The Grohe Method and Quinolone Antibiotics
Total Page:16
File Type:pdf, Size:1020Kb
The Grohe method and quinolone antibiotics Antibiotics are medicines that are used to treat bacterial for modern fluoroquinolones. The Grohe process and the infections. They contain active ingredients belonging to var- synthesis of ciprofloxacin sparked Bayer AG’s extensive ious substance classes, with modern fluoroquinolones one research on fluoroquinolones and the global competition of the most important and an indispensable part of both that produced additional potent antibiotics. human and veterinary medicine. It is largely thanks to Klaus Grohe – the “father of Bayer quinolones” – that this entirely In chemical terms, the antibiotics referred to for simplicity synthetic class of antibiotics now plays such a vital role for as quinolones are derived from 1,4-dihydro-4-oxo-3-quin- medical practitioners. From 1965 to 1997, Grohe worked oline carboxylic acid (1) substituted in position 1. as a chemist, carrying out basic research at Bayer AG’s Fluoroquinolones possess a fluorine atom in position 6. In main research laboratory (WHL) in Leverkusen. During this addition, ciprofloxacin (2) has a cyclopropyl group in posi- period, in 1975, he developed the Grohe process – a new tion 1 and also a piperazine group in position 7 (Figure A). multi-stage synthesis method for quinolones. It was this This substituent pattern plays a key role in its excellent achievement that first enabled him to synthesize active an- antibacterial efficacy. tibacterial substances such as ciprofloxacin – the prototype O 5 O 4 3 6 COOH F COOH 7 2 N N N 8 1 H N R (1) (2) Figure A: Basic structure of quinolone (1) (R = various substituents) and ciprofloxacin (2) Quinolones owe their antibacterial efficacy to their inhibition This unique mode of action also makes fluoroquinolones of essential bacterial enzymes – DNA gyrase (topoisomer- highly effective against a large number of pathogenic ase II) and topoisomerase IV. The active substances prevent bacteria that areCl resistant to penicillin, cephalosporin, ami- CCl2 HC COOR2 the bacterial DNA fromN supercoiling, meaning that the BasenoglycosideN and tetracycline.COOR2 1 pathogens can no longerCCl3 multiply and theyC ultimatelyR die. In3HCl 1 the medical context, quinolones areH2 Ntherefore also referred Cl N R to as gyrase inhibitors. (3) (4) (5) The Grohe method and quinolone antibiotics 1 O O HC COOR2 2 COCl Base I C C COOR2 Base II COOR R R R C R1 1 1 Hal HN HCl Hal C R HHal N R R3 HN R3 R3 (6) (7) (8) (9) O O O COOH N COOH F COOH N CH3 N N HN N N N R R CH3 (10) (11) (12) O F COCl HC COOEt F C Base Ⅰ C COOEt Base Ⅱ Cl Cl CH HCl Cl Cl CH HCl HN HN (13) (14) (15) O O F COOEt a) Verseifung F COOH Cl b) R N NH N R N N N (16) (2) O Mg(OEt)2 F C (+) (a) CH(COOEt)2 H3O 13 CH2 (COOEt)2 HCl Cl Cl O O C CH COOEt C F 2 HC(OEt)3 F C COOEt NH2 15 Cl Cl Ac2O Cl Cl CH ETOH OEt O (b) 13 HC COOEt Base F C C COOEt NH2 CH HCl 15 Cl Cl (CH3)2NH (CH3)2N CH (CH3)2N O O H H F COOH F COOH N H N H N N N N OCH CN H 3 H (17) (18) O 5 O 4 3 6 COOH F COOH 7 2 N N N 8 1 H N When Grohe started working as aR chemist at Bayer AG’s as cycloacylation. The cyclocondensation of polyfunctional O WHL in 51965, he initially focused on the synthesis of acylatingO agents with tautomerizable enamines and en- 4 3 (1) (2) organochlorine6 andCOOH organofluorine intermediates. InF 1969, hydrazinesCOOH enabled him to synthesize compounds such as at his own request, he transferred to the WHL’s pharma- pyrimidines, thiazolones, uracils and pyrazolium betaines. 