CA1039285A - Preparation of 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivatives - Google Patents
Preparation of 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivativesInfo
- Publication number
- CA1039285A CA1039285A CA217,002A CA217002A CA1039285A CA 1039285 A CA1039285 A CA 1039285A CA 217002 A CA217002 A CA 217002A CA 1039285 A CA1039285 A CA 1039285A
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- Prior art keywords
- methyl
- oxo
- dihydro
- ethyl
- naphthyridine
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
A B S T R A C T
Process for the preparation or 1-alkyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acids useful as antibacterial agent.
A compound of the general formula II
Process for the preparation or 1-alkyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acids useful as antibacterial agent.
A compound of the general formula II
Description
~3~ 2 -This invention relates to the preparation of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, and other 1-all<yl-7-methyl-4-oxo-1,4-dihydro-1 J8-naphthyridine-3-carboxylic acids.
; 1-Alkyl-7-methyl-4-oxo-1~4-dihydro-1l8-naphthyridine-3-carboxylic acids are well-l<nown valuable antibacterial agents, being used in therapy. These compounds were prepared by alkylation and subsequent hydrolysis of 7-methyl-4-oxo-3-alkoxycarboilyl-1,4 dihydro-1l8-naphthyridine (British patent No. 1,000l892)r It has bean found according to the present invention . that 1-all<yl-7-methyl-4-oxo-1,4-dihydro-'l~8-naphthyridine-.: 3-carboxylic acids of the general formula I
H C / ~ ~
. all<yl ~ 20 may be prepared in a pure state with good yields by sub;ecting ~ compounds of the general formula II 1;:
~CO - C ~ Y~Z ~ ~
: H3C
all<yl ;
to hydrolysis J
11511-77 /Fné
''' ' '':~
: . . . .. ... :.
.. .. .
.. :......... . ..... . . .. ...
.:...... . ~ .. :.- .. ~ . , ~(~3g:Z85 /wherein -R stands for hydrogen, -/CH2/m-CH3~ a /OH2/n,aryl~ or --/C~l2/p-cycloalkyl groups;
/ H2/m-CH3, -/CH2/n-aryl, or /CH2/ -cycloalkyl;
Y stands for a tertiary nitrogen-containing aromatic, heterocyclic ring attached through the nitrogen atom or a trialkylamino group;
Z is an anion; `~
n, m and p stand for an integer number of 0 to 5, and ~ ;;
wherein alkyl represents a lower alkyl group.
This process has the advantage to use starting materials which can be purified easily.
Hydrolysis is carried out preferably in the presence of alkaline agents. Thus alkali hydroxide~/e.g~
potassium hydroxide or sodium hydroxide/ or alkaline earth metal hydroxides /e.g. calcium hydroxide/ or ammonium hydroxide or carbonates may also be used as alkaline hydro-lysing agents. Hydrolysis may be accomplished also in ; neutral or acidic medium.
Hydrolysis may also be carried out in aqueous medium in the presence of a trialkylamine. For this purpose lower trialkylamines such as trimethylamine or advantage-ously triethylamine may be used.
According to a preferred embodiment of the present inventionj a compound o-f the general formula II is -.'. ' ~, : , . :
. .: . . :
. : : .
~a3s~
treated with an aqueous alcoholic, preferably ethanolic sodium hydroxide or potassium hydroxide solution~ Hydrolysis may be carried out at a temperature of 2~-150C, preferably 80-120C
The compound of the formula I may be precipitated by acidifying the reaction mixture preferably by adding an acid. Mineral acids, such as hydrochloric acid, or organic acids, such as acetic acid, formic acidJ etc~l may be used for this purpose~
In the starting materials of the Formula II Y stands preferably For a pyridinel quinoline, or all<yl-sub-stituted pyridines~ such as pieoline ring, but it may also stand for a quinaldine~ lepidine or other lower-allcyl-substituted pyridine ring. Y may also stand for a trialkylamino ~e.g. trimethyl-, triethyl-J tri-propyl-, triisopropylamino-group, etc.) group~ The ;~
anion ot the starting material may be a halogenide, such as iodide, bromide or chlorideJ or sulphate, phosphatel perchlorate, etc.
The N-alkyl-group represents a straight or branched chained allcyl group, having 1-6 carbon atoms (e.g.
methyl, ethylJ n-propylJ isopropyl~l isobutyl, etc.).
In the specification the term "alkyl~ means -(CH2)m--CH3 ~e,.g. methyl~ ethyl3 n-propyl)~ the term incycloallcyl"
means -(CH2)p~cycloalkyl (eag. cyclopentyl, cyclohexyl, cyclohexylmethyl3 etc.)~ In these formulae m, n, and p are integers in the range of from 0 to 5~ The cycloallcyl ; group may have 3-6 carbon atoms. The aryl groups may optionally bear one or more substituents (e~g. halogen, allcyl or alkoxy~ The term "arallcyl" means -~CH2~n-aryl ~e~g~benzyl phenylethyl).
