PREPARATION OF 7-METHYL-4-OXO-1,4-DIHYDRO-1,8-NAPHTHYRIDINE DERIVATIVES

SYNTHESE DES DERIVES DE METHYL-7 OXO-4 DIHYDRO-1,4 NAPHTHYRIDINE-1,8

English Abstract

A B S T R A C T
New 1,6-naphthyridine derivatives of the formula (I)
<IMG> (I)
useful as intermediates in preparing antibacterial agents. In the compounds
R3 is hydrogen or C1-6 alkyl;
Y is a tertiary nitrogen-containing aromatic, heterocyclic ring attached
through the nitrogen atom, or a trialkyl-amino group and
Z is an anion. The process is selected from
a) Reacting a compound of the formula (III)
<IMG>
(III)
wherein the N-alkyl-group has 1-6 carbon atoms) with an aromatic tertiary base,
or a trialkylamine, in the presence of a halogen,
b) Reacting a compound of the formula (II)
<IMG>
(II)
wherein alkyl is as stated above, and X stands for halogen with a tertiary
base; and
c) Reacting the compound of the formula (IV)
<IMG>
(IV)
in the presence of a halogen with an aromatic tertiary base, or a trialkylamine,
and, if desired, alkylating the compound of the formula (I) thus obtained
(wherein R3 is hydrogen). If desired, the halide thus obtained may be converted
into an other halide or an other pharmaceutically acceptable anion.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of new 1,8-naphthyridine derivatives
of the formula (I)
<IMG>
(I)
(wherein R3 is hydrogen or C1-6 alkyl; Y is pyridine which may be substituted
by methyl groups; quinoline and isoquinoline; Z is an anion) which comprises
a) reacting a compound of the formula (III)
(III)
<IMG>
(wherein the N-alkyl-group has 1-6 carbon atoms) with an aromatic tertiary
base, or a trialkylamine, in the presence of a halogen; or
b) reacting a compound of the formula (II)
<IMG> (II)
(wherein alkyl is as stated above, and X stands for halogen) with a tertiary
base; or
c) reacting the compound of the formula (IV)
12

<IMG>
(IV)
in the presence of a halogen with an aromatic tertiary base, or a trialkyl-
amine, and, if desired, alkylating the compound of the formula (I) thus
obtained (wherein R3 is hydrogen)
and, if desired, converting the halide thus obtained into an other halide
or an other pharmaceutically acceptable anion.
2. Process according to claim 1, which comprises carrying out the
reaction a), b) or c) at a temperature of 20 to 200°C.
3. Process according to claim 1 which comprises carrying out the
reaction a), b) or c) at a temperature of 80 to 150°C.
4. Process according to claim 1, wherein the anion is halide or
sulphate, phosphate, perchlorate or nitrate.
5. Process according to claim 2 wherein the anion is halide, sulphate,
phosphate, perchlorate or nitrate.
6. Process according to claim 4 or 5 wherein the halide is iodide,
bromide or chloride.
7. Process according to claim 1, 2 or 4 which comprises using as
tertiary base pyridine, quinoline, isoquinoline, alkyl-substituted pyridines,
quinaldine or lepidine, or a trialkylamine.
8. Process according to claim 7 wherein the tertiary base is a
picoline.
9. Process according to claim 7 wherein the tertiary base is triethyl-
amine.
13

