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Publication numberUS3682927 A
Publication typeGrant
Publication dateAug 8, 1972
Filing dateJun 12, 1969
Priority dateJun 15, 1968
Publication numberUS 3682927 A, US 3682927A, US-A-3682927, US3682927 A, US3682927A
InventorsMassimo Carissimi, Franco Ravenna
Original AssigneeFranco Ravenna, Massimo Carissimi
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
5,7-bichloro-8-hydroxy-2-acetylamino quinoline
US 3682927 A
Abstract
An extensive series of quinoline derivatives is disclosed, more particularly several 5,7-bichloro-8-hydroxy-quinolines carrying various substituents in the 2-position. The most interesting substituents are the aldehyde grouping, the amino grouping, the alkylaminic groupings, the piperidino, morpholino and piperazino groupings as such and variously substituted, the halogenacetic groupings, the acylaminic groupings and the halogenalkylic grouping, and also the alcoholic radicals. These compounds have proven to be vary effective antiseptics and fungicides.
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United States Patent [151 3,682,927

Carissimi et a1. 45 A 8, 1972 [54] 5,7-BICHLORO-8-HYDROXY-2- 3,088,916 5/1963 Roman ..260/289 UX ACETYLAMINO QUINOLINE 3,136,768 6/ 1964 Griot ..260/289 X [72} Inventors: Massimo Carissimi, Piazlale 3,297,525 1/1967 Grier ..260/289 X Maciachini 16; Franco Raven 3,298,911 1/1967 Renz ..260/289 X via Vimenzo Monti, 57M both 3,362,960 1/1968 Hodel et a1. ..260/289 X Milan Italy 3,391,114 7/1968 Schaefer ..260/289 X [22] F1 d J 2 I969 3,391,146 7/1968 Godfrey ..260/289X 1e une 21 L N Primary Examiner-Donald G. Daus App 0 832,590

AtrorneyB. Edward Shlesinger [30] Foreign Application Priority Data 57] ABSTRACT June 1968 Italy "17755 N68 An extensive series of quinoline derivatives is disclosed, more particularly several 5,7-bichloro-8- [52] Cl "260/287 260/2472 260/270 hydroxy-quinolines carrying various substituents in the 260/268 260/288 260/289 2-position. The most interesting substituents are the m Cl 260/289 aldehyde grouping, the amino grouping, the al- I Q I I I I I I e 1 i Fldd 0f Search v piperazino groupings as Such and variously Sub stituted, the halogenacetic groupings, the acylaminic [56] References cued groupings and the halogenalkylic grouping, and also UNITED STATES PATENTS the alcoholic radicals. These compounds have proven 2 770 6'9 1 H1956 schraefstaner 260/289 Ux to be vary effective antiseptics and fungicides, 2,798,071 7/1957 Mathes ..260/289 1 Claim, 2 Drawing Figures 1 2 5,7-BICHIDRO-8-HYDROXY-2-ACE'IYLAMINO manner how their preparation can be arrived at with QUINOLINE means which are, however, simple enough when they BACKGROUND OFnlElNvENnON are compared with the complex nature of the compounds involved and of the numerous and various sub- FIELD OFTHElNVENI'lON stituents- This invention relates to a few quinoline derivatives BRIEF DESCRIPTION OF THE DRAWINGS which are useful as antiseptics and fungicides.

More particularly, the invention is concerned with a these reasons It has been deemed expedleml m few 5,7 bich1om 8 hydmxy quinolines with various 10 order to enable the reader to follow a convenient substituents in the 2-position of the quinoline ring. guideline of logical elassifieatiohto accompany the The considerable reactivity of 8-hydroxy-quinoline amp given in h following. with 80 to Speak, was already known, said reactivity being manifested by genealogical" patterns of FIGS. 1 and 2 in order to the ability of this compound to foml metal chelates, allow the identification, for each compound, of the especially with heavy metals; for this reason, the better way which is suggested to arrive, individually, to hydroxy quinoline is still used in analytical chemistry as the m d one i h t prepare,