,.. . i .
~l~3~Z~35 . - 5 -,~
As starting material of the formula II preferably the . following compounds may be used:
: 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1~8-naphthyridine-3-. -carbonyl-(methyl-methyl-pyridinium)-iodide;
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3- :
-carbonyl-(ethyl-methyl-pyridinium~-iodide;
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1~8-naphthyridine-3-.- -carbonyl-(propyl-methyl-pyridinium)-iodide~ ;
1-ethyl-7-methyl-~-oxo-1,4-dihydro-1,8-naphthyridine-3--carbonyl-(phenyl-methyl-pyridinium)-iodide~
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3~
-carbonyl-(benzyl-methyl-pyridinium~-iodide~
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3 -carbonyl-~cyclohexyl-methyl-pyridinium)-iodide;
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-:: -carbonyl C(cyclohexyl-methyl)-methyl-pyridinium~-iodide;
-- 1-ethyl-7-methyl-4~oxo-1,4-dihydro-1,8-naphthyridine-3--carbonyl-(dimethyl-methyl~pyridinium)-iodide, 1~ethyl-7-methyl-4-oxo-1,~-dihydro-1,8-naphthyridine-3-~ 20 -carbonyl-C~dimethyl-methyl)-triethyl-ammonium~-bromide.
`. The starting materials of the general formula II are ,..i.
new compounds and may be prepared as follows!: :
; 1-Alkyl-7-methyl-4-oxo-1~4-dihydro-1l8-naphthyridine-3-carboxylic acids are well-l<nown valuable antibacterial agents, being used in therapy. These compounds were prepared by alkylation and subsequent hydrolysis of 7-methyl-4-oxo-3-alkoxycarboilyl-1,4 dihydro-1l8-naphthyridine (British patent No. 1,000l892)r It has bean found according to the present invention . that 1-all<yl-7-methyl-4-oxo-1,4-dihydro-'l~8-naphthyridine-.: 3-carboxylic acids of the general formula I
H C / ~ ~
. all<yl ~ 20 may be prepared in a pure state with good yields by sub;ecting ~ compounds of the general formula II 1;:
~CO - C ~ Y~Z ~ ~
: H3C
all<yl ;
to hydrolysis J
11511-77 /Fné
''' ' '':~
: . . . .. ... :.
.. .. .
.. :......... . ..... . . .. ...
.:...... . ~ .. :.- .. ~ . , ~(~3g:Z85 /wherein -R stands for hydrogen, -/CH2/m-CH3~ a /OH2/n,aryl~ or --/C~l2/p-cycloalkyl groups;
/ H2/m-CH3, -/CH2/n-aryl, or /CH2/ -cycloalkyl;
Y stands for a tertiary nitrogen-containing aromatic, heterocyclic ring attached through the nitrogen atom or a trialkylamino group;
Z is an anion; `~
n, m and p stand for an integer number of 0 to 5, and ~ ;;
wherein alkyl represents a lower alkyl group.
This process has the advantage to use starting materials which can be purified easily.
Hydrolysis is carried out preferably in the presence of alkaline agents. Thus alkali hydroxide~/e.g~
potassium hydroxide or sodium hydroxide/ or alkaline earth metal hydroxides /e.g. calcium hydroxide/ or ammonium hydroxide or carbonates may also be used as alkaline hydro-lysing agents. Hydrolysis may be accomplished also in ; neutral or acidic medium.
Hydrolysis may also be carried out in aqueous medium in the presence of a trialkylamine. For this purpose lower trialkylamines such as trimethylamine or advantage-ously triethylamine may be used.
According to a preferred embodiment of the present inventionj a compound o-f the general formula II is -.'. ' ~, : , . :
. .: . . :
. : : .
~a3s~
treated with an aqueous alcoholic, preferably ethanolic sodium hydroxide or potassium hydroxide solution~ Hydrolysis may be carried out at a temperature of 2~-150C, preferably 80-120C
The compound of the formula I may be precipitated by acidifying the reaction mixture preferably by adding an acid. Mineral acids, such as hydrochloric acid, or organic acids, such as acetic acid, formic acidJ etc~l may be used for this purpose~
In the starting materials of the Formula II Y stands preferably For a pyridinel quinoline, or all<yl-sub-stituted pyridines~ such as pieoline ring, but it may also stand for a quinaldine~ lepidine or other lower-allcyl-substituted pyridine ring. Y may also stand for a trialkylamino ~e.g. trimethyl-, triethyl-J tri-propyl-, triisopropylamino-group, etc.) group~ The ;~
anion ot the starting material may be a halogenide, such as iodide, bromide or chlorideJ or sulphate, phosphatel perchlorate, etc.
