KR790001082B1 - Process for preparing pyrido(3,4-d)pyridazines - Google Patents

Abstract

Pyrido(3,4-d) pyridazines (I; R1 = H, Me, Et; X = halogen atom; R2 = substituted or unsubstitude cyclic amino), useful as diuretics, were prepd. by treating secondary cyclic amines with compd. (II; R3 = H, low alkyl or aralkyl) and then opening reaction of the ether group when R3 = low alkyl or aralkyl.

Description

Manufacturing method of pyrido [3,4-d] pyridazines

The present invention is a general formula

In the formula, R ¹ relates to a method for producing pyrido [3,4-d] pyridazines represented by hydrogen atom or methyl, ethyl group, R ² represents cyclic amino group.

The present inventors have studied variously,

General Formula,

Wherein R ¹ represents the same meaning as described above, X represents a halogen atom, R ³ represents a hydrogen atom, a lower alkyl or an aralkyl group, and the cyclic amine is reacted, and R ³ represents a lower alkyl or In the case where the aralkyl group is shown, the pyrodo [3,4-d] pyridazines (I) and the pyridazines (I) thus prepared are further blown by the cleavage reaction of the ether group. The present invention has been completed based on these findings, as well as exhibiting a strong diuretic effect and being used as an injection excellent in water solubility.

That is, this invention relates to the manufacturing method of the pyridazines (I) which, when reacting a compound (II) and a cyclic amine, and R < ³ > represents a lower alkyl or an aralkyl group, attaches again to the cleavage reaction of an ether group. .

As the lower alkyl group represented by R ¹ in the general formulas (I) and (II), methyl and ethyl are used. As the halogen represented by X in the general formula (II), for example, chlorine, cancellation, oxo and the like are used. . As the cyclic amino represented by R ² , for example, 5- or 6-membered ring having one or more nitrogen atoms such as piperidino, pyrrolidino, and morpholino group is represented. For example, 2-methylmorpholino, 2, 6 The lower alkyl group as described above may be substituted as a substituent, such as -dimethyl morpholino, 2, 3-dimethyl morpholino group, or the like. The cyclic amino groups in the 1st and 4th positions in the pyridazines (I) may be mutually dependent. R < ³ > represents aralkyl groups, such as benzyl and phenethyl, besides showing the lower alkyl group as mentioned above. In addition, an OH group is substituted in the 4th position of the phenyl group of a 7th position.

The raw material compound (II) in the method of the present invention is a general formula

In the formula, R ¹ and R ³ are obtained by halogenating the compound (III) represented by the above. This halogenation reaction is performed by making a halogenating agent act on the compound of General formula (III) in presence or absence of a solvent. As the halogenating agent used for the halogenation of this step, any one may be obtained as long as it is obtained by substituting a halogen atom for the oxo groups of the compounds of the general formula (III), and for example, halogenated pentachloride such as phosphorus pentachloride or pentaphosphate. Phosphorus oxyhalogenated phosphorus, such as phosphorus, phosphorus oxychloride, and oxy embrittlement phosphorus, thionyl halides, such as thionyl chloride, thionyl botomide, thionyl iodide, or a suitable mixture thereof, etc. are used. The usage-amount of these halogenating agents is about 5-20 mol normally with respect to 1 mol of compounds of General formula (III). When the reaction solvent is used in this step, as the solvent, for example, hydrocarbons such as benzene, toluene and hexane, ethers such as diethyl ether and tetrahydrofuran, halogenated carbonization such as chloroform and dichloroethane and hydrocarbons The solvent which does not inhibit this reaction, such as these, is used. In addition, alkalis of lower fatty acids such as tertiary amines such as pyridine, trimethylamine, triethylamine, N, N-dimethylaniline, sodium acetate, and the like are suitable for removing hydrogen halide generated at the time of reaction. Metal, etc.) may coexist in the reaction system as a deoxidizer. There is no restriction | limiting in particular in reaction temperature, It is preferable practically to carry out reaction at normal room temperature to about 130 degreeC. The reaction time is usually about 2-5 hours. The obtained compound (II) can be isolated and purified by a known method such as solvent extraction, liquid conversion, conversion, concentration, reduced pressure concentration, distillation, crystallization, recrystallization, chromatography, and the like. It is used as raw material for the next reaction without separation.

