KR810000519B1 - Process for preparing substituted 6-phenyl-1,2,4-triazolo (4,3-6) pyridazines - Google Patents

Abstract

Pyridazines (I; R1,R2,R3 = H or C1-3 alkyl; R4 = H, fluoro, chloro, bromo, cyano, CF3, nitro, amino, acetamido, carbamoyl or C1-4 alkyl) were prepd. by reaction of II and H2N-NHCOR3 in lower alkanol solvent. Thus, 10.0 g 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone and 100ml phosphorous reacted with oxychloride for 3 hr to give 3-(p-bromophenyl)-6-chloro-4-methylpyridazine, which was stirred with 0.64 g formylhydrazine for 18 hr to give title compd.

Description

Method for preparing [4,3-b] pyridazine with substituted 6-phenyl-1,2,4-triazol

The present invention relates to novel organic compounds, in particular novel substituted 6-phenyl-1,2,4-triazolo [4,3-b] pyridazines, the structural formula of which is given below.

Wherein R ₁ , R ₂ and R ₃ are each individually selected from the group consisting of hydrogen and alkyl having up to 3 carbon atoms; R ₄ is hydrogen, fluoro, chloro, bromo, cyano, tri Fluoromethyl, nitro, amino, acetamido, carabamoyl, thiocaramamoyl or alkyl with up to 4 carbons; when at least one of R ₁ and R ₂ is hydrogen and R ₁ , R ₂ and R ₃ may not be methyl when R ₄ is all hydrogen, and R ₁ and R ₄ may not be hydrogen when both R ₂ and R ₃ are methyl)

The present invention also relates to new compositions containing said compounds useful as anti-anxiety agents for mammals.

The novel compounds of the present invention are generally obtained as white-pale yellow crystalline materials having specific melting points and absorption spectra, which are refined by recrystallization with conventional organic solvents such as, for example, methanol, ethanol dimethylformamide, acetone, chloroform, ethyl acetate. can do. They are somewhat soluble in nonpolar organic solvents such as toluene and carbon tetrachloride, but relatively insoluble in water.

The organic base of the present invention forms a nontoxic acid addition salt with various pharmacologically acceptable organic and inorganic salt-forming reagents.

Acid addition salts are formed by adding 1-2 equivalents of an acid to an organic free base in a suitable neutral solvent, such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrochloric acid, sulfamic acid, citric acid, lactic acid, ringoic acid, succinic acid, tartaric acid, acetic acid, Such as benzoic acid, gluconic acid, ascorbic acid. Acid addition salts are relatively insoluble in nonpolar organic solvents such as diethyl ether, benzene and toluene, but somewhat soluble in water. Both organic bases and their nontoxic acid addition salts are the target compounds of the present invention.

The novel compounds of the present invention can be prepared according to the following reaction scheme.

Wherein R ₁ , R ₂ , R ₃ and R ₄ are defined as described above.

According to the reaction system, the appropriately substituted 3-benzoyl propionic acid (I) is reacted with the hydrazine hydrate at reflux for 12-24 hours in a lower alkanol solvent for a corresponding 4,5-dihydro-6-phenyl-3 (2H) -pyridazinone (II) is obtained. This 4,5-dihydro-6-phenyl-3 (2H) -pyridazinone (II) was treated with bromine at a bath temperature in a glacial acetic acid for 2-4 hours to give a corresponding 6-phenyl-3 (2H ) -Pyridazinone (III) is obtained. This 6-phenyl-3 (2H) -pyridazinone (III) was treated with excess phosphorus oxychloride at steam bath temperature for 4-8 hours to the corresponding 3-chloro-6-phenylpyridazine (IV). Is switched. Reaction of 3-chloro-6-phenylpyridazine (IV) with acylhydrazine (V) for 24 to 48 hours at reflux in a lower alkanol solvent corresponds to the corresponding 6-phenyl-1,2,4 of the present invention. Triazole gives [4,3-b] pyridazine.

The new compounds of the present invention can also be prepared according to the following reaction scheme.

Wherein R ₁ , R ₂ , R ₃ and R ₄ are defined as described above.

According to this reaction system, the appropriately substituted 3-chloro-6-phenylpyrazine (IV) is reacted with the hydrazine hydrate at reflux for 12-24 hours in a lower alkanol solvent for a corresponding 3-hydrazino-6- Obtain phenylpyridazine (VII). Ring formation of this 3-hydrazino derivative (VII) with a class alkyl alkyl orthoformate yields a compound of formula (VIII) wherein R ₃ is hydrogen. Ring formation of 3-hydrazino derivative (VII) with lower alkanoic anhydride, lower alkanoic acid chloride or ortho ester of lower alkanoic acid affords a compound of formula (IX) wherein R ₃ is lower alkyl. Ring formation can be effected with a base such as pyridine or tri (lower alkyl) amine, with or without a catalyst. Although ring formation using lower alkyl orthoformate and orthoester of lower alkanoic acid is preferably carried out without a catalyst and a solvent, an inert solvent may be used. Ring formation is usually carried out by heating to 50 ° C.-175 ° C. with or without solvent.

The new compounds of the present invention have antihypertensive action at nontoxic doses and are therefore useful as therapeutic agents for hypertension. Pharmacological testing of the compounds revealed that they possess the characteristics described above over a wide range of dosages that reduce blood pressure and toxic symptoms.

Characteristics of hypertension of the compounds of the present invention, when orally administered to mammals, particularly warm animals, were as follows: Conscious and normal blood pressure males, average 250 g, were tied on a board with a string tied on a board. . The thigh was anesthetized (subcutaneously injected with lidocaine), exposing the left or right iliac artery, pressing its center with arterial forceps and threading the end with thread. A short nylon catheter was inserted and tucked in place near the bare spot. The other end of the catheter was attached to a 24-gauge needle attached to a thick polyethylene tubing. The test compound was orally administered to the animals with a Gabbage tube. The compound was tested at 100 mg / kg and suspended or dissolved in 2% aqueous starch solution at 0.2 ml per 100 g of body weight would be the desired dose. Mean arterial blood pressure was taken 4 and 24 hours after compound administration. The results were compared to an average reference pressure of 122 mm Hg, which is the average obtained from experiments over several months. Test results for representative compounds of the present invention are shown in Table 1.

The antisolidification action of the new compounds of the present invention was also carried out using natural hypertensive rats as follows: For about 300 g of male rats (age 16-20 weeks), use or use 0.9% sodium chloride at 0 hours. Instead, the test compound was administered at 100 mg / kg using the Gabbage Toub. Another same dose was administered at 24 hours, at 28 hours to puncture the rat's femoral arteries to measure mean arterial blood pressure.

The results of this test on representative compounds of the present invention are also shown in Table 1.

TABLE 1

Antihypertensive action in rats

As described above, it has been found that the new compounds of the present invention are extremely useful for lowering hypertension in mammals when administered in the range of about 1.0-25.0 mg per day per kilogram of body weight. A more preferred dosage for optimal results is about 5.0-15.0 mg per kg body weight per day, which means that about 0.35-1.0 g of active compound is administered in total for 24 hours to a person weighing about 70 kg. The dosage can be adjusted to obtain the optimum therapeutic effect. For example, the dose may be divided into several doses for the day, or the dose may be proportionally reduced depending on the urgency of the treatment situation. A practical advantage of the present invention is that the active compound may be administered by any convenient method, such as oral administration, intravenous administration, intramuscular administration, subcutaneous administration, and the like.