The N-alkyl-group represents a straight or branched chained allcyl group, having 1-6 carbon atoms (e.g.
methyl, ethylJ n-propylJ isopropyl~l isobutyl, etc.).
In the specification the term "alkyl~ means -(CH2)m--CH3 ~e,.g. methyl~ ethyl3 n-propyl)~ the term incycloallcyl"
means -(CH2)p~cycloalkyl (eag. cyclopentyl, cyclohexyl, cyclohexylmethyl3 etc.)~ In these formulae m, n, and p are integers in the range of from 0 to 5~ The cycloallcyl ; group may have 3-6 carbon atoms. The aryl groups may optionally bear one or more substituents (e~g. halogen, allcyl or alkoxy~ The term "arallcyl" means -~CH2~n-aryl ~e~g~benzyl phenylethyl).
,.. . i .
~l~3~Z~35 . - 5 -,~
As starting material of the formula II preferably the . following compounds may be used:
: 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1~8-naphthyridine-3-. -carbonyl-(methyl-methyl-pyridinium)-iodide;
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3- :
-carbonyl-(ethyl-methyl-pyridinium~-iodide;
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1~8-naphthyridine-3-.- -carbonyl-(propyl-methyl-pyridinium)-iodide~ ;
1-ethyl-7-methyl-~-oxo-1,4-dihydro-1,8-naphthyridine-3--carbonyl-(phenyl-methyl-pyridinium)-iodide~
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3~
-carbonyl-(benzyl-methyl-pyridinium~-iodide~
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3 -carbonyl-~cyclohexyl-methyl-pyridinium)-iodide;
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-:: -carbonyl C(cyclohexyl-methyl)-methyl-pyridinium~-iodide;
-- 1-ethyl-7-methyl-4~oxo-1,4-dihydro-1,8-naphthyridine-3--carbonyl-(dimethyl-methyl~pyridinium)-iodide, 1~ethyl-7-methyl-4-oxo-1,~-dihydro-1,8-naphthyridine-3-~ 20 -carbonyl-C~dimethyl-methyl)-triethyl-ammonium~-bromide.
`. The starting materials of the general formula II are ,..i.
new compounds and may be prepared as follows!: :
2-Amino-6-methyl-pyridine or an acid addition salt thereof is condensed with a compound of the formula III
- CH
O ~ C (III) alkylO - CH - C
--: 30 COOall<yl ; .
... .. .
. ~, .
; . .
.
~.... . . . .
~39A~5 :
The compounds o~ the formula IV
R - CH (IV) H3C ~NH CH C
COOall<yl thus obtained are subjected to ring closurel whereupon the ~-1,8-naphthyridine-derivatives of the formula V
R~
~d~ co CH (V) ~;
H
thus obtained are N-all<ylated~ The compounds of the formula VI . .
~ C0 -CH2 (VI) H3C~r all<yl thus formed are reacted with a tertiary nitrogen-containing heterocyclic base or a trialkylamina in the presence of a halogen to yield the starting materials of the formula II.
The anion can be exchanged for an other anionO
Further details of our invention are disclosed in the following Examples~ serving merely the purpose o~ illustra-: 30 tion, but not of limitation.
~392~3S
Example 1:
A mixture of 1,22 g of 1-ethyl-7-methyl-3-propionyl~
4~oxo-1,4-dihydro-1,8-naphthyridine, 10 ml of pyridine and 1,27 g of iodine is s~i~red at 100 C~ whereupon the reaction mixture is evaporated in vacuo. The l-ethyl-7-methyl-4-oxo-1~4-dihydro-1~8-naphthyridine-3-carbonyl-/methyl-methyl-pyridinium/-iodide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution and heated to boiling~ The resulting clear solution is cooled, extracted with chloro-form, clarified with activated charcoal and filtered off.
the filtrate is acidified with hydrochloric acid, The precipitated crystals are filtered off and washed with water. The melting point oE the 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amounts to 224-226 C.
Example 2:
A mixture of 1,29 g of 1-ethyl-7-methyl-3-butyryl-; 4-oxo-1~4-dihydro-1~8-naphthyridine~ 10 ml of isoquinoline and 1,27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo. The l-ethyl-7-methyl-4-oxo-1~4-dihydro-1,8-naphthyridine-3-carbonyl-/ethyl-methyl-isoquinolinium/-iodide thus obtained is admixed ~ith 25 ml of a 10 % sodium hydroxide solution and heated to boil-ing. The resulting clear solution is cooled, extracted with chloroform, clarified with activated charcoal and filtered off. The filtrake is acidified , .:. - - :
:: ~,: : ..