10. Process according to claim 1c), which comprises alkylating a com-
pound of the formula (I), wherein R3 is hydrogen, with an alkyl,halide, a
dialkyl sulphate or trialkyl phosphate.
11. Process according to claim 10, which comprises using triethylphos-
phate as alkylating agent.
12. Process according to claim 1 wherein R3 is ethyl, Y is a pyridinium
ring and Z is iodide.
13. A 1,8-naphthyridine derivative of the formula (I)
<IMG> (I)
(wherein R3 is hydrogen or C1-6 alkyl; Y is pyridine which may be substituted
by methyl groups; quinoline and isoquinoline; Z is an anion) when prepared by a
process according to claim 1 or an obvious chemical equivalent thereof.
14. Process according to claim 1a), wherein 3-acetyl-1-ethyl-7-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine is reacted with pyridine in the presence
of iodine to produce 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carbonylmethyl-pyridinium iodide.
15. 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-
methyl-pyridinium-iodide when prepared by a process according to claim 14 or an
obvious chemical equivalent thereof.
16. Process according to claim 1 wherein R3 is ethyl, Y is an .alpha.-
picoline ring and Z is iodide.
17. Process according to claim 1a), wherein 3-acetyl-1-ethyl-7-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine is reacted with .alpha.-picoline in the presence
of iodine to produce 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carbonylmethyl-(.alpha.-picolinium)-iodide.
14

18. 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-
methyl-(.alpha.-picolinium)-iodide when prepared by a process according to claim 17
or an obvious chemical equivalent thereof.
19. Process according to claim 1 wherein R3 is ethyl, Y is a quinoline
ring and Z is iodide.
20. Process according to claim 1a), wherein 3-acetyl-1-ethyl-7-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine is reacted with quinoline in the presence
of iodine to produce 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-

naphthyridine-3-carbonylmethyl-quinolinium iodide.
21. 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-
methyl-quinolinium iodide when made by a process according to claim 20 or
an obvious chemical equivalent thereof.
22. Process according to claim 1 where R3 is hydrogen, Y is a
pyridine ring and Z is iodide.
23. Process according to claim 1c) wherein 3-acetyl-7-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine is reacted with pyridine in the presence of
iodine to produce 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-
methyl-pyridinium iodide.
24. 7-Methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-
pyridinium iodide when made by a process according to claim 23 or an obvious
chemical equivalent thereof.
25. Process according to claim 22 wherein the 7-methyl-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-carbonylmethyl-pyridinium iodide is reacted
with triethyl phosphate in the presence of potassium carbonate to produce
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-
pyridinium iodide.
26. 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-
methyl-pyridinium iodide when made by a process according to claim 25 or an
obvious chemical equivalent thereof.
27. Process according to claim 1 wherein R3 is ethyl, Y is a pyridine
ring and Z is perchlorate.
28. Process according to claim 13 or 24 which comprises reacting the
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-
pyridinium iodide with perchloric acid to produce 1-ethyl-7-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl pyridinium perchlorate.
16

29. 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-
methyl-pyridinium perchlorate when made by a process according to claim 27
or an obvious chemical equivalent thereof.
17

Description

3~3
This invention relates to the preparation of new 1,8-naphthyridine
derivatives, which are useful as intermediates in the preparation of known
l-alkyl-7-methyl-4-oxo-1,4-dihydro-1~8-naphthyridine-3-carboxylic acids,
being valuable antibacterial agents. These latter compolmds were prepared by
alkylation and subsequent hydrolysis of 7-methyl-4-oxo-3-alkoxycarbonyl-1,4-
dihydro-1,8-naphthyridines (British Patent Specification No. 1,000,892).
Moreover ~he new compounds of the present invention are also useful pesticides.
According to the present invention there is provided a process
for the preparation of new 1,8-naphthyridine-derivatives of the general
formula (I~
CO - CH2 -Y Z (I)
~13C
(wherein R3 is hydrogen or Cl 6 alkyl; Y is pyridine which may be substituted
by methyl groups; quinoline and isoquinoline; Z is an anion) which comprises
a) reacting a compound of the general formula (III~
~ ,
.
jj~ .
'
.. . .... . .. . . . .. . .. . .. . . .. . . . . ... .