Pyrido [3, 4-d] pyridazines (I) can be manufactured by making compound (II) obtained in this way and cyclic amine react. The reaction proceeds without a solvent, but the reaction can be carried out more smoothly by using a suitable solvent. Examples of the solvent used in the reaction include alcohols such as alcohols such as methyl alcohol and ethyl alcohol, ethers such as tetrahydrofuran and ethyl ether, hydrocarbons such as benzene and chloroform, halogenated hydrocarbons, and ethyl acetate. Esters are used. As for the usage-amount of a cyclic amine, about 2 mol-about 4 mol are normally used as a reaction solvent and a deoxidizer with respect to 1 mol of compounds of General formula (II). The reaction conditions such as reaction temperature and reaction time are not particularly limited. In other words, the reaction proceeds even at room temperature, but may be accelerated by heating to a temperature up to the boiling point of the solvent or cyclic amine, for example. The reaction time varies depending on the type of raw material compound, solvent used, etc., but is usually about 1-5 hours. The target compound represented by the general formula (1) thus produced can be isolated and purified by conventional processing means such as extraction with a suitable solvent (mole, ethyl acetate, benzene, chloroform, ethyl alcohol), recrystallization, column chromatography, and the like. Can be.

Moreover, in the method of this invention, when R <^3> represents lower alkyl or an aralkyl group, General formula obtained by said method.

The compound (IV) represented by [wherein R ¹ and R ² have the same meaning as described above and R ⁴ represents a lower alkyl or an aralkyl group] is added to the cleavage reaction of the ether group.

The method used for the cleavage reaction of the ether group may be any method capable of cleaving the substituent R ⁴ O of the 7th-phenyl group and leading to a hydroxyl group. For example, hydrolysis or reduction is commonly used. When using the method of hydrolysis, it is preferable to hydrolyze compound (IV) in the presence of a suitable catalyst in water or an organic solvent. As the catalyst, for example, inorganic acids such as hydrochloric acid, hydrobromic acid and hydrofluoric acid, organic acids such as trifluoroacetic acid and toluenesulfonic acid, and so-called Lewis acids such as aluminum chloride, boron trichloride, and the like are used. The organic solvent may be any one so long as it does not interfere with the reaction. However, when a liquid catalyst is used, a large excess of catalyst may be used as the solvent. Although the reaction temperature sufficiently reacts even at room temperature, it may be appropriately heated or cooled depending on the nature of the catalyst for the purpose of controlling the reaction rate. Usually, it is performed in the range of -70- + 130 ° C. As a method of reduction, it can carry out by reducing (IV) in water or an organic solvent. It is especially advantageous when R ³ is an aralkyl group. As the reduction method, any method for achieving the purpose may be used, but a mixture of metals such as palladium, platinum and Raney-nickel or carriers such as carbon, carbonate, barium, calcium carbonate and diatomaceous earth, etc. The method by catalytic reduction with hydrogen which uses as a catalyst is advantageous. Although reaction temperature is sufficient as normal room temperature, it is carried out by cooling or warming depending on a case, and the range of 0-100 degreeC is preferable. Although the pressure of hydrogen is sufficient as normal pressure, it is also performed by pressurizing in the range of about 1-150 kg / cm <2>. The target compound (I) thus obtained can be isolated and purified by the conventional treatment means as described above. The objective compound (I) is a general formula

Wherein R ¹ represents the same meaning as described above, R ⁵ represents a lower alkyl, aralkyl or aryl group, n represents 0, 1 or 2, or the cyclic amine as described above Or general formula

Wherein R ¹ and R ² represent the same meaning as described above, and R ⁶ represents an aralkyl or alkyl group. For example, permanganic acid, chromic acid, nitric acid, hydrogen peroxide, oxygen acid, metal complex salt, metal salt, air, It can manufacture by acting an oxidizing agent, such as ozone, nitrobenzene, or its related compound.