1(~39Z~95 - a -with hydrochloric acid. The precipitated crystals are - filtered off and washed with water. The melting point of the 1-ethyl-7-methyl-4-oxo-1,4-d~hydro-1,8-napht-hyridine~3-carboxylic acid amounts to 225~227 C~
Example 3 A mixture of 1t36 g of 1-ethyl-7-methyl-3-valeroyl-4-oxo-1,4-dihydro-1,8-naphthyridine, 10 ml of pycoline and 1~27 9 of io~ine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo. The 1-ethyl-7-methyl-4-oxo-114-dihydro-1j,8-naphthyridine-3-carbonyl-~propyl-methyl-pycolinium)-iodide thus obtain-ed is admixed with 25 ml o~ a 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clarified with activated charcoal and fil~red off. The filtrate is acidified with hydro~hloric acid~ The precipitated crystals are filtered otf and washed with water~ The melting point of the 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amounts to 223--225 C.
Example 4 A mixture of 1,53 9 of 1-ethyl-7-methyl-3-phena-cetyl-4-oxo-1~4-dihydro-1~8-naphthyridinel 10 ml of pyridine and 1,27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in ~Jacuo.
The 1-ethyl~7-methyl-4-oxo-1J4-dihydro-118-naphthyri-dine-3-carbonyl-~phenyl-methyl-pyridinium)-iodide thus :
~ .: - .. . . .............................. . . .
.
2~5 g obtained is admixed with 25 ml of 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clarified with activated charcoal and filtered off, The filtrate is acidified with hydrochloric acid~ The precipitated crystals are filtered off and washed wit~l water. The melting point of the 1-ethyl-7-methyl~4-oxo~1 ,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid amounts to 224-226 C.
Example 5 A mixture of 1160 g oF 1-ethyl-7-methyl-3-(3-phenyl-proplonyl)-4-oxo-1,4-dihydro-1J8-naphthyridine, 10 ml of quinoline and 1~27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evapor-ated in vacuo.
The 1-ethyl-7-methyl-4-oxo-1~4-dihydro-3-carbonyl-~benzyl-methyl-quinolinium)-iodide thus obtained is admixed with 25 ml oF a 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clariFied with 20 activated charcoal and filtered off. The filtrate is acidified with hydrochloric acid. The precipitated crystals are filtered oFf and washed with water~ The melting point of the 1-ethyl-7-methyl-4~oxo-1,~-dihydro-1 ,8-naphthyridine-3-carboxylic acid amounts to 227-228 C.
Example 6 A mixture of 1956 9 of 1-ethyl-7-methyl-3-cyclohexyl-1(~3~8~
acetyl-4 oxo~ -dihydro-1,8-naphthyridine, 10 ml of pyridine and 1,27 9 of iodine is stirred at 100 CJ
whereupon the reaction mixture is evaporated in vacuo.
The 1-ethyl-7-methyl-4-oxo-1~4~dihydro-1,8-naphthy-ridine-3-carbonyl-(cyclohexyl-methyl-pyridinium)-iodide thus obtained is admixed with 25 ml of a 10 %
sodium hydroxide solution and heated to boiling, The resulting clear solution is cooled~ extracted with chloroform, clarified with activated charcoal and filtered off. The Filtrate is acidified with hydro--chloric acid. The precipitated crystals are filtered oFf and washsd with water. The melting point of the 1-ethyl-7-methyl-4-oxo-1~4-dihydro-1~8-naphthyridine-
- CH
O ~ C (III) alkylO - CH - C
--: 30 COOall<yl ; .
... .. .
. ~, .
; . .
.
~.... . . . .
~39A~5 :
The compounds o~ the formula IV
R - CH (IV) H3C ~NH CH C
COOall<yl thus obtained are subjected to ring closurel whereupon the ~-1,8-naphthyridine-derivatives of the formula V
R~
~d~ co CH (V) ~;
H
thus obtained are N-all<ylated~ The compounds of the formula VI . .
~ C0 -CH2 (VI) H3C~r all<yl thus formed are reacted with a tertiary nitrogen-containing heterocyclic base or a trialkylamina in the presence of a halogen to yield the starting materials of the formula II.
The anion can be exchanged for an other anionO
Further details of our invention are disclosed in the following Examples~ serving merely the purpose o~ illustra-: 30 tion, but not of limitation.
~392~3S
Example 1:
A mixture of 1,22 g of 1-ethyl-7-methyl-3-propionyl~
4~oxo-1,4-dihydro-1,8-naphthyridine, 10 ml of pyridine and 1,27 g of iodine is s~i~red at 100 C~ whereupon the reaction mixture is evaporated in vacuo. The l-ethyl-7-methyl-4-oxo-1~4-dihydro-1~8-naphthyridine-3-carbonyl-/methyl-methyl-pyridinium/-iodide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution and heated to boiling~ The resulting clear solution is cooled, extracted with chloro-form, clarified with activated charcoal and filtered off.
the filtrate is acidified with hydrochloric acid, The precipitated crystals are filtered off and washed with water. The melting point oE the 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amounts to 224-226 C.