The new compounds of the present invention have been found to be very useful in relieving strain on mammals when administered in the range of about 0.03-10.0 mg / kg body weight per day. For optimal results a dosage of about 0.1-5.0 mg per kg body weight per day is more preferred, which means that a person weighing about 70 kg body weight of about 7.0 mg-0.35 g of active compound is administered in 24 hours. This dosage may be adjusted for optimal therapeutic effect. For example, the dose may be divided into several doses or the dose may be proportionally reduced depending on the urgency of the treatment situation.

The new compounds of the invention have an action on central nervous tissue at nontoxic doses and are therefore useful as a relaxant. In other words, the compound showed several reactions as a result of standard tests on laboratory animals known to have a good correlation with human relaxation. Pharmacological testing of the compounds has found that they possess these properties at a wide range of dosages that exhibit action on stress and toxic symptoms.

The anti-tension properties of the new compounds of the present invention have been confirmed by tests showing strain relaxation as a measure of protecting the spasm caused by administering pentylenetetrazole. Different levels of dosage of the compounds of the invention were administered orally in at least 5 mice in a 2% starch carrier. At the time calculated as maximal effect, mice were treated intravenously with pentylene tetrazole at a dose of 21-23 mg / kg body weight. This dose is estimated to cause convulsive fainting in 99% of unprotected mice. The effective dose (ED ₅₀ ) of this test compound to protect 50% of animals was calculated. Representative results are listed in Table 2, which compares the results of tests of the same method using chlorodiazepoxide or meprobamate. It is known that there is a high correlation between resistance to rat pentylenetetrazole fainting and anti-strain effects on larger warming animals.

TABLE 2

Protection against convulsive fainting in rats by pentylenetetrazole

Another test was conducted to evaluate the anti-tension effect of the compounds of the present invention. Six rats (200-220 g) were suspended in a 2% starch carrier containing a drop of polyethylene glycol and polysorbate 80 without feeding water for 24 hours or feeding for 24 hours. And those suspended in the test compound in the carrier alone (for reference) were administered orally at various different doses.

At the time of maximal effect, each rat was placed in a plexiglass box. The box is equipped with a drunkometer circuit connected between a stainless steel floor and a stainless steel drinking tube (inserted into a hole in one wall of the box). This dringometer circuit includes a stimulator for supplying a single-phase 60-cycle square wave with a maximum intensity of 0.2 milliamps, a timer for alternating 5 seconds of stimulus-free time and 5 seconds of stimulation time during a 5-minute test, and a stimulus time. It includes a counter that counts the number of stimuli that the rat receives during the day, and a device that causes a half second delay between successive stimuli. After the rats were placed in the box, they were asked to find and drink a 10% glucose solution supplied at the end of the tube. After 20 seconds of drinking without any stimulation, the timer and dringometer circuits were activated to alternate between applying 5 seconds of stimulation and 5 seconds of stimulation.

The number of stimuli the rat receives during the 5-minute test period was recorded. Percentages of rats receiving 9 or more stimuli in 4-5 minutes at each dose level were used as positive responses in calculating the median effective dose (ED ₅₀ ).

The results of this test for representative compounds of the present invention are shown in Table 3.

TABLE 3

Compositions of the present invention having the desired purity, stability and adaptability for parenteral use are obtained by dissolving 0.10-10.0% by weight of the active compound in a carrier consisting of polyhydric chain alcohols or mixtures thereof. Particularly satisfactory carriers are glycerin, propylene glycol, and polyethylene glycol. Polyethylene glycol is composed of a mixture of polyethylene glycols that are soluble in both water and organic liquids and have a molecular weight of about 200-1500 and are nonvolatile. The amount of active compound dissolved in the carrier may vary from 0.10-10.0% by weight, but more preferably 3.0-9.0% by weight of the active compound used. Although various mixtures of the nonvolatile polyethylene glycols described above can be used, mixtures having an average molecular weight of about 200-400 are more preferred.

-글리세롤에테르, 메틸 및 에틸파라벤, 그리고 티메로잘등이 있다. 현실적으로는 산화방지제를 사용하는 것도 편리하다. 적당한 산화 방지제의 예로는, 나트륨 바이설파이트, 나트륨 메타바이설파이트 및 나트륨 포름알데히드 설폭실레이트 등이 있다. 일반적으로 약 0.05-0.20% 농도의 산화방지제를 사용한다.Non-oral solutions can use various preservatives in addition to the active compound to prevent bacterial and fungal infections. Examples of preservatives used for this purpose include myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, P-chlorophenyl-

Glycerol ether, methyl and ethyl parabens, and thimerosal. In reality, it is also convenient to use antioxidants. Examples of suitable antioxidants include sodium bisulfite, sodium metabisulfite and sodium formaldehyde sulfoxylate and the like. Generally, antioxidants at concentrations of about 0.05-0.20% are used.

For intramuscular injection, the preferred concentration of active compound is 0.25-0.50 mg / ml of the final composition. The new compounds of the present invention can be used for intravenous administration when diluted with water or a diluent for treating intravenous veins such as isotonic glucose. For intravenous use, it is recommended to lower the initial concentration to about 0.05-.025 mg / ml of active compound.

The active compounds of the present invention can be administered orally, e.g., with inert diluents or edible incompatible carriers, or wrapped or encapsulated in gelatin capsules or incorporated directly into food. For oral administration, the active compound may be mixed with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, bags and the like. These compositions and preparations should contain at least 0.1% of active compound. The percentage of compositions and preparations may, of course, vary and it is convenient to be about 2-60% of the unit weight. The amount of active compound in such useful compositions should be such that an appropriate dosage will be obtained.

Preferred compositions or preparations of the invention are prepared to contain about 0.1-5.0 mg of active compound per unit of oral administration.

Tablets, pills, capsules and the like may also contain the following ingredients: binders such as gumtragacanth, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Splitting agents such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; Sweetening agents such as sucrose, lactose or saccharin; Perfume, such as peppermint, winter green oil, or peach flavoring, may be added. If the dosage unit is in the form of a capsule, in addition to the substances described above, a liquid carrier such as fatty oil may be added. Various other materials can be used to coat or change the dosage unit to other physical forms. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. Syrups or excipients may include active compounds, sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and fragrances such as peel or orange fragrance. Of course, any material used to make dosage unit forms must be pharmacologically pure and non-toxic in use.

The present invention also relates to a novel substituted 6-phenyl-1,2,4-triazolo [4,3-b] pyrazine useful as an antihypertensive and anti-inhibitory agent, which compound is represented by the following structural formula.

Wherein R ₁ , R ₂ and R ₃ are each individually selected from the group consisting of hydrogen and up to 3 carbon atoms, at least one of R ₁ and R ₂ is hydrogen; substituents R ₄ , R ₅ , R ₆ And two of R ₇ are hydrogen and the other two are fluoro, chloro, bromo, methyl, methoxy, nitro, amino or trifluoro methyl)

These new compounds are prepared by the method described above with one exception, except that

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Is replaced by. For the purposes of the present invention these free bases are comparable to their nontoxic acid addition salts.

The invention will be explained in more detail with reference to the following specific examples.

