1 -cyclopropyl- 6-fluoro-7-

Substance E R = H and R = F systematic name is 1-cyclopropyl-6-fluoro-7-(piperazin-l-yl)quinolin-4(l//)-one (also known as the decarboxylated compound). 

Dimethyl-[l-methoxy-2,2,3,3-tetra-methyl-cyclopropyl]- -fluoro-sulfonate 1666... 

Cyclopropyl-3-fluoro-2-hydroxy-6-oxo-6//-pyrido[l,2-n]pyrimidine-7-carboxylates 340 were obtained in the reaction of 2-cyclopropyl-2-(5-fluoro-4-hydroxy-2-pyrimidinyl)acetaldehyde (339) and ethyl, rerr-butyl and dibenzyl malonates in the presence of piperidine and AcOH (95MIP1, 96JMC3070, 96MIP4, 96USP5580872). 

CN l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid... 

CN 1 -Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4a5,7a5)-octahydro-6//-pyrrolo[3,4-fc]pyridin-6-yl]-... 

Photolytic cleavage (at 320nm) of the substituent at position 1 of 9-cyclopropyl-l-[(4,5-dimethoxy-2-nitrophenyl)-methoxycarbonyl-3-fluoro-2,6-dioxo-l,2-dihydro-6//-pyrido[l,2-tf]pyrimidine-7-carboxylate gave 9-cyclopropyl-3-fluoro-2-hydroxy-6-oxo-6//-pyrido[ 1,2-tf]pyrimidin-7-carboxylate <1995WO95/010519, 1996WO96/039407,... 

Metabolism of ciprofloxacin by Pestalotiopsis guepini yielded /V-acetylcipro-floxacin (the most abundant metabolite), desethylene-W-acetylciprofloxacin, A-formylciprofloxacin, and 7 -amino-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-... 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The final coupling reaction of l-cyclopropyl-6-fluoro-7-chloro-l,4-dihy-dro-4-oxo-l,8-naphthyridine-3-carboxylic acid (7a) and 4-( er -butoxycarbo-nylaminomethyl)pyrrolidin-3-one-0-methyloxime (15a) proceeds according to the methods described by Sanchez et al. [13], Domogala et al. [16], and Kimura et al. [17], followed by acid hydrolysis to afford gemifloxacin, 7 - (4 - (aminomethyl) - 3 - (methoxyimino)pyrrolidin -1 - yl) -1 - cyclopropyl - 6 -fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid and other corresponding derivatives, according to Scheme 5. 

N-Cyclopropyl-N-(2,3-disubstituted 4-fluoro-6-nitrophenyl)aminometh-ylenemalonates (689) were cyclized to l-cyclopropylquinoline-3-carboxyl-ates (690) in a mixture of acetic anhydride and concentrated sulfuric acid at 50-70°C in 29-66% yields [86JAP(K) 143363 87NEP471 88EUP287951 89USP4874764],... 

Cyclopropyl-1,4-dihydro-1,8-naphthyridine-3-carboxylate (1025) was prepared in 43-48% yields by the cyclization of jV-cyclopropyl-M-[6-(4 - ethoxycarbonyl -1 - piperazinyl) -5- fluoro -2-pyridyl ] aminomethylene -malonate (111) in acetic acid by the action of concentrated sulfuric acid at 55-60°C for 1 hr (85EUP153163, 85EUP153828, 85EUP159174 86EUP172651 88EUP265230). 

Ciprofloxacin Ciprofloxacin, l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piper-azinyl)-3-qninolincarboxylic acid (33.2.19), is synthesized in a completely analogous scheme, except that instead of using ethyl iodide in the alkylation stage, cyclopropyl bromide is nsed [76-78]. 

A detailed study of the inhibition of MAOs by fluorophenyl cyclopropyl amines shows that the presence of fluorine has very important effects on this inhibition. While some of the regioisomers are inhibitors of the CAO (copper-containing amine oxidase), some other ones, such as 2-fluoro-l-arylcylopro-pyl amines, are excellent selective and irreversible inhibitors of MAO A. In this latter case, the nonfluorinated parent compound is a poor inhibitor of MAO B (Figure 7.55). ° " ... 

The products obtained in the reaction of A -cyclopropyl-4,5-difluoroanthranilic acid hydrazides 429 with triphosgene were dependent on the steric hindrance imposed by substituent R at position 3, and not the electronic effect of this group. While the unsubstituted compound 429 (R = H) gave exclusively the 4-hydrazono-3,l-benzoxazin-2-one-type product 430, the similar reactions of the chloro-, methyl-, and methoxy-substituted analogs 429 (R = Cl, Me, OMe) resulted in formation of the corresponding quinazoline-2,4-diones 431 as the sole products. For the fluoro-substituted compound 429 (R = F), a 20 80 mixture of the products 430 and 431 was obtained (Equation 46) <2005JHC669>. 

Fluoro-1,1.2-trimethyl-buty I )-2-methyl-3-oxo- ElOa, 111 [Cyclopropyl — CH(OII) —... 

Cyclopropyl-meihoxy)-(2,5-diliydro-2-imidazolyl)-amino]-6-fluoro-2-trifluoromethyl- E16a/1, 296 (OH - OR)... 

Amino-2-aza-spiro[4.2]hept-2-yl)-3-carboxy-8-chloro-6-fluoro-1 -(2-fluoro-cyclopropyl)-4-oxo-ElOa, 184 (Educl)... 

Amino-ethylsulfanyl)-3-carb-oxy-8-chloro-1 -cyclopropyl-6-fluoro-4-oxo- El0b2, 447 (F - SR)... 

Carboxy-1 -cyclopropyl-6.8-di-fluoro-7-(2-dimethylamino-ethylsulfonyl)-4-oxo- E10b2. 446 (F SR)... 

Carboxy-l-cyclopropyl-b.S-di-fluoro-y-. b-dimethyM-pyri-dyl)-4-oxo-5-phenylsulfanyl-F.10h2, 448 (F - S-Ar)... 

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