NO744716L - - Google Patents

Description

Procedure for the production of new 1,8-naphthyridine derivatives.

The present invention relates to the preparation of new 1,8-naphthyridine derivatives, which are useful as intermediates in the preparation of known 1-alkyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine^3-carboxylic acids , which are valuable anti-bacterial agents. These latter compounds are prepared by alkylation and subsequent hydrolysis of 7-methyl-4-oxo-3-alkoxycarbonyl-1,4-dihydro-1,8-naphthyridines (British Patent Application No. 1.ooo.892). Moreover, the new compounds according to the present invention are useful pesticides.

According to the present invention, a method for the production of new 1,8-naphthyridine derivatives of the general formula (I) has been provided

3

wherein R is hydrogen or alkyl,

Y is a tertiary nitrogen-containing aromatic heterocyclic ring attached to the nitrogen atom, or a trialkylamino group,

Z is an anion

which includes

a) reacting a compound of the general formula (III)

wherein the N-alkyl group has 1-6 carbon atoms, with an aromatic tertiary base or a trialkylamine in the presence of halogen, or

b) reacting a compound of formula (II)

wherein alkyl is as above indicated and

X is halogen,

with a tertiary base, or

c) reacting a compound of the formula (IV)

in the presence of a halogen with an aromatic tertiary base

or a trialkylamine and, if desired, alkylate the compound of general formula (I) thus obtained (in which R 3 is hydrogen) and, if desired, convert it thus. obtained halide to another halide or another pharmaceutically acceptable anion.

IN

In the general formula (I), Z may be halogen, such as iodine,

bromine or chlorine, or sulfate, phosphate, perchlorate or nitrate j anion, etc. Y is preferably a 5- or 6-membered nitrogen-containing ring, such as pyridine, quinoline, isoquinoline or alkyl-substituted pyridines, such as picoline, quinaldine or lepidin, or other lower alkyl-substituted pyridine rings. The trialkylamino group has straight-chain or branched alkyl groups, with 1-6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl etc). The trialkylamino group can e.g.

be trimethylamino or triethylamino etc. The term "halogen" includes chlorine, bromine, iodine and fluorine.

If R. means an alkyl group, it represents a straight-chain or branched alkyl group with 1-6 carbon atoms (eg methyl, ethyl, n-propyl, isopropyl, isobutyl etc).

According to a preferred embodiment of method a) of the present invention, the compound of the general formula (III) is reacted with pyridine in the presence of iodine. The reaction can take place at a temperature between 2o and 2oo°C, preferably between 8o - 15o°C. The reaction time depends on the base used and the reaction temperature, under the above conditions, the reaction is generally completed within 10 - 60 min.

According to a preferred embodiment of method b) of the present invention, the compound of the general formula (II) is reacted with pyridine in the presence of an inert solvent. The reaction can be carried out at a temperature between 2o and 2oo°C, preferably at 8o - 15o°C. The reaction time depends on the base used and the reaction temperature.

As an inert solvent, an excess of the appropriate tertiary aromatic base can be used, known from other quaternary reactions, such as dimethylformamide, nitromethane or dimethylsulfoxide.

According to method c) of the present method, a compound of the formula (IV) is reacted with a tertiary nitrogen-containing. base in the presence of halogen. The reaction conditions and reactants are the same as those used in reaction variant a). Thus, compounds of the general formula (I) are obtained, in which R 3 is hydrogen. These compounds can be N-alkylated.

The reaction can be carried out using alkyl halides (such as alkyl iodides, preferably ethyl iodide), dialkyl sulphates (e.g. diethyl sulphate), alkyl benzene sulphonates (preferably ethyl benzene sulphonate) or alkyl p-toluene sulphonates (preferably ethyl p-toluene sulphonate). According to a particularly preferred form of the method, triethyl phosphate is used as the alkylating agent. The reaction is carried out in the presence of an acid-binding agent.