Example 1

Preparation of [4,3-b] pyridazin-6-yl) benzonitrile with p- (7-methyl-1,2,4-triazol

200 g of p- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile are suspended in 500 ml glacial acetic acid with stirring up at a steam bath temperature and again 56 ml A solution of liquid bromine in another 500 ml acetic acid is added to the stirred mixture at once. After stirring for about 30 minutes, excess bromine and hydrogen bromide are released, causing a severe exothermic reaction. The reaction mixture is diluted with 4 L of distilled water, the resulting solid is filtered, the filter cake is washed well with water and air dried. Recrystallization of this material from a large amount of ethyl alcohol gives the product p- (1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile as a white solid.

45.9 g of the material and 250 ml of phosphorus oxychloride are heated to steam bath temperature for 3 hours. The reaction mixture is slowly added to crushed ice with stirring to decompose excess phosphorus oxychloride. The resulting solid is filtered, washed with water and dried in vacuo. Recrystallization of this material from methyl alcohol gives p- (6-chloro-4-methyl-3-pyridazinyl) benzonitrile.

14.6 g of the compound, 9.4 g of formyl hydrazine and 175 ml of butyl alcohol are stirred at reflux for 18 hours. The reaction mixture is concentrated to remove the solvent, and the concentrate is triturated with petroleum ether and filtered. The filter cake is air dried, the yellow solid is recrystallized twice from methylalcohol and the resulting pale yellow crystals are again recrystallized from methanol to obtain the title compound. Melting Point 240˚-243 ℃

Example 2

Preparation of [4,3-b] pyridazin-6-yl) benzonitrile with p- (3,7-dimethyl-1,2,4-triazol

1.48 g of hydrazine acetate was dissolved in 50 ml of butyl alcohol, and 4.58 g of p- (6-chloro-4-methyl-3-pyridazinyl) benzonitrile (prepared in Example 1) was added for 10 minutes. Heat more while it becomes a complete solution. The solution is heated to reflux for 18 hours. Concentrate the reaction mixture to yield 5.8 g of an orange solid which is washed with petroleum ether. This product is dissolved in 1: 1 ethyl alcohol / acetone and filtered through a silica gel plate. Wash the filter cake sufficiently with acetone and combine the filtrates to give a yellow solid. The solid is dissolved in 100 ml of acetone and the solution is cooled in dry ice-acetone to give a brown solid which is collected by filtration, washed thoroughly with petroleum ether and air dried. This product is dissolved in methyl alcohol, treated with activated charcoal and filtered. Recrystallization using the filtrate yields 1.06 g of a yellowish crystal. 500 mg of this product is recrystallized twice from methanol and the product is dried in vacuo to give the title product.

Melting Point 242˚- 244 ℃

Example 3

Preparation of [4,3-b] pyridazin-6-yl) benzonitrile with p- (3-ethyl-7-methyl-1,2,4-triazol

A mixture of 102.13 g of ethyl propionate 50 g of hydrazine hydrate, 150 ml of ethyl alcohol, and the like is stirred at reflux for 24 hours. The reaction mixture is concentrated to remove the solvent, cooled in ice and stirred with petroleum ether. The resulting white solid is filtered off, washed with petroleum ether and dried in vacuo to give propionic acid hydrazine as white crystalline solid.

Dissolve 30.8 g of the compound in 1 L butyl alcohol, then add 40.0 g of p- (6-chloro-4-methyl-3-pyridazinyl) benzonitrile (prepared in Example 1) and add the reaction mixture for 18 hours. During reflux. The reaction mixture is concentrated to remove the solvent, and the concentrate is triturated with petroleum ether and filtered. Vacuum drying of the filter cake yields a yellow solid, which is recrystallized from methylalcohol again to give the title product.

Melting Point 192˚-195 ℃

Example 4

Preparation of [4,3-b] pyridazin-6-yl) benzonitrile with p- (3-ethyl-7-methyl-1,2,4-triazol

50 ml of ethyl in 4.5 g of p- (3-ethyl-7-methyl-1,2,4-triazol [4,3-b] pyridazin-6-yl) benzonitrile (formulated in Example 3) After dissolving by heating in alcohol, 50 ml of 30% hydrogen peroxide is added by stirring, and 50 ml of 2N sodium hydroxide is added by stirring. Leave for 3 hours at room temperature to allow reaction to occur and concentrate to near dryness using as little heat as possible. The concentrate is diluted with water and filtered, the filter cake is washed with water and air dried. The product is dissolved in acetone, filtered to remove insoluble matters and recrystallized to give the title product as a yellow solid. Melting Point 210˚- 213 ℃

Example 5

Preparation of [4,3-b] pyridazine with 7-methyl-6- (m-nitrophenyl) -1,2,4-triazol

28 g of 3- (m-nitrobenzoyl) butyronitrile are added to 1 L of 6N hydrochloric acid and stirred at reflux for 1 hour using a magnetic stirrer and a heating mantle. The reaction mixture is cooled down and extracted with methylene chloride. The organic layer is separated and extracted with saturated sodium bicarbonate. A drop of sodium bicarbonate was added dropwise to the stirred cold hydrochloric acid solution, and the resulting solid was kept cold in ice, filtered and air dried to yield 27.24 g of 3-m-nitrobenzoyl butyric acid as a white solid. The total amount of the compound is combined with a mixture containing 12.8 ml of 99% hydrazine hydrate in 140 ml of ethyl alcohol and stirred at reflux for 3 hours. After 1/2 hour a solid begins to form. The reaction mixture was cooled in an ice bath, and the resulting solid was filtered and air dried to yield 4,5-dihydro-5-methyl-6- (m-nitrophenyl) -3 (2H) -pyridazinone white to pale yellow. Get into the decision

24.9 g of this substance is dissolved in 200 ml of hot stirred glacial acetic acid, and 6.2 ml of bromine dissolved in 50 ml glacial acetic acid is added dropwise over 15 minutes to release hydrogen bromide gas. The reaction mixture is again heated for 20 minutes to release hydrogen bromide and then the mixture is poured onto crushed ice. The resulting solid was filtered, washed with plenty of water and dried in vacuo to yield 24.2 g of 5-methyl-6- (m-nitrophenyl) -3 (2H) -pyridazinone as a cream solid.

22.7 g of the compound are combined with 230 ml of phosphorus oxychloride and heated in a steam bath for 3 hours. The reaction mixture is poured into crushed ice little by little with stirring. The resulting solid was filtered, washed sufficiently with water and air dried to give 16.6 g of 3-chloro-5-methyl-6- (m-nitrophenyl) pyridazine as a brown solid.