L'~3~ _ 3
, s~",~/ao CH3
H C ~ ~ ll ~ ~ (III)
alkyl '~.
(~hereln the N-Alk~l-group has 1-6 carbon atom~) with an
aromatic tertiary base or a trialkylami~e in th~ pre~s~ce
of a halogen~ or
b) reacting a compound of the formula (II)
R
~ ao
C ~ ~ ~ (II)
alk~l
- (~herein alkyl is as ~tated aboYe, and ~ ~tand~ for
,
h~lo~ with a tertiary ba~e~ ar
G~ reac~in~ a compou~d of the fQrmula (IV)
:
~: . O
~ 20~ ; ~ ~ a~ c~
~ (IY)
~3~
3a
~ 25; in the presence of a halogen with a~ aromatic tertiar~ ~
,
a~e or a trialkylamine a~d, if desired, alk~latin~ th& :::
, ~ompou}ld Of the general formula ~I) thu~ obtained
(wherei~ R3 i~ h~rdrogen)
:
:
"
\
\
:
~.... . .. . .

4 ~
and~ if desired9 conver~ing the hal:ide~ thus obtained into
an other halide or an other pharmaceuti~ally acceptable
anion~
In the general foxmula (I) Z may stand for haloge~
such as iodine~ bromine~ or chlorine, or ~or sulphate,
phosphate~ perchlorate or nitrate anion,.etc~ Y ~tand~
preferabl~ ~or a 5- or 6-membered n t~ogen-cGnt~ini~g ri~g9
~uch as p~ridi~e, quinoline9 or alk~l-susbstituted
p~ridines, such as picoline9 quinaldine, or lepidine 3 ar.
~ther lower alkyl substituted pyridine ringsa ~he tri~
alkylamino group bears stxaight or branched chained
: alkyl groups, havlng 1-6 carbon atoms (e~g~ methyl~ eth~l~
prop~l~ isopropyl~ etc~)O ~he trialkylamino gro~p ma~
be e~g~ trimeth~lami~o or triethylamino, etc. ~he term
9: : nh~logen" e~compasses chlorlne~ bromine9 iodine and
: fl~orine.
.
If R3 sta~ds for an alkyl group~ it repre~e~t~ a
traight or branched chained al~l group, havi~g 1-6
carbon atom~ (e.g~ meth~l? ethyl, n-propyl, isoprop~l,
:2Q ~ obutg~ et¢~
coording to a preferred embodiment o~ the method
) o:~the pre~en~ inventlon, the compou~d of bhe generaI . .
f~rmulQ (III) i~ rea~ted with pyridine.in ~he pre~ence~
; D~ iodine. ~he reaction ma~ be car~ied QU~ at a
25~ te~perature ~otween 2Q C ànd 2~Q a~ preferabl~ at
8o-15~: ~2 ~a reaction peri~d depend~ on the ba~e used
a~d th~ reaction temperature~ under the condition~ disclo~0d
b~ve the rea~tion i~ complete generall~ wlthin 10~60
.
.
.
: i
.: ~,. ........... . . . ., . . . ... ~ . . .

2;3 ~
-- 5 --
mi~ute~
Ascording to a preferred embodiment of the method
b) of the present invention the compound. of the general
formula (II) i~ reacted with p~ridine in the pre~ence oX ~n
~ert solvent. ~he reaction may be carried ou~ at a
temperatur2 between 20 C and 2ao oc~ preferably at 80 150~.
~he reaction period depends on the ba~ used and tha reactl~
temp~rature.
4e inert ~olvent an e~ce~ of the appropriate
1 tertiar~ aromatic base or other ~olvent~ may be u~ed, know~
fr~m other quaternarization reaction~, ~uch a~ dimeth~l-
formamide, nltrome~hane or dimethyl~ulfoxide~
According to metho~ c) o~ our proce~ a compou~d
~ of the formula (~ reacted i~ the presence of a haloge~
with a tertiary nitrogen-containing ba~e. ~he reactio~
oonditlorL~ and the reacta~t~ are ~imilar to those used i:~
the reaction variant a). lhu~ compound~ of the general
ormul~ re obtained7 in which R3 is h~drogen~ ~he~e
oompo~d~ may be ~-clk~ylatedO
2Q . ~ Le reaction may be accompli~hed b;y u~ing all~
,
~ halid~s (~uch a~ alk~l iodides~ preferably ethyl iodlde)~
; ~ di~Ik~l ~ulIa~e~ (e.g~ ~ie~h~l ~ulIate)s alkyl-ben~ene
ul~nate~(preI~rabl~ eth~l-be~ze~e sulfonate) or alk~l-p-
toluene-~ulfo~ate~ (p~e~era~ly e~h~l-p~tolu~ne-~ulfonate).
25~ coor~ding to a particularly pre~exred'form oY realization
o~ th~ prace~ trieth~l pho~phat~ i~ ~ed a~ alk~lating
a~;e~" ~he reactioll i9 car~l~d out ln the pre~en~a of an
a~id bi~diD4~ agerlt. For this p~po~e th~ con~eD:tlonal acid
. .

