QUINOLONE DERIVATIVES AND THE PREPARATION THEREOF

DERIVES DE LA QUINOLONE ET METHODE DE PREPARATION

English Abstract

ABSTRACT OF THE DISCLOSURE
New quinolone derivatives and their process of preparation
are provided of the formula (I):-
<IMG> (I)
in which R1 is a hydrogen atom or a lower alkyl or lower alkenyl
radical, R3 is a hydrogen atom or a lower alkyl radical and n
is 1 or 2; the derivatives of the present invention have an
excellent antimicrobial activity in vivo and especially in
mammalian urinary tracts.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:-
1. Process for the preparation of quinolone derivatives
of the formula (I):-
<IMG> (I)
in which R1 is a hydrogen atom or a lower alkyl or lower alkenyl
radical containing up to 6 carbon atoms, R3 is a hydrogen atom or
a lower alkyl radical of 1 to 6 carbon atoms and n is 1 or 2
comprising
a) treating a compound of the formula (II):-
<IMG> (II)
in which R1, R3 and n are as defined above and X is a hydroxyl
group or a lower acyloxy or lower alkoxy radical or a halogen
atom, with an elimination agent capable of eliminating HX,
with elimination of HX: or
b) when R1 is to be a lower alkyl or lower alkenyl
radical, cyclising a compound of the formula (III):-
<IMG>
(III)
11

in which n and R3 are as defined above, R2 is a lower alkyl or
lower alkenyl radical containing up to 6 carbon atoms and X' is a
hydroxyl group or a lower acyloxy or lower alkoxy radical, under
conditions for elimination of HX'.
2. A process according to claim 1 for the preparation of
quinolone derivatives of the formula (I) as defined in claim 1,
comprising treating a compound of the formula (II):-
<IMG> (II)
in which R1, R3, X and n are as defined in claim 1 with an
elimination agent, with elimination of HX.
3. A process according to claim 1 for the preparation of a
quinolone derivative of the formula (I) as defined in claim 1,
in which R1 is a lower alkyl or lower alkenyl radical, comprising
cyclising a compound of the formula (III):-
<IMG> (III)
in which n, R2, X' and R3 are as defined in claim 1, under
conditions for elimination of HX'.
4. A process according to claim 2 wherein, when R1 is a
hydrogen atom in the derivative of formula (I) obtained, the
derivative is subsequently N-alkylated or N-alkenylated to
produce a different derivative of said formula (I).
12

5. A process according to claim 1, 2 or 3 wherein the
derivative obtained is subsequently hydrolysed or esterified
at the 3-position.
6. A process according to claim 1 wherein, when R3 in the
derivative of formula (I) obtained is a hydrogen atom, the
derivative is converted into a pharmaceutically acceptable,
pharmacologically compatible salt.
7. A process according to claim 2 wherein, when R3 in the
derivative of formula (I) obtained is a hydrogen atom, the
derivative is converted into a pharmaceutically acceptable,
pharmacologically compatible salt.
8. A process according to claim 3 wherein, when R3 in the
derivative of formula (I) obtained is a hydrogen atom, the
derivative is converted into a pharmaceutically acceptable,
pharmacologically compatible salt.
9. A process according to claim 1 wherein R1 is a hydrogen
atom or a lower alkyl or lower alkenyl radical of 1 to 4 carbon
atoms, R3 is a hydrogen atom or a lower alkyl radical of 1 to
4 carbon atoms, and n is 1 or 2.
10. A process according to claim 2 wherein X is a hydroxyl
group, a lower acyloxy or lower alkoxy radical and said
elimination agent is polyphosphoric acid.
11. A process according to claim 2 wherein X is a halogen
atom and said elimination agent is an inorganic or organic
base.
12. A process according to claim 3 wherein said cyclising
and elimination is carried out by heating with polyphosphoric
acid.
13