A mixture of 14.97 g of the compound, 7.2 g of formyl hydrazine and 200 ml of butyl alcohol is stirred at reflux for 18 hours. The reaction mixture is tilted to remove insoluble matters and the liquid portion is cooled in an ice bath to yield 13.28 g of brown crystalline solid. This material is dissolved in breaking methyl alcohol and filtered to remove insoluble matter. The filtrate is treated with active charcoal, purified and filtered. The solution is concentrated to a small amount and cooled to afford the title compound as a brown solid. Melting Point 213˚- 218 ℃

Example 6

Preparation of [4,3-b] pyridazine with 6- (m-aminophenyl) -7-methyl-1,2,4-triazol

2.28 g of 7-methyl-6- (m-nitrophenyl) -1,2,4-triazolo [4,3-b] pyridazine (prepared in Example 5), 100 ml of ethyl alcohol and catalytic amount The mixture comprising platinum oxide and the like is shaken under 40 pounds of hydrogen pressure for 1.5 hours. The mixture is filtered to remove the catalyst and the filtrate is concentrated to afford the title compound as a yellow solid. Melting Point 182˚- 186 ℃

Example 7

Preparation of [4,3-b] pyridazine with 6- (P-bromophenyl) -1,2,4-triazol

A mixture of 3.76 g of 3- (P-bromophenyl) -6-chloropyridazine, 1.80 g of formal hydrazine and 50 ml of butylalcohol is heated to reflux and left to reflux overnight. Allow the reaction mixture to cool, then wash the precipitated product with water and air dry to recrystallize from methyl alcohol. Melting Point 209˚ ~ 211 ℃

Example 8

Preparation of [4,3-b] pyridazine with 6- (P-fluorophenyl) -1,2,4-triazol

Into a 3-necked 2-liter flask, 87 g of 6- (P-fluorophenyl) -4,5-dihydro-3 (2H) -pyridazinone and 800 ml of glacial acetic acid were added and stirred in a steam bath. In a dropping funnel, create a solution of 24.1 ml bromine in 100 ml glacial acetic acid. 15 ml bromine solution is added dropwise to the reaction mixture and heated with stirring until the color of the reaction mixture becomes lighter. The rest of the bromine solution is added again with heating and stirring over 30 minutes. The reaction mixture is further heated for 1 hour and poured onto crushed ice. The solid formed is collected by filtration, washed with water and air dried overnight. Drying this material at 65 ° C. yields 82.0 g of 6- (P-fluorophenyl) -3 (2H) -pyridazinone as crystals. Melting Point 265˚ ~ 268 ℃

The entire amount of the compound is combined with 500 ml of phosphorus oxychloride and heated in a steam bath for 5 hours. The reaction mixture is cooled down and excess phosphorus oxychloride is removed using a rotary evaporator followed by addition of 1 L ice-water with stirring. The resulting solid is filtered, washed with water and air dried overnight. The solid is placed in 2 l of chloroform and treated with activated charcoal and filtered through diatomaceous earth. The chloroform filtrate is concentrated to a small amount. The precipitate formed is dilute with filtration, washed with chloroform and air dried to obtain 3-chloro-6- (P-fluorophenyl) pyridazine as pink crystals.

2.5 g of the compound are mixed with 1.46 g formylhydrazine and 40 ml butyl alcohol. The reaction mixture is heated to reflux and refluxed overnight. The reaction mixture is cooled in an ice bath and the precipitated product is collected by filtration, washed with butyl alcohol and dried overnight. Recrystallization of the dried material from methyl alcohol gives the title compound as crystals. Melting Point 197˚ ~ 198 ℃

Example 9

Preparation of [4,3-b] pyridazin-6-yl) benzonitrile with P- (1,2,4-triazolo

86.3 g of 6- (P-bromophenyl) -4,5-dihydro-3 (2H) -pyridazinone is dissolved in 500 ml of glacial acetic acid and heated to 80 ° C. with continued stirring. A solution of 60 g bromine dissolved in 80 ml of acetic acid is added dropwise at 75 DEG C. to 80 DEG C over 1 hour. The solids are separated by the end of the addition. The reaction mixture is heated with stirring in the steam bath for 30 minutes and poured into 3 liters of crushed ice-water.

The white solid formed is collected by filtration and air dried. Recrystallization of the product from ethyl alcohol yields 6- (P-bromophenyl) -3 (2H) -pyridazinone.

A mixture containing 19.20 g of the product and 9.10 g of cyanide first in 70 ml of dimethyl formamide is stirred at reflux for 5.5 hours. During this time, a solid precipitates out. The hot solution is poured into a solution containing 46 ml of ethylenediamine in 230 ml of water. The mixture was stirred at ice bath temperature for 30 minutes, the precipitate was filtered off and washed with water until the wash was colorless and the P- (1,6-dihydro-6-oxo-3-pyridazinyl) benzonitrile turned into a yellow solid. Get

A solution of 3.42 g of the material dissolved in 25 ml of phosphorus oxychloride is stirred and heated to reflux for 3 hours. Most of the excess phosphorus oxychloride is removed under reduced pressure, then crushed ice-water is added to the concentrate and stirred. The solids are recovered by filtration, air dried and recrystallized from dimethylformamide-water to give P- (6-chloro-3-pyridazinyl) benzonitrile as crystals. Melting Point 236˚ ~ 238 ℃

1.00 g of the product, 0.84 g formylhydrazine. The mixture of 25 ml of n-butyl alcohol is stirred at reflux for 17 hours 45 minutes. The solvent is removed under reduced pressure and the residue is triturated with ethyl alcohol. The mixture is filtered and recrystallized from dimethylformamide-water to give [4,3-b] pyridazin-6-yl) benzonitrile as an orange solid with P- (1,2,4-triazol). Melting Point 272˚ ~ 274 ℃

Example 10

Preparation of [4,3-b] pyridazin-6-yl) benzonitrile with m- (7-methyl-1,2,4-triazol

15.0 g of m- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile is suspended in 75 ml of glacial acetic acid with stirring at temperature with steam. Then, 25 ml of acetic acid was added dropwise over 3.75 ml of bromine over 15 minutes. The reaction mixture is again heated in a steam bath for 30 minutes and then poured onto crushed ice. The resulting solid is collected by filtration, washed sufficiently with water and dried to give m- (1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile as a cream solid.

10.0 g of the material and 100 ml of phosphorus oxychloride are heated in a steam bath for 3 hours. The reaction mixture is slowly added to cold water with stirring to break down the phosphorus oxychloride of the fruit. The resulting solid is filtered off and the filter cake is washed thoroughly with water. The product was air dried to give a cream solid of m- (6-chloro-4-methyl-3-pyridazinyl) benzonitrile.

A mixture of 3.0 g of the compound, 1.57 g of formyl hydrazine and 100 ml of butyl alcohol is stirred for 18 hours on a fire. The reaction mixture is cooled in an ice bath and the solid formed is collected by filtration. Recrystallization from methylalcohol yields the title compound as a cream solid. Melting Point 214˚ ~ 216 ℃

Example 11

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-트리플루오로-m-톨릴)-1,2,4-트리아졸로 [4,3-b] 피리다진의 제조3-propyl-6- (

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Preparation of [4,3-b] pyridazine with -trifluoro-m-tolyl) -1,2,4-triazol

112 g of P-toluene sulfonic acid is dissolved in 500 ml of tetrahydrofuran with stirring. Next, 106 g of morpholine is added little by little with stirring. 95.63 g of m-trifluoromethyl benzaldehyde is added and the reaction mixture is stirred at reflux for 2 hours. The reaction mixture is cooled and a solution of 42.2 g of potassium cyanide dissolved in 75 ml of water is added. Allow the mixture to stir at reflux overnight. The reaction mixture is concentrated to remove solvent and the concentrate is partitioned between water and chloroform. The organic layer is washed with saturated sodium bisulfite, dried over magnesium sulfate, treated with activated charcoal and filtered.