3~
. ~, , .
binc1ing agents may be used~ ~uch ~ alkali carbonate~
(e~g. sodium or po-tassium c arb ona t e ) ~ a lk~l hydrogen
~arbonate~ (e.g~ sodi.um or pot;a~sium hydrogen carbonate),
alkali hydroxides (eOg~ sodium or pota~si~m hydroxide~
5 etc~), or organic bases (e~g~ p~ridine). '~he reacti.on ~-;J
ma-~ be carried o-ut i~ the presence of an iner-t organic I .
solven-t. For -~his purpose eOgO dimethylformamide, di
methyl~ulfoxi.de~ nltrome-thane, acetoni-trile or lower alkanol~
ma~ he useda ~he excess of the alkylating agent may al~o
~er~e as reaction medium (preferably i~ triethyl phosphate
is used). ~he reaction temperature depends on the
alkylating agent used, and one ma~ work preferabl~ at an
elevated temperature~ ~he reaction mixture may be worked
up by oonventional me-thod~ 9 i~ eO by removing the solvent~
etQ~
he anion of the halide of the general formula
(I) may be convérted iIltO another anion~ ~his procass ma~
,, ~ "
barried out in aqueous medium by reacting a compou~d of
s~ thè~general formula (I) with an alkali or alkallne earth
O~ m~tal ~alt containing th~ desired anion. ~ccordin2 to
another~ embodiment o~ the prooe~ a compou~d of the
general formula (I) lS added to a ion exchanger i~ ~`
hgdrogen pha6e~ and th~ ba~e thu~ bound is elu-ted with
a~acid~ containing the desired anionO
he reactlon mixture ma~ be wo:rked up b~ methods
I`h ;'i~,f'o iT~
known~per se~ ~he compou~d of the general formula (I)
- preciipitate~ generall~ on cooling the reaction mixture and
5~y b~ olated b~ mean~ of iiltratior or oentrifuging.
:~

~3~ 3~
- 7 -
Th~ new compounds of the ~eneral formula (I)
may be converted in-to 1-alk~l-7-me-thyl~4~oxo-1~4~dihydro-
1,8-naphthyrldirLe 3-carboxyllc acids a~ descrlbed and
cl~imed in ou.r copending ~atent application ser. No.
. ~he new compounds of the general formula (I),
where~n Z and Y are de:Eined abo~e 5 e~hibit pesticidal
ect and ma~ be used in the form o~ pesti~idal com-
pq~itionsc ~he said compositions conta~n a compound of the
general ~ormula (I) in admixture with useful, inert solid
10 or liquid diluent~ or carriersO ~he compositions ma~ be
I
p~epared by methods k~ow~ per ~e by admixi~ the activ~
i~,gredient with inert ~ solid or liquia diluents or
, I .
c~rri~rsO ~he compositions ma~ be finished in conventional
~ folrm~ (~pray, dusting pow~er9 granule9 concentrate~ etc~)O
~ ~he startlng materials of the proce~s of the pre- :
~h~ invention are prepared as follows:
2-amino-6-meth~l-pyridine or acid addltion`~alts
~h~o are conden~ed with a compound of the formula (~
~ . I
2~Q; ~ (V~
. ~ alkyl~ - aH - ~
OOalkyl
U~R~t ~ g the compounds of the formula ( ~I~
~: ~5 ~ 3
3~ ~NE - aE = ~ tVI)
~OOalk;srl
,
.
:' ' . .' ... , . ~

