3 million deaths • Disease is caused by protazoan parasites of the genus Plasmodium ( falciparum , vivax, ovale and malariae ) • Disease spread by the Anopheles mosquito (female) Cinchona pubescens 47 Anopheles mosquito Plasmodium monocyte

4. Quinolines - Synthesis Structure N N • pK a values (4.9 and 5.4) are similar to that of pyridine • Possess aspects of pyridine and naphthalene reactivity e.g. form N -oxides and ammonium salts Combes Synthesis (“3+3”) Me O Me O Me O Me O O Me − H 2 O N H 2 Me − H 2 O N Me 23% Me O Me O O Me N Me O Me O Me O H N H Me O Me O Me Me O Me O Me Me O H Me O N Me H c-H 2 SO 4 , Me O N Me H 48

5. Quinolines - Synthesis Conrad-Limpach-Knorr Synthesis (“3+3”) Me N H 2 O O rt, − H 2 O O Et O N O Et Me 270 °C O H N Me O N Me H 70% H • Very similar to the Combes synthesis by a β-keto ester is used instead of a β-diketone • Altering the reaction conditions can completely alter the regiochemical outcome O O Me O Et 140 °C, − H 2 O N H 2 Me O 250 °C, − H 2 O N O H Me Me N O N O H 50%H 49

6. Quinolines - Synthesis Skraup Synthesis (“3+3”) O H H 130 °C, H 2 SO 4 N H 2 [O] (e.g. I 2 ) N 85% H O N H − H 2 O N H H H O N H H O H N H • Acrolein can be generated in situ by treatment of glycerol with conc. sulfuric acid • A mild oxidant is required to form the fully aromatic system from the dihydroquinoline Me N H 2 1. O Me Me ZnCl 2 or FeCl 3 , EtOH, reflux 2. [O] 65% Me N 50

7. Quinolines - Synthesis Friedlander Synthesis (“4+2”) Ph O N H 2 Ph O N H 2 Ph O Me Me c-H 2 SO 4 , AcOH heat N H Ph O Me Me KOH aq., EtOH 0 °C N O H H H O Me − H 2 O Me O − H 2 O Me 88% 71% Ph Me N Me Ph N Me • The starting acyl aniline can be difficult to prepare • Acidic and basic conditions deliver regioisomeric products in good yields 51

8. Isoquinolines - Synthesis Pomeranz-Fritsch Synthesis (“3+3”) Et O O Et H 2 N O − H 2 O H Bischler-Napieralski Synthesis (“5+1”) MeCOCl N H 2 N H O Me O Et O EtH , EtOH N P 4 O 10 , heat N Me N Pd-C, 190 °C 93% N Me • Cyclisation can be accomplished using POCl 3 or PCl 5 • Oxidation of the dihydroisoquinoline can be performed using a mild oxidant 52

9. Isoquinolines - Synthesis Pictet Spengler Synthesis (“5+1”) Me O Me O Me O HCHO 20% aq. 20% HCl aq. N H 2 heat N 100 °C N H Me O Me O Me O [O] N N H N H 80% H • An electron-donating substituent on the carboaromatic ring is required • A tetrahydroisoquinoline is produced and subsequent oxidation is required to give the fully aromatic isoquinoline 53

10. Quinolines/Isoquinolines - Electrophilic Reactions * Regiochemistry N N H H * • Under strongly acidic conditions, reaction occurs via the ammonium salt • Attack occurs at the benzo- rather than hetero-ring • Reactions are faster than those of pyridine but slower than those of naphthalene N O 2 Nitration fuming HNO 3 , N cH 2 SO 4 , 0 °C N N 72% 8% N O 2 • In the case of quinoline, equal amounts of the 5- and 8-isomer are produced 54

11. Quinolines/Isoquinolines - Electrophilic Reactions Sulfonation H O 3 S 30% oleum 3 , >250 °C 90 °C N N N S O 3 H 54% thermodynamic product • Halogenation is also possible but product distribution is highly dependent on conditions • It is possible to introduce halogens into the hetero-ring under the correct conditions • Friedel-Crafts alkylation/acylation is not usually possible 55

12. Quinolines/Isoquinolines - Nucleophilic Reactions Regiochemistry N N • Attack occurs at hetero- rather than benzo-ring • They are enerally more reactive than pyridines to nucleophilic attack Carbon Nucleophiles 2-MeOC 6 H 4 Li H 2 O Et 2 O, rt H O Me H O Me N N N H Li [O] N 56 Me O

13. Quinolines/Isoquinolines - Nucleophilic Reactions n -BuLi H 2 O N benzene, rt N Li H n -Bu • Oxidation is required to regenerate aromaticity Amination KNH 2 , NH 3 (l) − 65 °C N N N H H n -Bu >− 45 °C H [O] N n -Bu H N H 2 N K KMnO 4 , − 65 °C N 50% N H 2 N H 2 K KMnO 4 , − 40 °C N H 2 N 60% thermodynamic product 57

14. Quinolines/Isoquinolines - Nucleophilic Substitution Displacement of Halogen NaOEt, EtOH reflux N Cl N Cl NaOMe, MeOH N DMSO 100 °C N Cl O Et O Me Cl 87% N O Et O Me N 58

15. Quinolines/ Isoquinolines - The Reissert Reaction PhCOCl -Benzyl chloride N KCN N N C N O Ph O H C N Ph base, MeI -Methyl Chloride NaOH aq. N Me N H O O Me CN Ph O Me N CN Ph • The proton adjacent to the cyano group is extremely acidic • The reaction works best with highly reactive alkyl halides 59

16. Isoquinolines - Synthesis of a Natural Product Synthesis of Papaverine O Me O Me Me O Me O N Me O Me O Me 2 CH(CH 2 ) 2 ONO, NaOEt, EtOH, rt Me O Me O P 4 H 10 , xylene, heat Me O O N 75% H O H O N H Me O ZnCl 2 , HCl, rt O H Me O KOH aq., rt Me O Na-Hg, H 2 O, 50 °C Me O O N H 2 O Cl O O Me O Me O N H 30% 60% O Me O Me O Me Me O Me O Me O • Cyclisation is achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski reaction 60

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