13. A process according to claim 2 for preparing 1-ethyl-
3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one comprising
treating 1-ethyl-3-carboxy-1,4-dihydro-7-hydroxy-cyclopenteno-
[1,2-h]quinol-4-one with polyphosphoric acid to remove the
elements of water therefrom.
14. A process according to claim 2 for preparing 1-ethyl-
3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one comprising
treating 1-ethyl-3-carboxy-1,4-dihydro-7-acetoxy-cyclopenteno
[1,2-h]quinol-4-one with polyphosphoric acid to remove the
elements of acetic acid therefrom.
15. A process according to claim 2 for preparing 1-ethyl-
3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one comprising
treating 1-ethyl-3-carboxy-1,4-dihydro-7-chlorocyclopenteno[1,2-
h]quinol-4-one with ammonia to remove the elements of hydrogen
chloride therefrom.
16. A process according to claim 2 for preparing 1-ethyl-
3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one comprising
treating 1-ethyl-3-carboxy-1,4-dihydro-7-ethoxy-cyclopenteno[1,2-
h]quinol-4-one with polyphosphoric acid to remove the elements
of ethanol therefrom.
17. A process according to claim 2 for preparing 1-propyl-
3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one comprising
treating 1-propyl-3-carboxy-1,4-dihydro-7-hydroxy-cyclopenteno
[1,2-h]quinol-4-one with polyphosphoric acid to remove the
elements of water therefrom.
18. A process according to claim 13 including the step of
esterifying said 1-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one with ethanol to produce 1-ethyl-3-ethoxycarbonyl-
1,4-dihydro-9H-cyclopenta[h]quinol-4-one.
14

19. A process according to claim 14 including the step of
esterifying said 1-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one with ethanol to produce 1-ethyl-3-ethoxycarbonyl-
1,4-dihydro-9H-cyclopenta[h]quinol-4-one.
20. A process according to claim 15 including the step of
esterifying said 1-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one with ethanol to produce 1-ethyl-3-ethoxycarbonyl-
1,4-dihydro-9H-cyclopenta[h]quinol-4-one.
21. A process according to claim 16 including the step of
esterifying said 1-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one with ethanol to produce 1-ethyl-3-ethoxycarbonyl-
1,4-dihydro-9H-cyclopenta[h]quinol-4-one.
22. A process according to claim 2 for preparing 1-(prop-1-
en-1-yl)-3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one
comprising treating 1-(prop-1-en-1-yl)-3-carboxy-1,4-dihydro-
7-hydroxy-cyclopenteno[1,2-h]quinol-4-one with polyphosphoric
acid to remove the elements of water therefrom.
23. A process according to claim 3 for preparing 1-ethyl-3-
carboxy-1,4,9,10-tetrahydrobenzo[h]quinol-4-one comprising
cyclising ethyl N-ethyl-N-(1-hydroxytetralinyl-5)-aminomethylene
malonate, under conditions for the elimination of the elements
of water with polyphosphoric acid, with hydrolysis of the
ester group to leave the free carboxylic acid group in the
3-position.
24. A process according to claim 3 for preparing 1-ethyl-3-
carboxy-1,4,9,10-tetrahydrobenzo[h]quinol-4-one comprising
cyclising ethyl N-ethyl-N-(1-ethoxytetralinyl-5)-aminomethylene-
malonate, under conditions for the elimination of ethanol, with
polyphosphoric acid, with hydrolysis of the ester group to leave
the free carboxylic acid group in the 3-position.