a reachve t heavy metals- As a general information criterion, it can be said that More p f ys the ObJeet of the lahonous expenthe starting point of the reaction patterns indicated in mental work whlch led to the preparation of a large 1.16s 1 and 2 is chloroquinaldol, or 57 bich]oro 8 "F f gz of IZ 'E hydroxy quinaldine. Using it as the starting compound, qlnno en m 0 to e clmFal the benzyl derivatives are first prepared, that is, those cloners, sophisticated weapons for combating several hi h min th 8 th 0 syndromes either due to bacteria or tofungi. w c con m 6 P081 y Thus, numerous compounds have been prepared, f From the latter m j' m which have in common the 5,7-bichloro-8-hydroxy been mtr9dueds at FheProper m the z'posmoni quinoline skeleton and differ from each other by the f'mcnoflal gmupmg Involved selected among those different substituents in the 2-position. listed heremaboveone arrives through a debehzyla' Th z-position b tit t hi h are conducive m tion, to the quinoline derivatives which contain, in the the most interesting compounds to the ends of the -P the desired radical. present invention are the following: the aldehyde In Order to p i y the reaction Patterns, the f0ll0W- grouping, the amino grouping, the alkylaminic ing symbols have been adopted in the graphical groupings, the piperidino, piperazino and morpholino representation of FIGS. 1 and 2: grouping, either as such or variously substituted, the halogen-acetylic groupings, the acylaminic groupings and the halogenoalkyl groupings, and the alcoholic 1 radicals as well.

In the light of the foregoing, the compounds which are most interesting from a pharmacological standpoint, as prepared according to the teachings of the present invention, are the following:

in the first place, the

5,7-bichloro-8-hydroxy-Z-piperidinomethyl-quinoline, and:

5,7-bichloro-8-hydroxy-2-diethylaminomethyl-quinoline 5 ,7-bic hloro- 8-hydroxy-Z-morpholinomethyl-quinoline 5 ,7-bichloro-8-hydroxy- 2-acetylamino-quinoline 5,7-bichloro-8-hydroxy-2-quinaldehyde J- i hlOr0-8-hydroxy-2-amino-quinoline Numerous examples will now be given, which cor- 5,7-bichlor y r y; y respond to the reaction patterns of FIGS. 1 and 2: it piperazinome hyl-q h e should be noticed that each of the compounds s7- f y y' 'q!- h prepared with the reactions of the above indicated pat- 5,7-lblchloro-8-hydroxy-2-dlethylamlnoethyl-qu1nterns has been numbered both in the FIGS and in the o description of the examples, with a Roman numerical 5,7-blchloro-8-hydroxy-2-chloroacetyl-qulnolme so as to ename anyone to find immediately and to 5,7-bichloro-S-hydroxy-2-chloromethy-quinoline. th It is quite obvious that, to prepare sowideararlge of mogul: m c pattern the Sequence of reacuons derivatives with substituents which are so sharply difadPted to Pf P the deslreq compound- II shoutd be ferent from each other, it is impossible to suggest a sinnomad 8 that the patterns of FIGS- 1 gle reaction scheme for the process of preparation. Inand 2 e merely exemplary, In that the Compounds stead, it will be pointed out, at the outset, that the concerned. o at least. a c r be ther o could several methods selected for the preparation of the difalso be prepared otherwise. In the example concerned ferent quinoline derivatives in question, are not critical herein, there has been selected, for each individual per se and have been given in this specification by way compound, the way which has been deemed the shorof example only, in order to show in a comprehensive test and the most convenient to prepare it.

5 ,7-BICHLORO-S-BENZYLOXY QUINALDINE Twelve (12) grs. chloroquinaldol are slowly introduced in a solution of 3.6 gm. KOH in 600 mls.ethanol, maintained at 70 C. Upon total dissolution, 7.4 mls. of alpha-bromo-toluene are added dropwise with stirring and the solution is refluxed during 3 hours. Upon cooling, a filtering step is carried out and the filtrate is concentrated in a vacuo to dryness. The semi-solid substance thus obtained is taken up with ethyl acetate: the inorganic portion which is still present is filtered and the solution concentrated once more. The oily residue is distilled and the fraction between 190 C and 200 C (11 millimeters of mercury) is collected and taken up with 20 mls. of hot ethanol. Upon cooling, the crystallizate is collected on a filter and there are obtained grs. of a product having a m.p. of 6263 C, which, however, is still slightly impure due to chloroquinaldol.