Example 2:
A mixture of 1,29 g of 1-ethyl-7-methyl-3-butyryl-; 4-oxo-1~4-dihydro-1~8-naphthyridine~ 10 ml of isoquinoline and 1,27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo. The l-ethyl-7-methyl-4-oxo-1~4-dihydro-1,8-naphthyridine-3-carbonyl-/ethyl-methyl-isoquinolinium/-iodide thus obtained is admixed ~ith 25 ml of a 10 % sodium hydroxide solution and heated to boil-ing. The resulting clear solution is cooled, extracted with chloroform, clarified with activated charcoal and filtered off. The filtrake is acidified , .:. - - :
:: ~,: : ..
1(~39Z~95 - a -with hydrochloric acid. The precipitated crystals are - filtered off and washed with water. The melting point of the 1-ethyl-7-methyl-4-oxo-1,4-d~hydro-1,8-napht-hyridine~3-carboxylic acid amounts to 225~227 C~
Example 3 A mixture of 1t36 g of 1-ethyl-7-methyl-3-valeroyl-4-oxo-1,4-dihydro-1,8-naphthyridine, 10 ml of pycoline and 1~27 9 of io~ine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo. The 1-ethyl-7-methyl-4-oxo-114-dihydro-1j,8-naphthyridine-3-carbonyl-~propyl-methyl-pycolinium)-iodide thus obtain-ed is admixed with 25 ml o~ a 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clarified with activated charcoal and fil~red off. The filtrate is acidified with hydro~hloric acid~ The precipitated crystals are filtered otf and washed with water~ The melting point of the 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid amounts to 223--225 C.
Example 4 A mixture of 1,53 9 of 1-ethyl-7-methyl-3-phena-cetyl-4-oxo-1~4-dihydro-1~8-naphthyridinel 10 ml of pyridine and 1,27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in ~Jacuo.
The 1-ethyl~7-methyl-4-oxo-1J4-dihydro-118-naphthyri-dine-3-carbonyl-~phenyl-methyl-pyridinium)-iodide thus :
~ .: - .. . . .............................. . . .
.
2~5 g obtained is admixed with 25 ml of 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clarified with activated charcoal and filtered off, The filtrate is acidified with hydrochloric acid~ The precipitated crystals are filtered off and washed wit~l water. The melting point of the 1-ethyl-7-methyl~4-oxo~1 ,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid amounts to 224-226 C.
Example 5 A mixture of 1160 g oF 1-ethyl-7-methyl-3-(3-phenyl-proplonyl)-4-oxo-1,4-dihydro-1J8-naphthyridine, 10 ml of quinoline and 1~27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evapor-ated in vacuo.
The 1-ethyl-7-methyl-4-oxo-1~4-dihydro-3-carbonyl-~benzyl-methyl-quinolinium)-iodide thus obtained is admixed with 25 ml oF a 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clariFied with 20 activated charcoal and filtered off. The filtrate is acidified with hydrochloric acid. The precipitated crystals are filtered oFf and washed with water~ The melting point of the 1-ethyl-7-methyl-4~oxo-1,~-dihydro-1 ,8-naphthyridine-3-carboxylic acid amounts to 227-228 C.
Example 6 A mixture of 1956 9 of 1-ethyl-7-methyl-3-cyclohexyl-1(~3~8~
acetyl-4 oxo~ -dihydro-1,8-naphthyridine, 10 ml of pyridine and 1,27 9 of iodine is stirred at 100 CJ
whereupon the reaction mixture is evaporated in vacuo.
The 1-ethyl-7-methyl-4-oxo-1~4~dihydro-1,8-naphthy-ridine-3-carbonyl-(cyclohexyl-methyl-pyridinium)-iodide thus obtained is admixed with 25 ml of a 10 %
sodium hydroxide solution and heated to boiling, The resulting clear solution is cooled~ extracted with chloroform, clarified with activated charcoal and filtered off. The Filtrate is acidified with hydro--chloric acid. The precipitated crystals are filtered oFf and washsd with water. The melting point of the 1-ethyl-7-methyl-4-oxo-1~4-dihydro-1~8-naphthyridine-
3-carboxylic acid amounts to 226-228 C.
: ` .
Example 7 A mixture of 1f63 9 of 1-ethyl-7-methyl-3-(3-cyclo-hexyl-propionyl)-4-oxo-1~4-dihydro-1~8-naphthyridine 10 ml of pyridine and 1?27 9 of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo. The 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[lcyclohexyl-methyl)-methyl-pyridinium]-iodide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clarified with activatecl charcoal and filtered off. The filtrate is acidified .
-., . - ~
, .
~L~3~3Z85 with hydrochloric acid. The precipitated crystals are filtered off and washed with water. The melting point of the l-ethyl-?-methyl-4-oxo-1,4-dihydro-1,8-Mapht-hyridine-3-carboxylic acid amounts to 221-223 C.