~ 1~ 4 L ~ ~ ~
-- 8 --
~hu~ obtain~d to c~clisation the startlng m~t~rials of the
formula (IV) are formed~ N alk~l~tion o~ the~e compound~
lead~ to the formation of the ~tarting material~ of the
formul~ (III~. The starti~g ma-terial~ o~ the ~ormula (II)
may be prepared by replacing the compou~d of the formula
(V) b~ an ethyl-halogeno-~ubstitu~ed-aceto-acetate-derivati~
in the above p:roces~
~ he starting material of the formula (II) ma~ be
p~epared b~ r~acting a compou~d of the formula (III) ~ith
1Q a halogenating agent such a~ bromlne~ or chlorlne, pyridinium-
:parbromide or cupric bromide. ~he halogenation ma~ be carried
out preferably in the pre~ence of an inert solvent ~uch a~
ace~c acid~ halogenated h~drocarbons (e.~0 ca~bon t~tra-
chloride, chlorobenzene etcO ) 9 ' '.
15~rther detail~ of our proce~s a~e to be ~ound in
~: the ~xamples~
~ ' ' '
1,15 g (QqQ05 moles) of ~-acetyl 1-ethyl-7 methyl-
~ 4-~x~ 4-dihydrQ-1,8-naphthy~.idine ~;mp~: 185-186 a) are
-~2Q ~ haated ln 10 ml of p~ridir:l.e in the presence of 1.27 g
o~::iodi~e ~n a w~;er ~ath, whereupon the reactio~ mixture
oo~led a~d the precipitated product i~ fil~ered Off~ .
æ~u~ 1~9 g of 1-ethyl-7-meth~l-4-oxo-1~4-dih~dro-1,8-~aph~hy-.
ridi~e-3 carbo~lmethyl-p~ridiniu~-idQdide are o~tained~
25~ ~Yleld ~5%. ~he meltln~ point of ~he produc~ i~ 25Q O (de-
~ ompo~ition)-
naly~ f the formula ~1~H1 ~ 302
:. ~ .' '

~ 8
Calculated~ 9,67 ~ol ~ 7 v/o N 9~6~ % I 29~15 /0
~ound: C ~9~9 % x 3~97 % N 9~G0 % I 29~48 %9
~xa~ple 2
.
A mixture of 19~15 ~ (1~7 moles) o.~ ~-acet~
ethyl-7-methyl-4-oxo-1~4-dihydro-1,8-naph-thyr.~di~e, 1~ 27 g
(0.005 mole~) of iodine and 10 ml of ~ ~picollne are
heated on water bath~ ~h0 precipitation ot' cry~-tals begin~
~he reaction mixture is cooled to room temperature ~nd the
preoipitated crystals are filtered off~ ~he melting point
1Q of the 1 eth~l-7-methyl-4-oxo-1~4-dihydrO-1~8~naphthyridine-
- 3-carbon~lmeth~l~( ~ -picolinium)-iodide .amounts to 223-225C~
~nalysi~ for the ~ormula C19H2 ~ ~02I:
C~lculatedo C 50,79 % H 4,49 ~ ~' 9,35 % I 28~25 %
~Qund: C 51~19 % H 4~22 % ~ 9 9 42 ~ I 28~40 %~
1~i ,
A mixture of 1,15 g (0~005 mole~) of 3-ace-t~
eth~l-7-methyl-4-oxo 1,4-dihydro-1,8-naphthyridine and
27 g (0~005 mole~) o~ iodine is heated i.n quinoli~e ~n a
~wat~r bath~ ~he reaction mixture i~ allowed to ~tand at
room temperature~ ~hereupo~ it is cooled,~ the precipitated
ar~tal~ ~ are f iltered o~f~ a~d washed with a ~mall amount
5- o~ 96~alcohol~ ~he 1-ethyl~7-meth~l-4-oxo-1~4-dlhydro~
~ , . . . . .
1t~-naphthyridine-3-carbonylmethyl-quinolinium-io~ide melta
~at 22Q-221 a~ i
;~ 2g~al~ia for ~he formula ~2 ~2 ~ ~Q2I; . ,'
.
alculated: C 54945 h :E ~,15 % ~ 8g66 % I 26,~6 %
Fou~d~ Q YQ H 3,96 h N 8,52 % I 2~,20 /9
: :-: : .: :. . - : :