The target compound (I) thus obtained may be used as a free sieve with the seventh-position phenolic hydroxyl group, but may be used by forming a salt with a non-toxic cation such as sodium or potassium. The compound (I) may also form salts with organic acids such as hydroxyl, fumaric acid, tartaric acid, nitric acid, and trifuroacetic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. It can also be used as these acid salts.

In addition, the said compound (III) can be manufactured as shown, for example by following formula. That is, compound (V) and N-substituted maleinimide are subjected to diyl alder type addition reaction to compound (VI), followed by treatment with acid or base to form compound (VI), followed by reaction with hydrazine to give compound ( III) can be prepared.

[Wherein R represents an aliphatic group or an aromatic group and R ¹ represents the same significance as above]

In addition, the compound (V) may be used as a raw material instead of the compound (V), and may be produced in the same manner as in the above case. This is shown below.

[Equation, R, R ¹ , R ² , R ³ and X are the same as above]

Alternatively, as shown in the following formula, compound (XV) obtained from compound (XIII) and cyanothioacetamide is desulfurized to give compound (XV), which is then hydrolyzed to obtain (XVI), which dehydrates (XVI). And ring-closing to form compound (X ') and reacting hydrazine with it yield compound (XI), whereby (III) can be produced as described above.

[Wherein R ¹ and R ³ are as defined above and R ⁷ represents a lower alkyl group]

The target compound (I) of the present invention thus obtained has excellent diuretic action, is useful as a medicament such as a diuretic agent, and these compounds are also water-soluble in the basic region and have excellent characteristics in preparation. When used as a medicament, in addition to oral use as tablets, capsules, powders, granules and the like, it may be administered parenterally as an injection. The daily dose is about 10-200 mg for oral administration and about 5-100 mg for parenteral administration.

Next, reference examples and examples of the present invention are given.

Reference Example 1

A mixture of 35 g of 4-hydroxy penicylburomide, 150 ml of formamide and 120 ml of glacial acetic acid was heated at 120-130 ° C. for 6.5 hours, acetic acid was distilled off under reduced pressure, and the residue was poured into 300 ml of ice water to give acetic acid. Extract four times as ethyl. After drying the extract with anhydrous sodium sulfate, ethyl acetate is distilled off to give 4- (4-hydroxyphenyl) oxazole. This product is mixed with 30 g of N-phenylmarine imide, heated to an oil bath phase at 120-130 ° C. for 4 hours, ethanol is added after cooling, and crystals are filtered to give 2- (4-hydroxyphenyl). -N-phenylpyridine-4. 25 g of 5-dicarboxyimide are obtained. Melting point 250-260 ℃

(Dissolve)

Elemental Analysis C ₁₉ H ₁₂ O ₃ N ₂

Calculated C 72.14, H 3.82, N 8.86

Found C 71.82, H 3.71, N 8.40

Reference Example 2

2- (4-hydroxyphenyl) -N-phenylpyridine-4. A mixture of 4 g of 5-dicarboxyimide, 30 ml of glacial acetic acid, and 4 g of catcher hydradine was refluxed for 1 hour, and the precipitates precipitated after cooling were filtered to 7- (4-hydroxyphenyl). 3.2 g of) -1, 2, 3, 4-tetrahydropyrido [3, 4-d] pyridinedine-1, 4-dione are obtained. Melting point over 300 ℃

Elemental Analysis by C ₁₃ H ₉ O ₃ N ₃

Calculated C 61.17, H 3.55, N 16.47

Found C 60.48, H 3.29, N 16.27

Reference Example 3

A mixture of 16 g of ethyl 4- (4-benyloxy) benzoylpyruvate, 6.7 g of cyanorioacetamide, 1 ml of triethylamine and 50 ml of ethanol was refluxed in the aqueous phase for 2 hours. After cooling, the precipitated red defect was filtered off, and washed with ethanol to give 6- (4-benzyloxyphenyl) -3-cyano-4-ethoxycarbonyl-2 [1H] -thiopyridone at a melting point of 155-160 ° C. This 14 g is obtained.