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,

,

-트리플루오로-m-톨릴)-4-모르폴린아세토니트릴을 짙은 황색 기름으로 얻는다. 67.0g의 상기 기름을 2ℓ의 테세라하이드로푸란에 실온에서 교반하면서 용해시킨다. 반응액을 혼합물에 5시간에 걸쳐서 에틸 아크릴레이트를 10ml씩 8번, 그리고 에틸 알코홀내의 30% 수산화칼륨 용액을 5ml씩 9번 가하면서 교반을 계속한다. 이 반응은 미세한 발열 반응이다. 반응 혼합물이 실온에서 반새도록 교반되게 한다. 혼합물을 활성 목탄으로 처리하여 여과한다. 여액을 농축하여 용매를 제거하고 톨루엔으로 여러번 스트리핑한다. 농축물을 디에틸에테르와 함께 교반하고 여과하여 불용성물질을 제거한다.When the filtrate is concentrated in vacuo

-(

,

,

-Trifluoro-m-tolyl) -4-morpholine acetonitrile is obtained as a dark yellow oil. 67.0 g of this oil are dissolved in 2 L of tecerahydrofuran with stirring at room temperature. Stirring was continued while adding the reaction solution to the mixture for 5 hours by adding 10 ml of ethyl acrylate 8 times and 5 ml of 30% potassium hydroxide solution in ethyl alcohol 9 times. This reaction is a fine exothermic reaction. Allow the reaction mixture to stir at room temperature. The mixture is filtered by treatment with activated charcoal. The filtrate is concentrated to remove the solvent and stripped several times with toluene. The concentrate is stirred with diethyl ether and filtered to remove insoluble matters.

-시아노-

-(

,

,

-트리플루오로-m-톨릴)-4-모르폴린 부티레이트를 황색 기름으로 얻는다.Concentrate the filtrate to give a yellow oil, which is subjected to chromatography on a 750m × 80m glass column containing chloroform as a solvent and containing silica gel. Stripping the chromatographed material with chloroform leads to 47.0 g of ethyl.

-Cyano-

-(

,

,

Trifluoro-m-tolyl) -4-morpholine butyrate is obtained as a yellow oil.

The total amount of the product is combined with 2 L of ethyl alcohol and 7.3 ml of hydrazine hydrate. The mixture was stirred at reflux for 18 hours, concentrated to remove the solvent to give a yellow oil which was stirred with petroleum ether to give 14.56 g of 4,5-dihydro-6- (α, α, α-trifluoro -m-tolyl) -3 (2H) -pyridazinone is obtained as a white solid.

,

,

-트리플루오로 -m-톨릴)-3(2H)-피리다지논을 크림색 고체로 얻는다.The total amount of the product was dissolved in 225 ml of glacial acetic acid at ambient temperature, and 2.5 ml of a solution of 3.33 ml of bromine in 25 ml of acetic acid was added at room temperature. The reaction mixture was added dropwise with the addition of the remaining bromine-acetic acid solution for 30 minutes. Heat in steam bath. Once the color is completely gone, the reaction mixture is heated in a steam bath for 30 minutes and concentrated to remove solvent. The solid concentrate was washed with water, filtered and air dried.

,

,

-Trifluoro-m-tolyl) -3 (2H) -pyridazinone is obtained as a cream solid.

,

,

-트리플루오로-m-톨릴)피리다진을 크림색 고체로 얻는다.12.55 g of this product and 200 ml of phosphorus oxychloride are heated in a steam bath for 18 hours. The reaction mixture is concentrated to remove with excess phosphorusoxychloride and the concentrate is triturated with cold water. The resulting solid is filtered off and the filter cake is washed with water. When air dried, 3-chloro-6- (

,

,

Trifluoro-m-tolyl) pyridazine is obtained as a cream solid.

A mixture of 6.0 g of the compound, 4.74 g butyric acid hydrazine and 75 ml of butyl alcohol is allowed to stir at reflux for 48 hours. The reaction mixture is concentrated to remove the solvent, the concentrate is placed in ethyl alcohol and treated with activated charcoal and filtered. The filtrate is concentrated to a small amount of residue, cooled in an ice bath to filter the resulting solid to give the title compound as a cream solid. This material is recrystallized from ethyl alcohol and dried in vacuo to give crystals. Melting Point 118˚ ~ 120 ℃

Example 12

Preparation of 3- (7-methyl-1,2,4-triazolo [4,3-b] pyridazin-6-yl) acetanilide

1.5 g of 6- (m-aminophenyl) -7-methyl-1,2,4-triazole was added [4,3-b] pyridazine (prepared as in Example 6) to 30 ml of pyridine at room temperature. Dissolve. 6.0 ml of acetic anhydride is added to this solution, and the reaction mixture is heated in a steam bath for 1 hour. The reaction mixture is cooled by cooling in an ice bath. The filter cake was washed with petroleum ether and dried to afford the title compound as cream colored crystals. Melting Point 298˚ ~ 301 ℃

Example 13

Preparation of [4,3-b] pyridazine with 6- (P-bromophenyl) -7-methyl-1,2,4-triazol

10.0 g of 6- (P-bromophenyl) -5-methyl-3 (2H) -pyridazinone and 100 ml of phosphorus oxychloride are heated in a steam bath for 3 hours. The mixture is added dropwise to cold water with stirring. The resulting solid was filtered and washed with water to give 3- (P-bromophenyl) -6-chloro-4-methylpyridazine as a gray solid.

A mixture of 1.5 g of the compound, 0.64 g of formylhydrazine and 25 ml of butyl alcohol is stirred at reflux for 18 hours. The reaction mixture is cooled in an ice bath and filtered to recrystallize the resulting solid from methylalcohol to yield the title product as a yellow solid. Melting Point 219˚ ~ 222 ℃

Example 14

Preparation of [4,3-b] pyridazin-6-yl) thiobenzamide with P- (7-methyl-1,2,4-triazol

2.1 g of P- (7-methyl-1,2,4-triazol [4,3-b] pyridazin-6-yl) benzonitrile (prepared as in Example 1) was added with 50 ml of pyridine and Partially soluble in a solvent of a mixture of 5.0 ml triethylamine. Emulsified hydrogen gas is passed through the reaction mixture over 3 hours to form bubbles, during which time the color of the reaction mixture changes from yellow to green. About 15 minutes after the start of the addition of the emulsified hydrogen gas, solids begin to form in the reaction mixture. The mixture is filtered to wash the yellow solid with petroleum ether to give the product as a light yellow solid. Melting Point 268˚ ~ 272 ℃

Example 15

Preparation of [4,3-b] pyridazine with 6- (3-bromo-P-methoxyphenyl) -1,2,4-triazol

A suspension containing 100 g of 6- (3-bromo-4-methoxyphenyl) -3 (2H) -pyridazinone in 150 ml of phosphorus oxychloride is refluxed (about 5 hours) until a clear solution is formed. . The solution is cooled and excess phosphorus oxychloride is removed under reduced pressure to give a brown solid which is triturated with ice water. The solid is collected under filtration and recrystallized to give 3- (3-bromo-4-methoxyphenyl) -6-chloropyridazine.