For this purpose, a conventional acid-binding agent can be used, such as alkali metal carbonates (e.g. sodium or potassium carbonates), alkyl hydrogen carbonates (e.g. sodium or potassium hydrogen carbonate), alkali metal hydroxides (e.g. sodium or potassium hydroxide, etc.) or organic bases (e.g. pyridine}. The reaction can be carried out in the presence of an inert organic solution. For this purpose, e.g. dimethylformamide, dimethylsulfoxide, nitromethane, acetonitrile or lower alkanols can be used. The excess of the .. alkylating agent can also serve as reaction medium (preferably if triethyl phosphate is used).The reaction temperature depends on the alkylating agent used,

and one can preferably work at an elevated temperature. The reaction mixture can be processed by conventional methods,

i.e. by removing the solvent etc.

The anion of the halide of the general formula (I) can be converted into another anion. The process can be carried out in an aqueous medium by reacting a compound of the general formula (I) with an alkali or alkaline earth metal salt containing the desired anion. According to another embodiment of the method, a compound of the general formula (I) is added to an ion exchanger in the hydrogen phase, the base thus produced is eluted with an acid containing the desired anion.

The reaction mixture can be treated by known methods. The compound of the general formula (I) is generally precipitated

by cooling the reaction mixture and can be isolated by filtration or centrifugation.

IN

The new compounds of the general formula (I) can be converted into 1-alkyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acids as described and claimed in our patent application no. .

The new compounds of the general formula (I), in which Z and

Y is described above, shows pesticidal effect and can be used in the form of pesticidal compositions. Said compositions contain a compound of the general formula (I) in admixture with useful, inert solids or liquid solvents. or carriers. The compositions can be prepared by known methods by mixing the active ingredient with inert, solid or liquid diluents or carriers. The compositions can be finished in conventional forms (spray, powder, granules, concentrate, etc.)

The starting materials of the process according to the present invention are prepared as follows: 2-amino-6-methyl-pyridine or acid addition salts thereof are condensed with a compound of formula (V) By subjecting compounds of formula (VI)

obtained in this way cyclization, the starting material of formula (IV) is formed. N-alkylation of these compounds leads to the formation of the starting material of formula (III). The starting material of formula (II) can be prepared by

j replace the compound of formula (V) with an ethyl halogeno-

substituted-aceto-acetate derivative in the method shown above.

IN

Starting material of formula (II) can be prepared by reacting

a compound of the formula (III) down a halogenating agent such as bromine or chlorine, pyridinium perbromide or copper (I) bromide. The halogenation can preferably be carried out in the presence of an inert solvent such as acetic acid, halogenated hydrocarbons (e.g. carbon tetrachloride, chlorobenzene, etc.).

Further details of the procedure can be found in the examples.

EXAMPLE 1

1.15 g (0.oo5 mol) of 3-acetyl-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine (m.p. 185-186°C) is heated in ml of pyridine in the presence of 1.27 g of iodine on a water bath, after which the reaction mixture is cooled and the precipitated product is filtered off. Thus 1.9 g of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-pyridinium iodide are obtained.

Yield 85%. The melting point of the product is 25o°C (decomposition). Analysis of the formula C^gH^gN^C^I.

Calculated: C 49.67% H 4.17% N 9.65% I 29.15%

Found: C 49.49% H 3.97% N 9.6o% I 29.48%

EXAMPLE 2

A mixture of 1.15 g (0.oo5 mol) 3-acetyl-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine, 1.27 g (0.oo5 mol ) iodine and lo ml a-picoline are heated on a water bath. The precipitation of crystals begins. The reaction mixture is cooled to room temperature and precipitated crystals are filtered off. The melting point of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-(α-picolinium)-iodide is 223-225°C. Analysis of the formula<c>i9H2O<N>3<0>2'I':

Calculated: C 5o.79% H 4.49% N 9.35% I 28.25%

Found: C 51.19% H 4.22 N 9.42% I 28.4o%.

EXAMPLE 3

A mixture of 1.15 g (0.oo5 mol) of 3-acetyl-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine and 1.27 g (0.oo5 mol ) iodine is heated in quinoline on a water bath. The reaction mixture is left at room temperature, after which it is cooled, precipitated crystals

IN

is filtered off and washed with a small amount of 96% alcohol. 1-Ethyl-.7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbon-ylmethylquinolinium iodide melts at 220-221°C.