Elemental Analysis C ₂₂ H ₁₈ O ₃ N ₂ S

Theoretical C 67.67, H 4.65, N 7.18

Experimental values C 67.44, H 4.53, N 7.17

Reference Example 4

After stirring 60 g of 6- (4-benzyloxyphenyl) -3-cyano-4-ethoxycarbonyl-2 [1H] -thiopyridone and 1.2 kg of acetone 1.2 liters under reflux for 1 hour, The Ranikel was filtered off, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography. The colorless needles of 6- (4-benzyloxyphenyl) having a melting point of 135-137 占 폚 are obtained. 16 g of) -3-cyano-4-ethoxycarbyl pyridine is obtained.

Elemental Analysis C ₂₂ H ₁₈ O ₃ N ₂

Theoretical C 73.73, H 5.06, N 7.82

Experimental value C 73.81, H 5.01, N 7.63

Reference Example 5

9 g of 6- (4-benzyloxyphenyl) -3-cyano-4-ethoxy carbonyl pyridine and 180 ml of 10% aqueous sodium hydroxide solution were heated to 150-160 for 3 hours in a sealed tube, and the reaction was carried out. Concentrate, acidify with concentrated hydrochloric acid, and precipitate the crystals. After drying, recrystallization from acetic acid, 8.7 g of 6- (4-benzyloxyphenyl) cincomeronic acid with a pale yellow phosphorus crystal having a melting point of 253-255 ° C Obtained.

Elemental Analysis C ₂₀ H ₁₄ O ₅ N

Theoretical C 68.76, H 4.33, N 4.01

Experimental value C 68.30, H 4.29, N 3.84

Reference Example 6

8.0 g of 6- (4-benzyloxyphenyl) shincomeronic acid and 160 ml of acetic anhydride were refluxed for 1 hour, and the insoluble matters were separated on time, and the filtrate was cooled. As a yellow crystal having a melting point of 216-218 ° C, 6- ( 4.7 g of 4-benzyloxyphenyl) cincomeronic anhydride are obtained.

Elemental Analysis C ₂₀ H ₁₂ O ₄ N

Theoretical C 72.50, H 3.96, N 4.23

Experimental value C 72.75, H 3.94, N 3.99

Reference Example 7

6.5 g of 6- (4-benzyloxyphenyl) cincomeric anhydride and 65 ml of 13 ml of catcher hydrazine are added under stirring at reflux for 2 hours. After cooling, the precipitates are filtered by adding water to the reactants, and when washed and dried, they are colorless crystals having a melting point of 300 ° C. or higher, 7- (4-benzyloxyphenyl) -1, 4-dioxo-1, 2, 3, 4-tetra 6.0 g of hydropyrido [3,4-d] pyridazines are obtained.

Elemental Analysis C ₂₀ H ₁₅ O ₃ N ₃

Theoretical C 69.55, H 4.38, N 12.17

Experimental value C 69.27, H 4.16, N 11.83

Reference Example 8

10 g of 7- (4-benzyloxyphenyl) -1, 4-dioxo-1, 2, 3, 4-tetrahydropyrido [3, 4-d] pyridazine, 100 ml of phosphorus oxychloride and 10 ml of α-phycoline The mixture is stirred for 3 hours at 100-110 ° C while stirring. The reaction product was concentrated under reduced pressure, and ice-water was added to the residue to decompose the residue, and the precipitated crystals were filtered off, washed with water, dried and then obtained 7- (4-benzyloxyphenyl) -1,4-dichloropyrido [3, 4-d ] Pyridazine and 50 ml of morpholine are reacted under reflux for 4 hours. The reaction product was concentrated under reduced pressure, and the precipitated crystal was added by adding water to the residue. The crystals were filtered off, washed with water and dried and then recrystallized from a mixed solvent of ethyl acetate-ethanol to give 7- (4-benzyl) as a yellow crystal having a melting point of 206-208 占 폚. 8.5 g of oxyphenyl) -1 and 4-dimorpholinopyrido [3,4-d] pyridazine are obtained.