Reflux mixture by heating a mixture of 5.28 g of the compound, 75 ml of butyl alcohol and 2.88 g of formylchidrazine. And reflux overnight. The reaction mixture is cooled to room temperature and the product is collected by filtration. Recrystallization of this material from methyl alcohol gives the title product as crystals. Melting Point 226˚ ~ 228 ℃

Example 16

Preparation of [4,3-b] pyridazine with 6- (P-chlorophenyl) -3-methyl-1,2,4-triazol

47.5 g of 6- (P-chlorophenyl) -4,5-dihydro-3 (2H) -ropyridazinone is dissolved in 250 ml of glacial acetic acid with stirring at 65 ° to 70 ° C. Next, a solution of 14 ml (42 g) bromine dissolved in 50 ml of acetic acid is added in small portions for 20 minutes. The reaction mixture is stirred at 65 ° C. for 3 hours and cooled to 0 ° C. The precipitate is collected and washed with 100 ml of ethyl acetate. The solid is suspended in 500 ml of water, 25 ml of concentrated sodium hydroxide is added and the mixture is stirred at rt overnight. The precipitate is collected, washed with 500 ml of water and dried at 60 ° C. to give 6- (P-chlorophenyl) -3 (2H) -pyridazinone.

A mixture of 34.5 g of the material and 150 ml of phosphorus oxychloride is refluxed for 4 hours. The reaction mixture is cooled and poured on 2 kg of ice.

Leave with occasional stirring for 2 hours, then collect the precipitate and wash with water. The solid is dissolved in 500 ml of boiling benzene, purified with activated charcoal and filtered. The filtrate is cooled to room temperature, the solid collected, washed with a small amount of benzene and air dried. After treatment with activated charcoal the material is recrystallized from ethylalcohol. The product was collected and washed sequentially with ethyl alcohol and ether to give 3-chloro-6- (P-chlorophenyl) pyridazine. Melting Point 209˚ ~ 211 ℃

A mixture of 10.0 g of the product, 6.6 g of hydrazine hydrate and 150 ml of butyl alcohol was refluxed overnight. The reaction mixture is cooled and filtered, and the solid is washed sequentially with butyl alcohol and water. The butyl alcohol filtrate is concentrated on a rotary evaporator to give further crystalline product, which is washed sequentially with butyl alcohol and water. These materials are combined to give 6- (P-chlorophenyl) -3-hydrazinopyridazine. Melting Point 156˚ ~ 160 ℃

A mixture of 0.6 g of the material, 140 ml of P-dioxane and 4.64 g of diisopropylethylamine is heated until solution. The solution is cooled to near room temperature and 2.66 g of acetyl chloride is added. The reaction mixture is cooled in an ice bath and allowed to stir overnight. The solvent is removed under reduced pressure and ethyl alcohol is added to the residue. Heating the flask precipitates a solid. Removal of this material by filtration and further concentration of ethanol affords the title product. Melting Point 208˚ ~ 210 ℃

Example 17

Preparation of [4,3-b] pyridazine with 6- (P-chlorophenyl) -8-methyl-1,2,4-triazol

Carefully add 270 g of aluminum chloride to a solution of 114 g of methylsuccinic anhydride in 400 ml of chlorobenzene. The mixture is heated to 65 ° C. for 1.5 h, cooled, quenched with ice and concentrated hydrochloric acid and extracted with benzene. The benzene layer is extracted with an aqueous sodium bicarbonate solution. Adjust the pH of the sodium bicarbonate solution to 6.3, then slowly add concentrated hydrochloric acid, stirring for several hours.

At pH 5.7, 78 g of white crystals are filtered out. Recrystallization of this material from ethanol-water gives 3- (P-chlorobenzoyl) -2-methylpropionic acid as white crystals. A mixture of 35.50 g of the compound, 85 ml of hydrazine hydrate and 400 ml of ethyl alcohol was allowed to stir at reflux for 18 hours. The reaction mixture is concentrated to 75% of its original volume, cooled in an ice bath and filtered to give 26.62 g of 6- (P-chlorophenyl) -4,5-dihydro-4-methyl-3 (2H)- Pyridazinone is obtained as a yellow solid. More 4.7 g of product is obtained from the filtrate.

The products are combined (31.32 g) and dissolved in 250 ml of glacial acetic acid with stirring at room temperature. 8.2 ml of liquid bromine is dissolved in 50 ml of glacial acetic acid and 25% of this solution is added to the reaction mixture. Raise the temperature of the reaction mixture until no color is due to bromine. The remaining bromine solution is added over 20 minutes with heating. The reaction mixture is again heated in a steam bath for 1/2 hour and diluted with ice water. The resulting solid was filtered, washed with water and air dried to afford 6- (P-chlorophenyl) -4-methyl-3 (2H) -pyridazinone as a cream solid.

15.0 g of the compound and 200 ml of phosphorus oxychloride are heated in a steam bath for 18 hours. The mixture is concentrated to remove the solvent and the concentrate is stirred with cold water. The precipitate is filtered off and the solid is washed with water to give 3-chloro-6- (P-chlorophenyl) -4-methylpyridazine as a pink solid.

2.0 g of the compound are mixed with 1.08 g formylhydrazine and 60 ml butyl alcohol. The mixture is refluxed for 48 hours. The reaction mixture is cooled in an ice bath, the resulting solid is filtered off, washed with petroleum ether and air dried to give a brown solid. Treatment with activated charcoal and then recrystallization from methylalcohol yields the title compound as white crystals. Melting Point 230˚ ~ 233 ℃

Example 18

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로 [4,3-b] 피리다진의 제조3-methyl-6- (

,

,

Preparation of [4,3-b] pyridazine with -trifluoro-m-tolyl) -1,2,4-triazol

,

,

-트리플루오로-m-톨릴) 피리다진(실시예 11에서와 같이 제조됨), 3.44g의 아세틸히드라진 및 75ml의 n-부틸알콜을 48시간 동안 환류 시킨다. 용매를 진공하에 제거하고, 잔여물을 에틸 알코홀에 용해하여 활성 목탄으로 처리한다. 여액을 농축하여 냉각하고 여과하면 오랜지색 고체를 얻는다. 메틸알코홀로부터 재결정시키면 표제의 생성물을 결정으로 얻는다. 융점 193˚~ 194℃6.0 g 4-chloro-6- (

,

,

-Trifluoro-m-tolyl) pyridazine (prepared as in Example 11), 3.44 g of acetylhydrazine and 75 ml of n-butyl alcohol are refluxed for 48 hours. The solvent is removed in vacuo and the residue is dissolved in ethyl alcohol and treated with activated charcoal. The filtrate is concentrated, cooled and filtered to give an orange solid. Recrystallization from methylalcohol yields the title product as crystals. Melting Point 193˚ ~ 194 ℃

Example 19

Preparation of [4,3-b] pyridazine with 6- (P-chlorophenyl) -1,2,4-triazol

A mixture of 9.0 g 3-chloro-6- (P-chlorophenyl) -pyridazine (prepared as in Example 6), 5.1 g formylhydrazine and 60 ml butylalcohol was refluxed for 40 hours. Heat. The reaction mixture is cooled and filtered and the solid is washed with petroleum ether and water. The material is heated with 125 ml of ethanol and the insoluble material is collected by filtration. Cool the filtrate and collect the precipitate and combine with the insoluble material. Recrystallization of the mixed solid from 130 ml of ethyl alcohol gives the title product as crystals. Melting Point 216˚ ~ 218 ℃