25. A process according to claim 3 for preparing 1-ethyl-3-
carboxy-1,4,9,10-tetrahydrobenzo[h]quinol-4-one comprising
cyclising ethyl N-ethyl-N-(1-acetoxytetralinyl-5)-aminomethylene-
malonate, under conditions for the elimination of acetic acid,
with polyphosphoric acid, with hydrolysis of the ester group to
leave the free carboxylic acid group in the 3-position.
26. Quinolone derivatives of the formula (I):-
<IMG>
(I)
wherein R1 is a hydrogen atom or a lower alkyl or lower alkenyl
radical containing up to 6 carbon atoms, R3 is a hydrogen atom or
a lower alkyl radical of 1 to 6 carbon atoms and n is 1 or 2,
whenever prepared by the process of claim 1, 2 or 3 or by an
obvious chemical equivalent.
27. A pharmaceutically acceptable, pharmacologically
compatible salt of a derivative of formula (I), whenever
prepared by the process of claim 6, 7 or 8 or by an obvious
chemical equivalent.
28. 1-Ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-
4-one, whenever prepared by the process of claim 13 or 14 or
by an obvious chemical equivalent.
29. 1-Ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-
4-one, whenever prepared by the process of claim 15 or 16 or
by an obvious chemical equivalent.
30. 1-Propyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-
4-one, whenever prepared by the process of claim 17 or by an
obvious chemical equivalent.
16

31. 1-Ethyl-3-ethoxycarbonyl-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one, whenever prepared by the process of claim 18 or
19 or by an obvious chemical equivalent.
32. 1-Ethyl-3-ethoxycarbonyl-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one, whenever prepared by the process of claim 20 or
21 or by an obvious chemical equivalent.
33. 1-(Prop-1-en-1-yl)-3-carboxy-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one, whenever prepared by the process of claim 22 or by
an obvious chemical equivalent.
34. 1-Ethyl-3-carboxy-1,4,9,10-tetrahydrobenzo[h]quinol-4-
one, whenever prepared by the process of claim 23, 24 or 25 or
by an obvious chemical equivalent.
17

Description

~37~
~ he present invention is concerned with new quinolone
derivatives and their preparation.
The new quinolone derivatives of the present invention
have an excellent antimicrobial activity in vivo and especially
in mammalian urinary tracts.
According to one aspect of the invention there is
provided new quinolone derivatives of the formula:-
\\ ~ (I)
CH2)n Rl '
' . :': '
wherein Rl is a hydrogen atom or a lower alkyl or lower alkenyl . . -.
radical, R3 is a hydrogen atom or a lower alkyl radical and n
is 1 or 2; and the pharmaceutically acceptable pharmacologically
compatible salts thereof. ~ -
According to another aspect of the invention there is
provided a method for preparing the new quinolone derivatives of
formula (I) comprising
a) treatment of a compound of the formula:-
O
COOR3
~ J (II)
X-CH R
H2C-(CH2)n
wherein Rl, R3 and n are as defined above and X is a hydroxyl . :
group, a lower acyloxy or lower alkoxy radical or halogen atom,
20 with an eliminating agent capable of eliminating HX, with : :,
elimination of HX, or `~
~.. .. .
',~ ' ,'
- 1 - .~ -

~37~4S
b) cyclisation of a compownd of the formula:-
R300C ,COOR3
CI/ ,'
~ CH (III)
X'-CH 2
H2C-(CH2)n
wherein n and R3 are as defined above, R2 is a lower alkyl or
lower alkenyl radical and X' is a hydroxyl group or a lower
acyloxy or lower alkoxy radical, under conditions for eliminat-
ing HX'-
The quinolone derivative obtained of formula (I) can,if desired, be converted to a different derivative of formula
(I). For example, a derivative of formula (I) in which Rl is
hydrogen can be converted into a derivative of formulal(I) in
which Rl is lower alkyl or lower alkenyl by lower alkylating or
lower alkenylating the nitrogen atom. A derivative of formula
(I) in which R3 is hydrogen can be esterified to produce a
derivative of formula (I) in which R3 is lower alkyl; and a
derivative of formula (I) in which R3 is lower alkyl can be
hydrolysed to produce a derivative of formula (I) in which R3
is hydrogen.
The free acids of formula (I) can be converted into -~
pharmaceutically acceptable, pharmacologically compatible salts
thereof.
The elimination of HX from the compounds of formula
(II) can take place, for example, when X is a hydroxyl group
or a lower acyloxy or lower alkoxy radical, by heating with
, . . . .
agents eliminating HX, for example, polyphosphoric acid. When
X is a halogen atom, the elimination of HX can be accornplished -~
by treatment with an inorganic or organic base, for ex~nple
..
triethylamine, piperidine or the like. ~
.~ : , .-'.':
~ ~ - 2 - ~;