7 2 ceutical researchN division. In the early 1970s, Grohe’sN basic CycloacylationN of trichloromethyl isocyanide dichloride (3) 8 1 H N research work led to the discovery of a general synthesis with enamino esters (4), for example, produced pyrimidine R principle for 5- and 6-membered N-heterocycles known carbon esters (5) (Figure B). (1) (2) Cl CCl2 HC COOR2 N Base N COOR2 1 CCl3 C R 3HCl 1 H2N Cl N R Cl CCl2 HC COOR2 N (3) Base(4) N COOR2 (5) 1 CCl3 C R 3HCl 1 Figure B: SynthesisH2 ofN pyrimidine carbon esters (5) using cycloacylationCl N R (3) (4) (5) Despite all kinds of further pharmaceutical and crop In 1975, Grohe modified the general reaction principle, protection research on numerous derivatives of these using o-halogenated benzoyl chlorides (6) as a cyclocon- heterocycles, there was no breakthrough that resulted in a densation agent for the first time. Based on combined marketable product. acylation and arylation with secondary enamino esters (7) by way of intermediates (8), he thus obtained the quinolone carboxylic acid esters (9) inO a completely new way. O HC COOR2 2 COCl Base I C C COOR2 Base II COOR R R R C R1 1 1 Hal HN O HCl Hal C R O HHal N R COCl HC COOR2 C 2 Base3 I C COOR2 BaseHN II COOR 3 R R R R R C R1 1 1 Hal HN HCl Hal C R HHal R3 N R R3(6) (7) HN (8) R3 (9) R3 (6) (7) (8) (9) Figure C: Grohe process (Hal = Cl, Br) Known as cycloaracylation (Figure C), this approach was Grohe was keen to continue his work on quinolones, so subsequently referred to in literature Oas the Grohe process that same yearO the new head of research transferredO him or Grohe method. from the WHL’s pharmaceutical research division to the O COOHO cropN protection team,OCOOH where he Fwas able to pursueCOOH this COOH COOHresearchF alongside hisCOOH other activities. N N CH3 N N HN N N N N CH3 N N HN N N N R R CH3 R R CH3 (10) (11) (12) (10) (11) (12) The Grohe method and quinolone antibiotics O O 2 F COCl HC COOEt F C F COCl BaseHC Ⅰ COOEt C COOEtF Base ⅡC Base Ⅰ C COOEt Base Ⅱ Cl Cl CH HCl Cl Cl HCl CH Cl Cl ClHN Cl CH HNHCl CH HCl HN HN (13) (14) (15) (13) (14) (15) O O F COOEt a) OVerseifung F COOH O Cl b) R N NH F N F COOEt R a)N VerseifungN N COOH Cl b) R N NH N R N N N (16) (2) (16) (2) O Mg(OEt)2 F C (+) (a) CH(COOEt)2 H3O 13 CH2 (COOEt)2 HCl Cl Cl O Mg(OEt)2 F C (+) O (a) O CH(COOEt)2 H3O 13 CH2 (COOEt)2 C CH COOEt HClC Cl Cl F 2 HC(OEt)3 F C COOEt NH2 15 Cl Cl Ac2O Cl Cl CH ETOH O O OEt C CH COOEt C F 2 HC(OEt)3 F C COOEt NH2 O 15 (b) 13 HC COOEtCl Cl Ac2O Cl Cl CH ETOH Base F C C COOEt NH2 OEt CH HCl 15 Cl Cl (CH3)2NH (CH3)2N CH (CH3)2N O (b) 13 HC COOEt Base F C C COOEt NH2 CH HCl 15 Cl Cl (CH3)2NH (CH3)2N CH (CH3)2N O O H H F COOH F COOH N H N H N N N N OCH CN H 3 H (17) O (18) O H H F COOH F COOH N H N H N N N N OCH CN H 3 H (17) (18) O 5 O 4 3 6 COOH F COOH 7 2 N N N 8 1 H N R (1) (2) Cl CCl2 HC COOR2 N Base N COOR2 1 CCl3 C R 3HCl 1 H2N Cl N R (3) (4) (5) O O HC COOR2 2 COCl Base I C C COOR2 Base II COOR R R R C R1 1 1 Hal HN HCl Hal C R HHal N R R3 HN R3 R3 (6) (7) (8) (9) As someone who was passionate about experimenting, came across nalidixic acid (10), pipemidic acid (11) and Grohe was spurred on by the many different new chemical flumequine (12) (Figure D), also led him to believe that the possibilities of his method when compared with the quinolones he had produced offered huge medical and traditional Gould-Jacobs reaction. Associated docu- pharmaceutical potential. mentary research carried out by Grohe, during which he O O O COOH N COOH F COOH N CH3 N N HN N N N R R CH3 (10) (11) (12) Figure D: Nalidixic acid (10, R = ethyl), pipemidic acid (11, R = ethyl) and flumequine (12) The antibacterially effective azaquinolone carboxylic acids It was, however, perfectly possible to do so with the Grohe (10, 11) and tricyclic quinolone carboxylic acid (12) all method, as he was able to demonstrate using cyclopropyl have a similar structure to the compounds Grohe syn- variants of nalidixicO acid (10) and pipemidic acid (11) (R = thesized. Since they have only a relatively weak antibiotic cyclopropyl) as an example. As he had hoped, the antibac- F COCl HC COOEt F C effect against gram-negative bacteria, exhibit poor oralBase Ⅰ terial efficacy of bothC variantsCOOEt wasBase far superior Ⅱ to that of the absorption and lead to a rapid development of resistance, comparable compounds. Unfortunately, this clear progress Cl Cl CH HCl Cl Cl CH HCl how ever, they were primarily usedHN to treat urinary tract was not sufficientHN to justify further development at the time.