Example 20

,

,

-트리플루오로-m-톨릴) 피리다진(실시예 11에서와 같이 제조됨), 2.78g의 포르밀 히드라진 및 75ml의 부틸알코홀로 된 혼합물을 48시간 동안 환류로 교반되게 한다. 반응 혼합물을 농촉하여 용매를 제거하고, 잔여물을 에틸 알코홀에 용해 하여 활성 목탄으로 처리한 다음 여과한다. 여액을 얼음조내에서 냉각하고 크림색 고체를 수집한다. 고체를 디에틸에테르와 함께 가열하고 혼합물을 여과한다. 고체를 초산에틸로부터 재결정시키면 표제의 화합물을 크림색 결정으로 얻는다.6.0 g 3-chloro-6- (

,

,

A mixture of -trifluoro-m-tolyl) pyridazine (prepared as in Example 11), 2.78 g of formyl hydrazine and 75 ml of butylalcohol is allowed to stir at reflux for 48 hours. The reaction mixture is concentrated to remove the solvent, the residue is dissolved in ethyl alcohol, treated with activated charcoal and then filtered. The filtrate is cooled in an ice bath and the cream solid is collected. The solid is heated with diethyl ether and the mixture is filtered. Recrystallization of the solid from ethyl acetate gives the title compound as cream colored crystals.

Melting Point 140˚ ~ 143 ℃

Example 21

Preparation of [4,3-b] pyridazine with 6- (P-chlorophenyl) -3-ethyl-1,2,4-triazol

A mixture of 9.0 g 3-chloro-6- (P-chlorophenyl) -pyridazine (prepared as in Example 16), 7.4 g propionic acid hydrazine and 60 ml butyl alcohol was stirred at reflux for 48 hours do. The mixture is cooled and filtered, and the solid is washed with petroleum ether and water. Recrystallization of this material from 50 ml of ethyl alcohol gives the title product as crystals. Melting Point 197˚ ~ 199 ℃

Example 22

Preparation of [4,3-b] pyridazine with 6- (P-fluorophenyl) -3-methyl-1,2,4-triazol

A mixture of 6.25 g 3-chloro-6- (P-fluorophenyl) pyridazine (prepared as in Example 8), 4.65 g acetylhydrazine and 50 ml butyl alcohol was refluxed until a clear solution. . The reaction mixture is cooled and filtered, and the solid precipitate is washed with hexanes and water. The solid is recrystallized from 50 ml of ethyl alcohol to give the title product as crystals. Melting Point 227˚ ~ 229 ℃

Example 23

Preparation of [4,3-b] pyridazine with 3-methyl-6- (m-nitrophenyl) -1,2,4-triazol

A mixture of 9.9 g of 6- (m-nitrophenyl) -4.5-dihydro-3-pyridazine and 80 ml of glacial acetic acid was stirred and heated in a steam bath, followed by a solution of 2.41 ml of bromine dissolved in 10 ml of glacial acetic acid. Was added dropwise over 30 minutes. Continue heating and stirring for 45 more minutes and pour the reaction mixture onto crushed ice. The crystalline product is filtered off and washed with water. Obtain an approximate amount of 6- (m-nitrophenyl) -3-pyridazone. Melting point 275 ℃

A mixture of 6 g of this product and 35 ml of phosphorus oxychloride is heated in a steam bath for 4 hours and concentrated to remove excess POCl ₃ . The residue is poured into ice water, the insoluble solid is filtered off, washed with water and air dried. The product is dissolved in chloroform and purified by treatment with cyclic carbon. Concentration of the chloroform solution yields 4.0 g of 3-chloro-6- (m-nitrophenyl) pyridazine. Melting Point 206˚ ~ 208 ℃

A mixture of 3.0 g of the compound, 2.0 g of acetylhydrazine and 30 ml of butanol is heated to reflux for 72 hours and then cooled. The precipitate is filtered off, washed with hexane and water and air dried. The product is boiled with 100 ml of 95% ethyl alcohol and filtered. Insoluble matter is 3-methyl-6- (m-nitrophenyl) -1,2,4-triazol [4,3-d] pyridazine. Melting Point 241˚ ~ 243 ℃

Example 24

Preparation of [4,3-b] pyridazine with 6- (m-nitrophenyl) -1,2,4-triazol

Use of formyl hydrazine in place of acetylhydrazine in Example 23 affords the title product. Melting Point 231˚ ~ 233 ℃

Example 25

Preparation of [4,3-b] pyridazine with 6- (m-aminophenyl) -3-methyl-1,2,4-triazol

5.1 g of 3-methyl-6- (m-nitrophenyl) -1,2,4-triazolo [4,3-b] pyridazine (prepared as in Example 23), 60 ml of trifluoro acetic acid And a mixture of 0.9 g of 10% palladium on carbon catalyst and the like under hydrogen pressure of about 35 pounds of hydrogen pressure. The catalyst is filtered off and the reaction mixture is concentrated. The residue is dissolved in water and the pH is adjusted to 5 by addition of 5N NaOH. The insoluble material is filtered off and washed with water to give [4,3-b] pyridazine with 6- (m-aminophenyl) -3-methyl-1,2,4-triazole. Melting Point 193 ℃

Example 26

Preparation of [4,3-b] pyridazine with 6- (m-aminophenyl) -1,2,4-triazol

Reduction of [4,3-b] pyridazine (prepared as in Example 24) with 6- (m-nitrophenyl) -1,2,4-triazole in the manner of Example 25 affords the title compound . Melting point 225 ℃

Example 27

Preparation of [4,3-b] pyridazine with 6- (m-acetamidophenyl) -1,2,4-triazol

A mixture of 1.0 g of 6- (m-aminophenyl) -1,2,4-triazole with [4,3-b] pyridazine (prepared as in Example 26) and 4 ml of acetic anhydride at room temperature Leave for 2 hours, then triturated with ether and filtered. Recrystallization of the insoluble material from ethylalcohol yields [4,3-b] pyridazine as yellow crystals with 6- (m-acetamidophenyl) -1,2,4-triazole. Melting Point 248˚ ~ 250 ℃

Example 28

Preparation of [4,3-b] pyridazine with 6- (m-acetamidophenyl) -3-methyl-1,2,4-triazol

6- (m-aminophenyl) -3-methyl-1,2,4-triazol [4,3-b] pyridazine (prepared as in Example 25) was prepared as in Example 27 with acetic anhydride. Reaction gives the title compound.

Example 29

Preparation of 3-methyl-6- (P-tert-butylphenyl) -1,2,4-triazole- [4,3-b] pyridazine

A mixture of 16.5 g of 3-P-tert-butylbenzoyl propionic acid and 8.25 ml of hydrazine hydrate is dissolved in 140 ml of anhydrous ethyl alcohol. The clear solution is stirred for 4 hours under reduced pressure and cooled overnight. The product was recovered, washed with ethyl alcohol and dried in vacuo to afford 13.1 g of 6- (P-tert-butylphenyl) -4.5-dihydro-3 (2H) -pyrazazinone as a white solid.