Example 8:
A mixture of 1,29 g of 1-ethyl-7-methyl-3-/2-methyl-propionyl/-4-oxo-dihydro-1~8-naphthyricline~ 10 ml of pyridine and 1,27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo.
The l-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/dimethyl-methyl-pyridinium-/iodide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution is heated to boiling, then it i9 cooled~ extract-ed with chloroform~ clariEied with activated charcoal and filtered off. The filtrate is acidified with hydrochloric acid~ The precipitated crystals are filtered off and washed with water. The melting point of the l-ethyl-7-methyl-4_oxo-1,4_dihydro-1,8-naphthyridine-3_carboxylic acid amounts to 226-228 C.
Example 9:
A mixture of 1,69 g of 1-ethyl-7-methyl-3-/2-bromo-2-methyl-propionyl-/-4-oxo-1,4-dihydro-1,8-naphth~ridine and 50 ml of pyridine is heated to boiling, whereupon the reaction mixture is evaporated in vacuo~ The l-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
dimethyl-methyl-pyridinium/-bromide is admixed with 25 ~1 of a 10 % sodium hydroxide solution, whereupon the mixture _ 11 --.
.
' '. ' ~ , ~ . .', ' ' ' ' .: . , ~. . .
~()39;~
is heated to boiling~ The residual solution is cooled, extracted with chloroform~ the extract is clarified and acidified with diluted hydrochloric acid. The precipi~
tated l-ethyl-7 methyl-4-oxo-1~4-dihydro-1~8-naphthyri-ne-3-carboxylic acid melts at 225-226 C.
Example 10:
A mixture of 1,69 g of 1-ethyl-7-methyl-3-/2-bromo-2-methyl-propionyl/-4-oxo-1,4-dihydro-1,8-naphthy-ridine is heated to boiling in 100 ml of triethylamine, whereupon the reaction mixture is evaporated in vacuo.
The l-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphkhyridine-3-carbonyl-C/dimethyl-methy'l-/triethyl-ammonium]-'bromide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution, whereupon the reaction mixture is ,.;
heated to boiling. The residual solution is cooled, ex-tracted with chloroform~clarified with activated charcoal and acidified with diluted hydrochloric acid. The precip-itated l-ethyl-7-methyl-4-oxo-1~4-dihydro-1~8-naphthyridine-3-carboxylic acid is filtered off, washed with water and d~ied. Mp~: 226-227 C.
Example 11:
A mixture of 2,11 g of 7-methyl-4-oxo-1~4-dihydro-1,8-naphthyridine-3-carbonyl-/methyl-methyl-pyridinium/-iodide, 4,55 g of triethylphosphate, 0,7 g of potassium carbonate is heated to boiling. The reaction mixture is cooled, poured into a 10 % sodium hydroxide solution and the ., .: :
~ 12 -, ,,, ~ , : . ,.,, . : :
~, , .. . . . . , , . ., , . . ~
~03~Z8S - 13 -aqueous reaction mixture is heated to boiling~ The ` solution is cooled~ extracted with activated charcoal and filtered off. The filtrate is acidified with 20 %
hydrochloric acid. The precipitated crystals are filter-- ed off, washed with water and dried. The 1-ethyl-7-methyl-
: ` .
Example 7 A mixture of 1f63 9 of 1-ethyl-7-methyl-3-(3-cyclo-hexyl-propionyl)-4-oxo-1~4-dihydro-1~8-naphthyridine 10 ml of pyridine and 1?27 9 of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo. The 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[lcyclohexyl-methyl)-methyl-pyridinium]-iodide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution and heated to boiling. The resulting clear solution is cooled, extracted with chloroform, clarified with activatecl charcoal and filtered off. The filtrate is acidified .
-., . - ~
, .
~L~3~3Z85 with hydrochloric acid. The precipitated crystals are filtered off and washed with water. The melting point of the l-ethyl-?-methyl-4-oxo-1,4-dihydro-1,8-Mapht-hyridine-3-carboxylic acid amounts to 221-223 C.
Example 8:
A mixture of 1,29 g of 1-ethyl-7-methyl-3-/2-methyl-propionyl/-4-oxo-dihydro-1~8-naphthyricline~ 10 ml of pyridine and 1,27 g of iodine is stirred at 100 C, whereupon the reaction mixture is evaporated in vacuo.
The l-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/dimethyl-methyl-pyridinium-/iodide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution is heated to boiling, then it i9 cooled~ extract-ed with chloroform~ clariEied with activated charcoal and filtered off. The filtrate is acidified with hydrochloric acid~ The precipitated crystals are filtered off and washed with water. The melting point of the l-ethyl-7-methyl-4_oxo-1,4_dihydro-1,8-naphthyridine-3_carboxylic acid amounts to 226-228 C.