ForC H,,Cl,NO: Found: Cl%= 22.28

Calcd. 22.50

5 7-BICHLORO-8-BENZYLOX Y-2-QU[NOLINE ALDEHYDE To a solution of 6.73 grs. of SeO, in I40 mls. dioxane and i4 mls. water, heated on a boiling water bath, there are added, all at a time 14 grs. of 5,7 dichloro-8- benzyloxy quinaldine dissolved in 140 mls. dioxane. Upon stirring, in hot condition, during 3 hrs., the solution is filtered, cooled and the filtrate is concentrated in a vacuo. The residue, recrystallized from ligroin, melts at 125 C. 13 Yield: l2grs.

For C H CLNO, Found: C%== 61.34; H%=3.4l Calcd. 61.46 3.34 Found: N%= 4. l6 Cl%=2l.2l Calcd. 4.22 21.35

5 ,7-BICI-ILORO-8-BENZYLOX Y-2- QUINOLINECARBON'IC ACID To a suspension of 2 grs. of 5,7-benzyloxy-2-quinoline aldehyde in 140 mls. of a 7.5 percent aqueous solution of NaOH kept on a water bath at 80 C, is slowly added, with stirring, a solution of mls. hydrogen peroxide (120 volumes) in 20 mls. water. After 2 hrs. at 80 C, the solution is allowed to cool and the sodium salt of the acid is filtered and dissolved in hot condition in an aqueous solution of sodium carbonate. Upon filtration, the cool filtrate is acidified with glacial acetic acid. The solid ppte., collected on a filter, is thoroughly washed with water, dried and recrystallized from ligroin. There are obtained 1 l grs. of a product having a m.p. of 148 Cl49 C.

For C H CLNO Found C% 58.57 Hl: 3.34 N% 4.07 Clb 20.60 Calcd. 58.64 3. 19 4.02 20.3%

5,7-BICHLORO-8-BENZYLOXY-2- QUINOLINECARBONIC ACID CHLORIDE (XV) A mixture of 5 gm. of 5,7-dichloro-8-benzyloxy-2- quinoline carbonic acid and 6 grs. of PC]; in 300 mls. of CCl is refluxed during 5 hours. Upon cooling, the solvent is evaporated in a vacuo and the residue taken up with anhydrous ether. The inorganic portion is removed by filtration and the liquor is concentrated again, the residue is recrystallized from ligroin and gives 3.8 grs. of a yellow crystalline product having a m.p. of 132 C-133C.

H m a I Found N% =41)! Calcd. 3.82

5,7-BICl-ILORO-8-BENZYLOXY-2- QUINOLINECARBONIC ACID AZIDE For CHHIOCI'ZN4OI Found N% =I3.60 CH: =l9.l4 15.01 19.00

S,7-BICHI..ORO-8-BENZYLOXY-2- AMINOQUINOLINE A solution of 4.4 grs. of 5,7-dichloro-8-benzyloxy-2- quinoline carbonic acid azide dissolved in 650 mls. anhydrous dioxane (0.17 percent water) is refluxed during 5 hours. The solution is evaporated to dryness in a vacuo and from the residue, recrystallized from aqueous ethanol, 2.3 grs. of substance are obtained. mp. 188 C-l89 C.

Calcd. 8.78

The hydrochloride, recrystallized from ethanol, melts at 158 C-l60 C.

Found =s3.s7; n%=3.94; N%=7.77; c1%=29.42 Calcd. 54.03 3.69 7.88 29.90

5,7-BICHLOR0-8-HYDROXY'2- AMINOQUINOLINE 2.3 grs. of 5,7-dichloro-8benzyloxy-2-aminoquinoline in 15 mls. concJ-ICI are allowed to stand at room temperature during 2 days. The solution is evaporated to dryness under reduced pressures, the residue is taken up with an aqueous solution of sodium bicarbonate and the obtained ppte. is collected on a filter. The ppte. is thoroughly washed with water and dried H%=2.96 Calcd. 40.70 2.66

N%==l0.35 OM09 10.55 40.06

The base, recrystallized from ethanol, melts at 234 C235 C.