~37~
The cyclisation and the elimination of ~' thereby
involved from the compound of formula (III) is preferabl~
carried out by heating with polyphosphoric acid.
When Rl is a hydrogen atom, the products obtained can
be subsequently lower alkylated or lower alkenylated on the
nitrogen atom with lower alkylating or lower alkenylating
agents, for example lower alkyl halides and lower alkenyl halides,
in a conventional manner to produce a different derivative of
formula (I). In the case of an N-lower-alkenyl radical, a double
bond can be shifted from the allyl position to the M-vinyl posi- -
tion by treatment with an alkali. Compounds in which R3 is a
hydrogen atom can be esterified with an esterifying agent, to give
other derivatives of formula (I), in a conventional manner, pre-
ferably with a l~wer alkyl halide in dimethyl formamide in the
presence of a base, for example, potassium carbonate. Lower
alkyl esters of formula (I) can be hydrolysed in a conventional
manner, for example, by heating with a dilute aqueous solution
of sodium hydroxide to give the free acid of formula (I) in ~ ;
which R3 is a hydrogen atom.
The conversion of compounds of formula (I), in which
R3 is a hydrogen atom, into pharmaceutically acceptable,
pharmacologically compatible salts can be carried out in
conventional manner, for example, by neutralisation with a non-
toxic, pharmacologically compatible, inorganic base or wit~h a ,~
non-toxic, pharmacologically compatible amine.
: . . .
- 3 - ~
' " ~':
,' ':~, '''',

~3~4S
The lower alkyl and lower alkenyl radicals in the
above-given general formulae can contain up ~o 6 and preferably
up to 4 carbon atoms. The lower acyloxy and lower alkoxy radicals
can contain 1 to 4 carbon atoms.
The halogen atom in the compound of formula (II) is
one selected from fluorine, chlorine, bromine and iodine with
chlorine being preferredO
The present invention also provides pharmaceutical
compositions comprising at least one of the new derivatives
of formula (I) or a pharmaceutically acceptable, pharmacological-
ly compatible salt thereof in admixture with a solid or liquid
pharmaceutical diluent or carrier.
The derivatives of formula (I) can be administered
enterally and parenterally in solution, suspension or in
solid form by admixture with a solid or liquid pharmaceu~ical
diluent or carrier. They are preferably administered in the
form of tablets or dragees with a content of active material
of 100 - 500 mg. per tablet or dragee. The tablets can thereby -
contain further solid carrier materials, for example, starch,
lactose, methyl cellulose, talc, highly dispersed silicic acid,
high molecular weight fatty acids, magnesium stearate, gelatine,
solid high molecular weight polymers (for example polyethylene
glycols) and, when desired, also flavouring and/or colouring ~-
agents. ;
Suspensions are preferably administered with a content
of active materials of 20 - 100 mg./ml., using water as the
suepension agent. For the stabilisation of the suspenslons,
there can be added high molecular weight, water-soluble
~matexials, for example, cellulose ethers or polyethylene oxide.
Furthermore! there can also be added sweetening agents, flavour-
ing~agents, odiferous materials and/or colourlng agents.
'~ ' ' .