Example 9:
A mixture of 1,69 g of 1-ethyl-7-methyl-3-/2-bromo-2-methyl-propionyl-/-4-oxo-1,4-dihydro-1,8-naphth~ridine and 50 ml of pyridine is heated to boiling, whereupon the reaction mixture is evaporated in vacuo~ The l-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
dimethyl-methyl-pyridinium/-bromide is admixed with 25 ~1 of a 10 % sodium hydroxide solution, whereupon the mixture _ 11 --.
.
' '. ' ~ , ~ . .', ' ' ' ' .: . , ~. . .
~()39;~
is heated to boiling~ The residual solution is cooled, extracted with chloroform~ the extract is clarified and acidified with diluted hydrochloric acid. The precipi~
tated l-ethyl-7 methyl-4-oxo-1~4-dihydro-1~8-naphthyri-ne-3-carboxylic acid melts at 225-226 C.
Example 10:
A mixture of 1,69 g of 1-ethyl-7-methyl-3-/2-bromo-2-methyl-propionyl/-4-oxo-1,4-dihydro-1,8-naphthy-ridine is heated to boiling in 100 ml of triethylamine, whereupon the reaction mixture is evaporated in vacuo.
The l-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphkhyridine-3-carbonyl-C/dimethyl-methy'l-/triethyl-ammonium]-'bromide thus obtained is admixed with 25 ml of a 10 % sodium hydroxide solution, whereupon the reaction mixture is ,.;
heated to boiling. The residual solution is cooled, ex-tracted with chloroform~clarified with activated charcoal and acidified with diluted hydrochloric acid. The precip-itated l-ethyl-7-methyl-4-oxo-1~4-dihydro-1~8-naphthyridine-3-carboxylic acid is filtered off, washed with water and d~ied. Mp~: 226-227 C.
Example 11:
A mixture of 2,11 g of 7-methyl-4-oxo-1~4-dihydro-1,8-naphthyridine-3-carbonyl-/methyl-methyl-pyridinium/-iodide, 4,55 g of triethylphosphate, 0,7 g of potassium carbonate is heated to boiling. The reaction mixture is cooled, poured into a 10 % sodium hydroxide solution and the ., .: :
~ 12 -, ,,, ~ , : . ,.,, . : :
~, , .. . . . . , , . ., , . . ~
~03~Z8S - 13 -aqueous reaction mixture is heated to boiling~ The ` solution is cooled~ extracted with activated charcoal and filtered off. The filtrate is acidified with 20 %
hydrochloric acid. The precipitated crystals are filter-- ed off, washed with water and dried. The 1-ethyl-7-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid : melts at 225-227 C.
',' ~'"' ;'.,'' :
.
;
,, ~ ,
',' ~'"' ;'.,'' :
.
;
,, ~ ,
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of 1-alky1-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acids of the general formula I, which comprises subjecting to hydrolysis a compound of the general formula II
wherein R1 stands for hydrogen, -/CH2/m-CH3, a /CH2/n-aryl, or -/CH2/p-cycloalkyl groups, R2 is -/CH2/m-CH3, -/CH2/n-aryl, or -/CH2/p-cycloalkl;
Y stands for a tertiary nitrogen-containing aromatic, heterocyclic ring attached through the nitrogen atom or a trialkylamino group:
Z is an anion;
n, m and p stand for an integer number of 0 to 5, and wherein alkyl represents a lower alkyl group.
wherein R1 stands for hydrogen, -/CH2/m-CH3, a /CH2/n-aryl, or -/CH2/p-cycloalkyl groups, R2 is -/CH2/m-CH3, -/CH2/n-aryl, or -/CH2/p-cycloalkl;
Y stands for a tertiary nitrogen-containing aromatic, heterocyclic ring attached through the nitrogen atom or a trialkylamino group:
Z is an anion;
n, m and p stand for an integer number of 0 to 5, and wherein alkyl represents a lower alkyl group.
2. Process according to claim 1, which comprises to carry out hydrolysis in the presence of hydroxides or car-bonates, or organic amines.
3. Process according to claim 27 which comprises carrying out hydrolysis in the presence of ammonium-, alkali-, or alkaline earth metal hydroxides or -carbonates, or tri-ethylamine.
4. Process according to claims 1-3, which comprises carrying out the reaction at 20-150 °C.
5. Process according to claims 1-3, which comprises using as starting materials of general formula II quaternary iodide salts.
6. Process according to any of claims 1-3, which com-prises using as starting material 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/methyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
ethyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
propyl-methyl-pyridinium/-iodide, 1-ethyl-7-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
phenyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
benzyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
cyclohexyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[/cyclohexyl-methyl/-methyl-pyridinium]-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/dimethyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[/dimethyl-methyl/-triethyl-ammonium]-bromide.
ethyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
propyl-methyl-pyridinium/-iodide, 1-ethyl-7-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
phenyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
benzyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/
cyclohexyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[/cyclohexyl-methyl/-methyl-pyridinium]-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/dimethyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[/dimethyl-methyl/-triethyl-ammonium]-bromide.