Elemental Analysis C ₂₈ H ₂₉ O ₃ N ₅

Theoretical C 69.54, H 6.05, N 14..48

Experimental values C 69.54, H 6.09, N 13.94

Example 1

(1) 0.5 g of 7- (4-hydroxyphenyl) -1, 2, 3, 4-tetrahydropyrido [3, 4-d] pyridazine-1, 4-dione, 0.5 ml of α-phycoline, 1,4-dichloro-7- (4-hydroxyphenyl) pyrido [3,4-] which is heated with 5 ml of phosphorus oxychloride at 90-100 ° C. for 3 hours, concentrated under reduced pressure, and precipitated by adding 10 ml of water to the residue. d] 0.4 g of pyridazine is filtered out. The parts are used in the following reactions while being prepared.

(2) 10 g of morpholine was added to 0.4 g of 1,4-dichloro-7- (4-rohydroxyphenyl) pyrido [3,4-d] pyridazine obtained in (1), and the mixture was heated to 130 ° C for 4 hours. Heat. After morpholine was distilled off, 10 ml of water was added to the residue, and the insolubles were filtered off. The residue was purified by silica gel column chromatography (expanded liquid, benzene: acetone = 4: 1) to obtain 7- 0.1 g of (4-hydroxyphenyl) -1,4-dimorpholinopyrido [3,4-d] pyridazine is obtained. Melting Point 285-287 ℃

Elemental Analysis C ₂₁ H ₂₃ O ₃ N ₅

Calculated Value C 64.11, H 5.89, N 17.80

Found C 63.97, H 5.84, N 17.90

Example 2

7 g of 7- (4-benzyloxyphenyl) -1,4-dimorpholinopyrido [3,4-d] pyridazine 7.0 g of tripurouaceous acid 70 ml solution was stirred under reflux for 0.5 hour. The reaction is concentrated under reduced pressure and 50 ml of benzene is added to the residue. The residue is dissolved in 20 ml of methanol, and saturated aqueous sodium hydrogen carbonate is added to precipitate yellow crystals. This was filtered off, washed with water and dried and recrystallized from a mixture of ethyl acetate-methanol. As a pale yellow needle with a melting point of 285-287 ° C, 7- (4-hydroxyphenyl) -1 and 4-dimorpholinopyrido [3, 4] -d] 4.7 g of pyridazine are obtained.

Elemental Analysis C ₂₁ H ₂₃ O ₃ N ₅

Theoretical C 64.11, H 5.89, N 17.80

Experimental values C 63.98, H 5.74, N 17.94

Example 3

1 g of 7- (4-benzyloxyphenyl) -1 and 4-dimorpholinopyrido [3,4-d] pyridazine was dissolved in 20 ml of ethanol, 0.1 g of palladium carbon (10%) was added, and 5 at room temperature. Stir in hydrogen stream. The catalyst was filtered off, the solution was concentrated, and the residue was recrystallized from ethyl acetate-methanol mixture to obtain 7- (4-hydroxyphenyl) -1,4-dimorpholinopyrido [3, 4-d]. 0.5 g of pyridazine is obtained. Melting Point 285-287 ℃

Melting | fusing point drop does not show when it mixes with the brand goods obtained by the method of Example 1.

Example 4

1 g of 7- (4-methoxyphenyl) -1,4-dimorpholino pyrido [3,4-d] pyridazine was dissolved in 10 ml of methylene chloride, cooled to -40 ° C, and 1 g of boron trichloride was methylene chloride. The solution is slowly soaked while stirring with 1 molar solution. After 5 hours, the solvent was distilled off under reduced pressure, the residue was heated under reflux with ethanol for 1 hour, the reaction solution was distilled off, and the residue was recrystallized from a mixture of ethyl acetate-methanol to 7- (4-hydroxyphenyl). 0.5 g of -1,4-dimorpholino pyrido [3,4-d] pyridazine is obtained. Melting point 285-287 ° C. Melting with the standard product obtained in Example 1 does not show a melting point drop.

Example 5

2 g of 7- (4-isopurophyloxyphenyl) -1 and 4-dimorpholino pyrido [3,4-d] pyridazine were added to a mixture of 20 ml of glacial acetic acid and 6 ml of 47% aqueous hydrochloric acid solution, and refluxed for 2 hours. After drying under reduced pressure, the residue is dissolved in 5 ml of methanol and neutralized with saturated sodium carbonate.