~37~5
For injection solutions, the compounds of formula
(I) are preferably used in aqueous solution in amounts of frorn
10 - 100 mg./dosage. Such injection solutions preferably also
contain conventional additives, for example, stabilisation
agents, solubilising agents, buffers and mannitol or sodium
chloride in the amount necessary to produce an isotonic solu-
tion.
Having thus generally described the present invention,
reference will now be made to the following examples which
illustrate preferred embodiments thereof. It will be under-
stood that various modifications can be made thereto by those
skilled in the art, having regard to the foregoing and following ~ -
description.
Example 1.
l-Ethyl-3-carboxy-1,4-dihydro-9H-cyclopentarh ~uinol-4-one.
Variant I: ;
900 mg. 1-ethyl-3-carboxy-1,4-dihydro-7-hydroxy-
cyclopenteno[l,2-h]quinol-4-one are stirred for 2 hours at 100C.
in 18 g. polyphosphoric acid. The reaction mixture is sub- ~ ~
sequently mixed with about 30 - 40 ml. water and filtered. ; -
There are thus obtained 780 mg. 1-ethyl-3-carboxy-1,4-dihydro-
9H-cyclopenta[h]quinol-4-one which, after recrystallisation ~-
from dimethyl formamide, has a decomposition point of 248 -
251C.
Variant II:
0.1 g. 1-ethyl-3-carboxy-1,4-dihydro-7-acetoxy-
cyclopenteno[l,2-h]quinol-4-one are stirred for 30 minutes at
150C. with 1 g. polyphosphoric acid. After cooling, the
reaction mi~ture is diluted with water and the precipitated
product is filtered off with suction. There are obtained 65
mg. l-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]quinol-4-one
, ;'
- 5 - ~
~.

-
7~45
which, after recrystallisation from dimethyl formamide, melts,
with decomposition, at 248 - 251C.
Variant III:
0.1 g. 1-ethyl-3-carboxy-1,4-dihydro-7-chlorocyclo-
penteno[l,2-h]quinol-4-one are dissolved in 3 ml. dimethyl
sulphoxide and gaseous ammonia passed therein for 30 minutes
at ambient temperature. The precipitate formed is then filtered
off with suction. There are obtained 45 mg. 1-ethyl-3-carboxy-
1,4-dihydro-9H-cyclopenta[h]quinol-4-one, which has a decomposi-
tion point of 235C. After recrystallisation from dimethyl
~ .
formamide, the compound has a decomposition point of 246 - 250C.
The starting material is obtained by the chlorination
of l-ethyl-3-carboxy~1,4-dihydro-7-hydroxy-cyclopenteno[1,2-h]- ~
quinol-4-one by means of concentrated hydrochloric acid and zinc -
chloride, it has a melting point of 244 - 248C.
Variant IV:
0.1 g. 1-ethyl-3-carboxy-1,4-dihydro-7-ethoxy-cyclo- ;
penteno[l,2-h]quinol-4-one are stirred for 30 minutes at 120C.
with 1 g. polyphosphoric acid. After cooling, the reaction
mixture i5 introduced into water and filtered. After recrystal-
lisation of the product from dimethyl formamide, there are
obtained 55 mg. 1-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]- ---
quinol-4-one, which has a decomposition point of 248 - 2S1C.
The starting materials used in the above Examples
are described in Canadian Patent 981,684 of Alfred Rhomberg
et al~
Example 2.
,: :
l-Propyl-3-carboxy-1,4-dih~dro-9H-cyclopentarhlquinol-4-one.
1 g. 1-propyl-3-carboxy-1,4-dihydro-7-hydroxy-
cyclopentenoC1,2-h]quinol-4-one are stirred for 30 minutes at
120C. with 20 g. polyphosphoric acid. The reaction mixture
.
:; :
- 6 - ~ ~