7. Process according to claim 2 in which the organic amine is a trialkylamine.
8. Process according to claims 1-3, which comprises carrying out the reaction at 80-120°C.
9. Process according to claim 1 in which Y is a tertiary nitrogen-containing aromatic, heterocyclic ring.
10. Process according to claim 1 in which Y is a trialkylamino group.
11. Process according to claim 2 in which the hydrolysis is carried out in the presence of an alkali.
12. Process according to claim 11 in which the alkali is sodium hydroxide.
13. Process according to claim 1 in which 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8 naphthyridine-3-carboxylic acid is prepared by hydrolysing 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/methyl-methyl-pyridinium/-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/ethyl-methyl-isoquinolinium/-iodide or 1-ethyl-7-methyl-4-oxo-1,4 dihydro-1,8-naphthyridine-3-carbonyl-(propyl-methyl-pycolinium)-iodide, acidifying the reaction mixture and collecting the solid which separates.
14. Process according to claim 1 in which 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid is prepared by hydrolysing 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-(phenyl-methyl-pyridinium)-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-3-carbonyl-(benzyl-methyl-quinolinium)-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthy-ridine-3-carbonyl-(cyclohexyl-methyl-pyridinium)-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[(cyclohexyl-methyl)-methyl-pyridinium]-iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/dimethyl-methyl-pyridinium-/iodide, 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-/dimethyl-methyl-pyridinium/-bromide or 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-[/dimethyl-methyl-/triethyl-ammonium]-bromide, acidifying the reaction mixture and collecting the solid which separates.
15, Process according to claim 13 or 14 in which the hydrolysis is effected by reaction with aqueous sodium hydroxide.
16. 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid whenever prepared by the process of claim 13 or 14 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU73CI00001430A HU171561B (en) | 1973-12-29 | 1973-12-29 | Process for producing 1,8-naphtiridine derivatives |
| JP49007185A JPS514197A (en) | 1973-12-29 | 1974-01-16 | 1** nafuchirijinjudotaino seizoho |
| HU74CI00001522A HU171869B (en) | 1974-01-17 | 1974-12-05 | New process for preparing derivatives of 1,8-naphthyridine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1039285A true CA1039285A (en) | 1978-09-26 |
Family
ID=27270158
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA217,002A Expired CA1039285A (en) | 1973-12-29 | 1974-12-27 | Preparation of 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivatives |
Country Status (12)
| Country | Link |
|---|---|
| AR (1) | AR207855A1 (en) |
| BG (1) | BG25986A3 (en) |
| CA (1) | CA1039285A (en) |
| CH (1) | CH613968A5 (en) |
| DD (1) | DD116034A5 (en) |
| DK (1) | DK677274A (en) |
| FI (1) | FI375874A (en) |
| GB (1) | GB1493949A (en) |
| NL (1) | NL7416925A (en) |
| NO (1) | NO140595C (en) |
| SE (1) | SE419863B (en) |
| SU (1) | SU580838A3 (en) |
-
1974
- 1974-01-01 AR AR257147A patent/AR207855A1/en active
- 1974-12-23 DK DK677274A patent/DK677274A/da not_active Application Discontinuation
- 1974-12-24 GB GB55876/74A patent/GB1493949A/en not_active Expired
- 1974-12-24 CH CH1730774A patent/CH613968A5/en not_active IP Right Cessation
- 1974-12-27 NO NO744718A patent/NO140595C/en unknown
- 1974-12-27 CA CA217,002A patent/CA1039285A/en not_active Expired
- 1974-12-27 SU SU7402092458A patent/SU580838A3/en active
- 1974-12-27 NL NL7416925A patent/NL7416925A/en not_active Application Discontinuation
- 1974-12-27 FI FI3758/74A patent/FI375874A/fi unknown
- 1974-12-27 SE SE7416323A patent/SE419863B/en unknown
- 1974-12-30 BG BG7428617A patent/BG25986A3/xx unknown
- 1974-12-30 DD DD183434A patent/DD116034A5/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DD116034A5 (en) | 1975-11-05 |
| BG25986A3 (en) | 1979-01-12 |
| NO744718L (en) | 1975-07-28 |
| NO140595C (en) | 1979-10-03 |
| SU580838A3 (en) | 1977-11-15 |
| CH613968A5 (en) | 1979-10-31 |
| NO140595B (en) | 1979-06-25 |
| DK677274A (en) | 1975-09-01 |
| SE419863B (en) | 1981-08-31 |
| SE7416323L (en) | 1975-06-30 |
| FI375874A (en) | 1975-06-30 |
| NL7416925A (en) | 1975-07-01 |
| AR207855A1 (en) | 1976-11-08 |
| GB1493949A (en) | 1977-11-30 |
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