Analysis of the formula C„_H0 N-.0oI:

222o 3 2

Calculated: C 54.45% H 4.15% N 8.66% I 26.16%

Found: C 54.oo% H 3.96% N 8.52% I 26.2o%

EXAMPLE 4

A mixture of 2.02 g (0.00 mol) of 3-acetyl-7-methyl-4-oxo-1,4-dihydro-1,8 naphthyridine, 100 ml of pyridine and 2.54 g (0.000 mol) iodine is heated in a water bath. The reaction mixture is cooled to room temperature, the mixture remains in a refrigerator overnight. Precipitated crystals are filtered off and washed with pyridine

and ethanol. The melting point of 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-methyl-pyridinium iodide is 26o°C.

Analysis of the formula C^gH-^N^C^I:

Calculated: C 47.19% H 3.47% N lo, 32. I 31.16%

Found: C 47.18% H 3.37% N lo.69 I 3o.49%

EXAMPLE 5

A mixture of 2.o3 g (o.oo5 mol) 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-pyridinium iodide, 4.55 g (o.o25 mol ) triethyl phosphate and o.7 g (o.oo5 mol) potassium carbonate are formed

heated in an oil bath at 22o-225°C. 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-pyridinium iodide which is thus obtained is subjected to further reactions without isolation.

EXAMPLE 6

1 g of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl-methyl-pyridinium iodide is dissolved in 50 ml of water while heating. To the pale yellow solution thus obtained, 2 ml of 70% perchloric acid is added. Soon it is precipitated white product. After cooling the solution, precipitated crystals are filtered off and washed with water and methanol. Thus, 0.92 g of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonylmethyl-pyridinium perchlorate are obtained.

M.p.: 263°C. After recrystallization from methanol, the melting point remains unchanged. '

Analyze the formula: C18H<1>8N<3>°6C1,:

Calculated: C 53.o2% H 4.45% N lo,31% Cl 8.69% Found: C 52.86% H 4.26% N lo,lo% Cl 8.53%

Claims (8)

1. Procedure for the preparation of new 1,8-naphthyridine derivatives of the formula (I) wherein R 3 is hydrogen or C 1 -C alkyl, Y is a tertiary nitrogen-containing aromatic heterocyclic ring attached to the nitrogen atom, or a trialkylamino group, Z is an anion characterized by å) reacting a compound of the formula (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, orb) reacting a compound of the formula (II)' IN! wherein alkyl is as defined above, and X represents halogen, with a tertiary base, or c) reacting a compound of the formula (IV) in the presence of a halogen with an aromatic tertiary base, or a trialkylamine, and, if desired, alkylating the compound of formula (I) thus obtained (wherein R 3 is hydrogen. and, if desired, converting the halide thus obtained into another halide or another pharmaceutical acceptable anion. 2. Method according to claim 1, characterized by carrying out reaction a) or b) or c) at a temperature of 2o - 2oo°C, preferably 8o - 15o°C. 3. Method according to claims 1-2, characterized in that the anion is a halide such as iodide, bromide or chloride or sulphate, phosphate, perchlorate or nitrate. 4. Process according to one of claims 1-3, characterized by using as tertiary base pyridine, quinoline, isoquinoline, alkyl-substituted pyridines, preferably picoline, . inaldin or lepidin, or a trialkylamine, preferably triethylamine. 5. Process according to claim lc), characterized by alkylating a compound of the formula (I), in which R 3 is hydrogen, with an alkyl halide, a dialkyl sulfate or trialkyl phosphate. 6. Process according to claim 5, characterized by using triethyl phosphate as alkylating agent. 7. Pesticides characterized as active ingredients in a compound of formula (I) in mixture with suitable solid or liquid carriers or diluents. 8. Process for the production of pesticides, characterized by mixing a compound of formula (I) with inert, solid or liquid carriers or diluents.