20 ml of water was added, followed by extraction with chloroform, and the residue containing the extract was purified by column chromatography on silica gel (developing solution, benzene: acetone-1: 1) to obtain 7- (4-hydroxyphenyl) -1, 0.3 g of 4-dimorpholino pyrido [3,4-d] pyridazine is obtained. Melting point 285-287 ° C. Melting point of the product obtained in Example 1 does not show a melting point drop.

Example 6

0.5 g of a 13 ml solution of 1.3 g of 7- (4-benzyloxyphenyl) -1, 4-bis- (2-methylmorpholino) -pyrido [3, 4-d] -pyridazine and 13 ml of trifuuroacetic acid was refluxed for 0.5 hour. Stir under. The reaction is concentrated under reduced pressure, and 10 ml of benzene is added to the residue. The residue is dissolved in 5 ml of methanol, and saturated aqueous sodium hydrogen carbonate is added to precipitate yellow crystals. This was filtered off, washed with water and dried, and then recrystallized from an ethyl acetate-methanol mixture to give 7- (4-hydroxyphenyl) -1, 4-bis- (2-methylmorpholino)-as a yellow needle at a melting point of 266-268 ° C. 0.6 g of pyrido [3,4-d] pyridazine is obtained

Elemental Analysis C ₂₃ H ₂₇ O ₃ N ₅ 1 / 2H ₂ O

Theoretical C 64.63, H 6.56, N 16.27

Experimental values C 65.11, H 6.33, N 16.11

Example 7

Stir 1.2 g of 7- (4-benzyloxyphenyl) -1,4-dipiperidino pyrido [3,4-d] pyridazine in 12 ml of trifuuroacetic acid solution under reflux for 0.5 hour. The reaction is concentrated under reduced pressure, and 10 ml of benzene is added to the residue. The residue is dissolved in 5 ml of methanol, and saturated aqueous sodium hydrogen carbonate is added to precipitate yellow crystals.

This was filtered off, washed with water and dried, and then recrystallized from an ethyl acetate-methanol mixture. As a yellow powder crystal having a melting point of 300 ° C. or higher, 7- (4-hydroxyphenyl) -1,4-dipiperidino pyrido [3,4-d ] 0.6 g of pyridazine is obtained.

Elemental Analysis C ₂₃ H ₂₇ ON ₅ 1/2 H ₂ O

Theoretical C 69.82, H 7.08, N 17.57

Experimental values C 70.52, H 6.96, N 17.18

Example 8

A 20 ml solution of 2.0 g of 7- (4-benzyloxyphenyl) -8-methyl-1, 4-dimorpholino pyrido [3, 4-d] pyridazine 2.0 g of trifururoacetic acid was refluxed for 40 minutes. Trifluuroacetic acid is distilled off under reduced pressure, 20 ml of benzene is added to the residue, and it is concentrated to dryness. The residue is neutralized with saturated saline solution of sodium hydrogen carbonate and then extracted with chloroform. After drying the extract with anhydrous sodium sulfate, the crude crystals obtained by distilling chloroform were recrystallized from ethanol to give 7- (4-hydroxyphenyl) -8-methyl-1,4-dimorpholino as yellow needles. 1.2 g of pyrido [3,4-d] pyridazine are obtained. Melting point 264-266 ℃

Elemental Analysis C ₂₂ H ₂₅ O ₃ N ₅

Theoretical C 64.85, H 6.18, N 17.19

Found C 64.74, H 6.14, N 17.05

Claims (1)

As described above in the text, when the compound represented by the following general formula (I) is reacted with a cyclic amine, and R ³ represents a lower alkyl or aralkyl group, the general formula is added to the cleavage reaction of the ether group again. Manufacturing method of pyrido [3, 4-d] pyridazines represented by (II)

Wherein R ¹ represents a hydrogen atom or a methylethyl group. X is a halogen atom, R ³ is a hydrogen atom, a lower alkyl or an aralkyl group, R ² represents a cyclic amino group.