~L037~5
is subsequently mixed with about 100 ml. water and the pre-
cipitated product (0.9 g~) filtered off with suction. The
residue is stirred up twice with 40 ml. amounts of methylene
chloride. Evaporation of the methylene chloride extracts
gives a total of 0.58 g. 1-propyl-3-carboxy-1,4~dihydro-9H-
cyclopenta[h]quinol-4-one, which has a melting point of 266 -
269.5C.
Example 3.
l-Ethyl-3-ethoxycarbonyl-1,4-dihydro-9H-cyclopentarhl~uinol-4-one.
2.4 g. 1-ethyl-3-carboxy-1,4-dihydro-9H-cyclopenta[h]-
quinol-4-one are heated under reflux for 4 hours with 50 ml.
ethanol and 4.8 ml. concentrated sulphuric acid, whereafter the
bulk of the ethanol is evaporated off. The reaction mixture is
then mixed with ice and carefully adjusted to a pH of 5 with 2N
aqueous sodium hydroxide solution. The semi-crystalline product
which separates out is extracted with methylene chloride and the
methylene chloride phase is washed three times with a 1~ aqueous
sodium carbonate solution. The organic phase is subsequently
dried over anhydrous sodium sulphate, purified with active
charcoal and evaporated. The evaporation residue is recrystal-
lised ~rom 20 ml. ethyl acetate. There is obtained 0.75 g.
l-ethyl-3-ethoxycarbonyl-1,4-dihydro-9H-cyclopenta[h]quinol-4-
one, which has a melting point of 158C.
Example 4.
l-tProp-l-en-l-yl)-3-carboxy-1,4-dihydro-9H-cyclopentarhlq~inol-
4-one
0.1 g. 1-(prop-1-en-1-yl)-3-carboxy-1,4-dihydro-7-
hydroxy-cyclopenteno[1,2-h]quinol-4-one are stirred for 30
minutes at 120C. with 1 g. polyphosphoric acid. After cooling,
the reaction mixture is diluted with water and filtered with `~
suction. There are obtained 70 mg. 1-(prop-1-en-1-yl)-3-
,
.~ ~
, , , "

~37~4S
carboxy-1,4~dihydro-9H-cyclopenta[h]quinol~4-one, which has
a melting point o~ 220 - 227C.
Example 5.
l-Ethyl-3-carboxy~ ,9,10-tetrahydrobenzorhlquinol-4-one.
Variant I-
0.1 g. ethyl N-ethyl-N~(l-hydroxytetralinyl-5)-amino-
methylene-malonate are stirred for 2 hours at 110C. with 1.5 g.
polyphosphoric acid, whereafter the reaction mixture is cooled
and mixed with ice. The solution is extracted with methylene
chloride and the extract, after drying, is evaporated to dryness.
The residue (0.12 g.) is stirred with 2.4 ml. 2N aqueous sodium
hydroxide solution and a little ethanol for 3 hours at 90C.
The ~olution is filtered, cooled and acidified with 2N hydro-
chloric acid. The precipitate obtained is dissolved in methylene
chloride and the solution is dried, treated with acti~e charcoal,
filtered and evaporated. There are thus obtained 50 mg. (67% of --
theory) l-ethyl-3-carboxy-1,4,9,10-tetrahydrobenzo[h~quinol-4
one which, after recrystallisation from ethanol, melts at
230 - 233C.
The ethyl N-ethyl-~-(l-hydroxytetralinyl-5)-amino-
methylene-malonate used as starting material is prepared as
follows~
5.45 g. 5-aminotetral-1-one are dissolved in 152 ml.
dioxan, 93 ml. methanol and 15 ml. water and mixed portionwise
at 50C. with 2.57 g. sodium borohydride. After half an h~ur,
the reaction mixture is evaporated, mixed with water, extracted
with methylene chloride and the extract treated with active
charcoal, dried over anhydrous sodium sulphate and suction
filtered through a Seitz filter. The filtrate is evaporated
~30 and the residue dissolved in ethancl and reprecipitated with
water. 5.0 g. (90% of theory) 5-amino-1-hydroxy-tetraline are
thus obtained in the form of an oil.
: ~:
- 8 - ~ ~