L.~
Example L~
A mixture of 2~02 g (0~01 mole) of 3-acet~l-7-me-th~l
4-oxo-1,4-dihydro-198 naphthyridinet 100 ml of pyridine
and 2~54 g (001 mole)of iodine is heated on a water bath4
~he reaction mixture is cooled to room temperature~.the
mixture is allowed to ~tand in a refrigerator ov~rnlght~
~he precipitated cry~tals are filtered off and washed
with p~ridine and ethanolO ~he melti~g point of the 7-meth..yl-
4-s~o~1~4-dih~dro~1$8-naphthyridine-3-carbonyl-methyl- :
p~ridinium-iodide amount~ to 260 C~
~nal~is ~or the formula ~16~14N302I;
Calculated: C 47.19 % H 3O47 % ~ 10~32 I 31~16 %
~nd: C 47.18 % E 3.37 % N 10~69 I 30~4~ %,
: Example 5
: 15 ~ mixture o~ 2~03 g (0~005 mole~) of 7-methyl-4-
~o-1~4-dihydro-1~8-naphth~ridine-3-carbonylmethyl-
pgridl~ium-iodld0, 4~55 g (0~025 mole~) of triethyiphosphate
~d 0~7 ~ ~Q.Q05 moles) 0~ pota~ium carbona-te ls heated
Q~ an ~il bath at 220-225 C. ~he 1-ethyl-7-meth~1-4-oxo-
20 ~ dih~dro-1~8-naphth~ridine-3-carbon~lmethyl-pyridlnium
iodid~ thus obtained may be subjected to ~urther reactio~
. ~ ........ without i~lation~
1 g of 1-ethyl-7-~ethyl-'~oxo-174-dihydro-1,8-
5~ : ~ap~h~ridi~e;~3-carbon~lmethyl-pyridinium-iodide i~ dissol~ed
1~ 5Q ml of water u~der heatin~ ~o the faint yellow
.- ., ~. . ~ .
~olutio~ thU~ obtained 2 ml of 70% perchloriG acid are
: add~d~ ~ white product precipltates ~oon. After cooling
. .. , ~ .
.. . . . . ...

3~
the ~olution7 the precipitated cr~tals ~re filtered o~f
and washed with wat er and methanol O ~hus 0 0 92 g of 1~eth~rl-
7-methyl-4-oxo~1,4-dihydro-~8-naphthyridine~3-carbonyl-
methyl-pyridinium-perchlorate are ob-tained. Mp~: 263 C~
5 ~fter recry~talli~ation Prom methanol the melti~g poi~t
remain~ unchangqd,.
Ana1;y~is îor the formula C18Er18~3o6C1:
aalculat ed; a 5~ ~ 02 % H ~ ~ 45 % N 10~31 % Cl 8O69 %
~u~ 5 ~ 52 ~ 86 /0 H 4 . 26 % ~ 10 . 10 ~ Ol 8 L 53 %~
I