Found C% =47.55; H%=2.66; N%=l2.ll OM10 Calcd. 4719 2.64 [2.23 30.96 5,7-BlCHLORO-8-BENZYLOXY-2- ACETYLAMINOQUINOLINE 4.5 grs. of 5,7-dichloro-8-benzyloxy-2-aminoquinoline, free base in 350 mls. acetic anhydride are stirred during 3 hours on a water bath kept at 90 C. Upon cooling, the solvent is evaporated in a vacuo. The solid thus obtained, by taking up the residue with water, is collected on a filter and, after several washings with water, is recrystallized from aqueous ethanol. Yield 3 grs. m.p. 142 C-l43" C For C H CI,N,O, Found Cl: #004 H%=4.0l N%=7.45 Cl%=l9.58 Calcd. 59.85 3.90 7.76 19.63

For C, H,,CI,N,O, Found C%=48.75 Calcd. 48.73

5,7-BlCHLORO-8-BENZYLOXY-2- QUINOLINEMETHANOL To a solution of 3.5 grs. of 5,7-dichloro-8-benzyloxy- 2-quin0line aldehyde in 350 mls. of methanol, kept at 50C, are slowly added, with stirring, 2.04 grs. of NaBH dissolved in 25 mls. water. After refluxing dur- For c n cmo, Found cs0 =6l.25 H%=4.05 Nth-4.21 Clb-QLID Calcd. 61.09 3.92 4.19 21.22

5,7-BICHLOR0-8'BENZYLOXY-2- CHLOROME'T'HYL QUTNOLIN E 9 grs. of 5,7-dichloro-8-benzyloxy-2-quin- 3 .CHC iie ifi'lflfivflil sri-ifi d u ri n g s E0092 El' im coo ing, the solution is concentrated in a vacuo and the residue which has been obtained is taken up with water and extracted with ether. The extracts, after several washings with water and filtration over charcoal, are evaporated in a vacuo. The residue, recrystallized from hexane, melts at 93 C94 C -Yield 6. l grs.

For C H CI NO Found C% =58. Cl9o=30.48 Calcd. 57.90 30.16

5 ,7-BICHLORO-8-BENZYLOXY-2-TERT.AMINO METHYLQUTNOLINE To a solution of 2.84 millimoles of 5,7-dichloro-8- benzyloxy-2-chloromethyl quinoline in 15 mls. of ethyl acetate are slowly added 8.52 millimoles of an amine dissolved in 5 mls. of ethyl acetate. The mixture is refluxed during 7 hours and, upon cooling, is poured in 200 mls. ether. The solid precipitate is collected on a filter, thoroughly washed with ether and the ethereal solutions are combined and, after several washings with water, are dried over NA SO and evaporated under reduced pressures. The residue, converted into a hydrochloride, is purified by reprecipitation from alcohol and ether. The melting points and analyses are reported in Table B.

5,7-B[CHLORO-8-HYDROXY-2-TERT.AMINO METHYLQUINOLINE One millimole of aminobenzylate is allowed to stand during 4 hours at room temperature in 20 mls. of cone. HCl. The solution, poured in iced water, is brought to a slightly alkaline pH value with diluted soda and extracted with ethyl acetate. The extracts, washed with water and dried, are evaporated in a vacuo. The residue is converted into a hydrochloride and purified by recrystallizing it from ethanol.

The melting points and analyses of the compounds ing 4 hours, the cool solution is filtered and concenare reported in Table B.