~37~S
A suspension of 1.0 g. 5-amino-1-hydroxytetraline and
0.93 g. potassium carbonate in 10 ml. ethanol is rnixed porkion-
wise with a solution of 1.0 ml. ethyl iodide in 3.0 ml. ethanol
at the boil. After the reaction has taken place, the reaction
mixture is evaporated, mixed with water and extracted with
methylene chloride. The concentrated extract gives 1.05 g. of
oil which is fractionated by column separation (silica gel;
eluent ethyl acetate/ligroin (1:1)). 0.52 g. (44% of theory)
pure 5-ethylamino-1-hydroxy-tetraline are thus obtained in the
form of an oil.
2.38 g. 5-ethylamino-1-hydroxytetraline are boiled for
20 hours in 25 ml. toluene with 24.9 ml. ethyl ethoxy-methylene-
malonateO The reaction mixture is thereafter evaporated and the
residue obtained is purified through a column (silica gel; eluent
ethyl acetate/ligroin (1:1)). There is obtained 0.99 g. (22% of
theory) ethyl N-ethyl-N-(l-hydroxytetralinyl-5)-aminomethylene-
malonate in the form of an oil.
Variant II: -
59 mg. ethyl N-ethyl-N-(l-ethoxytetralinyl-5)-amino-
methylene-malonate are heated for 2 hours at 110C. in 0.9 g. poly-
phosphoric acidn The reaction mixture is then cooled, mixed with
ice-water, extracted with methylene chloride and the extract
evaporated. The residue is heated for 3 hours at 90C. with
1.4 ml. 2N aqueous sodium hydroxide solution. It is then filtered,
the filtrate is acidified with 2N hydrochloric acid and extracted
with chloroform. After evaporation of the extract, there are
obtained 13 mg. (27% of theory) 1 ethyl-3-carboxy-1,4,9,10-
tetrahydrobenzo[h]quinol-4-one, which has a melting point of
228 - 230C. After recrystallisation from ethanol, the product
melts at 230 - 233C.
The ethyl N-ethyl-N-(l-ethoxytetralinyl-5)-amino-
:, '
_ g _
. .. , , : . ~ .: . . : . : ,

~L~3~
methylene-malonate used as starting material is prepared as
follows:
80 mg. ethyl N-ethyl-N~ hydroxytetralinyl-5)-
aminomethylene-malonate are reacted in 1 ml. dimethyl ~ormamide
with 14 mg. sodium hydride. Subsequently, 0.1 ml. ethyl iodide
in 2 ml. dimethyl -formamide are added thereto portionwise ak
80C. When the reaction is finished, the reaction mixture is
evaporated and the residue is mixed with water and then extracted
with methylene chloride. By evaporation of the extract, there
are obtained 59 mg. (68% oE theory) ethyl N-ethyl-N-(l-ethoxy-
tetralinyl-5)-aminomethylene-malonate in the form of an oil.
Variant III-
1.12 g. ethyl N-ethyl-N-(l-acetoxytetralinyl-5)-
aminomethylene-malonate are heated to 150C. for 1 hour with
16.8 g. polyphosphoric acid. The reaction mixture is then
mixed with water, boiled for 10 minutes, filtered, cooled, ~ ~ -
filtered with suction and washed with water. There is obtained
0.~ g. (53/0 of theory) crude 1-ethyl-3-carboxy-1,4,9,10-tetra-
hydrobenzo[h]quinol-4-one, which has a melting point of 225 -
228C. After recrystallisation from ethanol, the product melts
at 230 - 233C.
The ethyl N-ethyl-~-(l-acetoxytetralinyl-5)-amino-
methyIene-malonate used as starting material is prepared as
follows:
1.04 g. ethyl N-ethyl-~-(l-hydroxytetralinyl-5)-
aminomethylene-malonate are stirred for 1 hour at 150C. with
1.4 ml. acetic anhydride. Upon evaporation, there is obtained
1.12 g. (96% of theory) ethyl ~-ethyl-~-(l-acetoxytetralinyl-
5)-aminomethylene-malonate in the form of an oil. ~
. :- ., . ,: -
: ;~ .
.. . .
- 10 ~
'"~ }~ ", ~ , ~; ,"" ~ "~ " " .