TABLE B G1 I N/ (GHQ-FR 03100., pelcent Found, percent Yield, N R R n M.P.,C percent Formula C H N Cl C H N Cl XxXIx.. lpiperidino C0I'l5-CH2 1 100-103 15 CnHq ClgNnO-HCI ,24.3o 23.00 XL ..do 1 271-213 00 cwHmcnmo-Hm 01.02 493 8.06 30.59 52.01 4.01 8.22 30.02 XLI l-4- methy1 plpera- C6H5-CH2- 1 222-223 00 01.112100011021101 8.69 28.29 8.64 29.10

ZlYlO. XLII H 1 230234 00 currflcnmo-mci 45.13 4.30 10.03 30.03 41.11 4.03 10.00 30.45 XLIII l-morphollno O0HiCH1 1 184-135 C HwChNmz-IICl 6.37 24.19 6.47 23.70 XLIV do H 1 266-268 40 01.111011112011101 48.09 433 1101 30.12 47.83 4.28 80.4 30.25 XLV ldiethylamlnd. com-c111- 1 150151 00 cfll-lnchmo-ncl 21.. .30 21.75 XLVI ..do H 1 235F231 a0 cunwcimnnioi 50.00 5.11 8.35 31.00 50.01 0.14 8.14 31.65

trated to a reduced volume. The solid precipitate is col- What is claimed is:

lected on a filter and purified by recrystallization from ligroin and melts at 109 C-l 10 C. Yield: 2.5 grs.

l. 5,7-bichloro-8-hydroxy-2-acetylamino quinoline.

I! l i t 1

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2770619 *Nov 12, 1953Nov 13, 1956Schenley Ind IncSubstituted 8-quinolinols
US2798071 *Jul 2, 1957 Process for the production of quinoline
US3088916 *Aug 11, 1958May 7, 1963Monsanto ChemicalsBacteriostatic and fungistatic cleansing compositions
US3136768 *Feb 23, 1962Jun 9, 1964Sandoz Ltd8-(benzoyloxy)-quinolines
US3297525 *Oct 19, 1962Jan 10, 1967Merck & Co IncFungicidal compositions comprising salicylates of 8 hydroxy quinoline carboxylic esters
US3298911 *Mar 24, 1964Jan 17, 1967Sandoz LtdBacteriostatic and fungicidal composition comprising 5, 7-dibromo-8-benzoyloxy-quinaldine in inert carrier
US3362960 *Apr 24, 1967Jan 9, 1968Geigy Chem CorpO-quinolyl-(8)-n-methyl carbamic acid esters
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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3895013 *Oct 20, 1972Jul 15, 1975Pechiney Ugine KuhlmannHydroxyquinoline derivative
US5563162 *Apr 26, 1994Oct 8, 1996Fujisawa Pharmaceutical Co., Ltd.Bradykinin antagonist quinolines
US5708173 *Jun 7, 1996Jan 13, 1998Fujisawa Pharmaceutical Co., Ltd.Heterocyclic compounds
US5922711 *Sep 19, 1997Jul 13, 1999Fujisawa Pharmaceutical Co., Ltd.8-substituted quinazolines, quinoxalines and benzopyridazines
US7619091 *Jul 16, 2003Nov 17, 2009Prana Biotechnology Limited8-hydroxy quinoline derivatives
US8975278Sep 19, 2007Mar 10, 2015Prana Biotechnology Limited8-hydroxy quinoline derivatives
US20140296251 *Apr 2, 2013Oct 2, 2014Annji Pharmaceutical Co., Ltd.Multifunctional quinoline derivatives as anti-neurodegenerative agents
CN1043344C *Apr 27, 1994May 12, 1999藤沢药品工业株式会社New heterocyclic compounds, preparing method, pharmaceutical composition and use
CN1681791BJul 16, 2003Mar 27, 2013普拉纳生物技术有限公司8-羟基喹啉衍生物
EP1539700A1 *Jul 16, 2003Jun 15, 2005Prana Biotechnology Ltd8-hydroxy quinoline derivatives
WO2003010146A1 *Jul 19, 2002Feb 6, 2003Jean-Jacques BourguignonCompositions derived from quinoline and quinoxaline, preparation and use thereof
Classifications
U.S. Classification546/159, 546/174, 544/363, 546/179, 546/168, 544/128, 546/176
International ClassificationC07D215/48, C07D215/28, C07D215/38
Cooperative ClassificationC07D215/48, C07D215/28, C07D215/38
European ClassificationC07D215/28, C07D215/48, C07D215/38