8.00 g of the above substance was added to 80 ml of glacial acetic acid, and while stirring, a solution of 5.82 g of bromine dissolved in 20 ml of glacial acetic acid was added dropwise. Decolorization occurs when the reaction mixture is heated to about 100 ° C. Add bromine / acetic acid solution as quickly as decolorization is completed in about 15 minutes. The mixture is stirred at 100 ° C. for 1 hour and then poured onto 150 ml of ice. The white solid formed is collected by filtration and dissolved in 400 ml of acetone. The acetone solution is dried over magnesium sulfate and concentrated with dilute hexane. Recrystallization from about 100 ml of acetone / hexane yields 4.82 g of 6- (P-tert-butylphenyl) -3 (2H) -pyridazinone as a pale yellow solid.

A mixture of 22.8 g of the compound and 115 ml of phosphorus oxychloride is heated in a steam bath until it becomes a clear solution. The solution is heated for 5 hours and then concentrated in vacuo. The residue is treated with ice water and the resulting solid is recovered and dried in vacuo to give 22.0 g of 3- (P-tert-butylphenyl) -6-chloropyridazine as a light gray solid.

A mixture of 5.0 g of 3- (P-tert-butylphenyl) -6-chloropyridazine, 3.13 g of acetylhydrazine and 50 ml of n-butanol is refluxed for 48 hours. The mixture is concentrated in vacuo and the residue is stirred with 100 ml of water and 100 ml of ether. Filtration of the mixture gave 3.0 g of a brown solid. Melting point 144 ° -146 ° C Recrystallization from acetone / hexane affords the title compound as pale yellow crystals. Melting Point 142˚ ~ 145 ℃

Example 30

Preparation of [4,3-b] pyridazine with 6- (P-tert-butylphenyl) -1,2,4-triazol

A mixture of 5.0 g of 3- (P-tert-butylphenyl) -6-chloropyridazine 2.54 g of formylhydrazine and 50 ml of n-butyl alcohol was stirred under reflux for 48 hours. Cool the mixture and filter. The solid is washed with petroleum ether and water and dried in vacuo to yield 0.80 g of product. The filtrate was concentrated in vacuo below 80 ° C. to yield more product, which was stirred with 150 ml of water and 150 ml of diethyl ether, collected by filtration and dried in vacuo to yield 3.0 g of an orange solid. Recrystallization from ethyl alcohol gives the title compound as light gray crystals. Melting Point 270˚ ~ 275 ℃

Example 31

Preparation of 50mg Tablets

[4,3-b] pyridazine, lactose and corn starch (for mixing) are mixed together with 3-methyl-6- (m-acetamidophenyl) -1,2,4-triazol. Corn starch (adhesive) is suspended in 600 ml of water and heated with stirring to form a pool. This paste is used to turn the mixed powder into particles. If necessary, add more water. The wet particles are passed through eight batches and dried at 120 ° F. Dry particles are passed through 16 houses. The mixture is lubricated with 1% magnesium stearate and tablets are made with a suitable purification machine.

Example 32

Preparation of Oral Suspension

ingredient

The sorbitol solution is added to 40 ml of distilled water and [4,3-b] pyridazine is suspended in 3-ethyl-6- (p-carbamoylphenyl) -1,2,4-triazole. Saccharin, sodium benzoate, flavors and dyes are added to dissolve. Distilled water is added to make the volume 100 ml. 5 mg of 3-ethyl-6- (p-carabamoylphenyl) -1,2,4-triazol contains [4,3-b] pyridazine per 1 ml of this syrup.

Example 33

Preparation of Parenteral Solutions

In a solution of 700 ml of propylene glycol and 200 ml of water (injectable), 20.0 g of 3,7-dimethyl-6- (p-aminophenyl) -1,2,4-triazol [4,3-b] Pyridazine monohydrochloride is suspended with stirring. Once the suspension is complete, the pH is adjusted to 5.5 with hydrochloric acid and the volume is added to a volume of 1000 ml. The preparation is sterilized and filled into 5.0 ml ampoules each containing 2.0 ml (each ampoule contains 40 mg of medicine) and sealed under nitrogen.

Example 34

Preparation of [4,3-b] pyridazine with 6- (p-chlorophenyl) -3.8-dimethyl-1,2,4-triazol

A mixture of 1.0 g of 3-chloro-6- (p-chlorophenyl) -4-methylpyridazine, 0.62 g of hydrazine acetate and 10 ml of n-butanol is held for 48 hours. The solvent is removed and the residue is dissolved in dichloromethane and filtered through magnesium. Recrystallization of the solid from the filtrate from dichloromethane-hexanes yields 0.6 g of solids. Melting point 209 ° to 212 ° C. Recrystallization from dichloromethane-hexanes gives the title product as light pink crystals. Melting Point 215˚ ~ 217 ℃

Example 35

,

,

-트리플루오로-p-톨릴)-1,2,4-트리아졸로 [4,3-b] 피리다진의 제조(6-

,

,

Preparation of [4,3-b] pyridazine with -trifluoro-p-tolyl) -1,2,4-triazol

-(

,

,

-트리플루오로-p-톨릴)-4-모르폴린아세토니트릴을 갈색고체로 얻는다. 융점 89˚~ 90℃69.5 g of morpholine is added while cooling a solution of 76.0 g of p-toluenesulfonic acid in 400 ml of tetrahydrofuran in an ice bath. The cooling bath is removed and 65.0 g of p-trifluoromethyl benzaldehyde is added when the ambient temperature is reached and again heated to reflux for 2 hours. The reaction mixture is cooled in an ice bath, a solution of 32.6 g of potassium cyanide dissolved in 55 ml of water is added and then heated to reflux for 18 hours. Solvent is removed and the residue is partitioned between chloroform and water. The organic layer was washed with water, saturated sodium bisulfite and saturated sodium chloride solution, dried and evaporated

-(

,

,

Trifluoro-p-tolyl) -4-morpholine acetonitrile is obtained as a brown solid. Melting Point 89˚ ~ 90 ℃

-(

,

,

-트리플루오로-p-톨릴)-4-모르폴린아세토니트릴이 용해된 용액을 주위온도에서 교반하면서, 1ml의 30% 에타놀내 수산화칼륨 및 25ml의 에틸 아크릴레이트를 반시간마다 가하여 전체적으로 5ml의 염기 및 150ml의 에틸아크릴레이트를 가한다. 다음에 혼합물을 주위온도로 48시간동안 교반한다. 여과한 다음 여액을 농축시켜서 염화메틸렌에 용해시키고, 마그네슘을통과시킨 다음 염화메틸렌/헥산으로부터 재결정시키면 에틸

-시아노-

(

,

,

-트리플루오로-p-톨릴)-4-모르폴린 부티레이트를 크림색결정으로 얻는다. 융점 96˚~ 97℃52.3 g in 500 ml dry tetrahydrofuran

-(

,

,

A solution of -trifluoro-p-tolyl) -4-morpholine acetonitrile was stirred at ambient temperature with 5 ml of base in total, adding potassium hydroxide and 25 ml of ethyl acrylate in 1 ml of 30% ethanol every half hour. And 150 ml of ethyl acrylate are added. The mixture is then stirred for 48 hours at ambient temperature. After filtration, the filtrate was concentrated to dissolve in methylene chloride, passed through magnesium, and recrystallized from methylene chloride / hexane.

-Cyano-

(

,

,

-Trifluoro-p-tolyl) -4-morpholine butyrate is obtained as cream colored crystals. Melting Point 96˚ ~ 97 ℃

,

,

-트리플루오로-p-톨릴)-4,5-디하이드로-3(2H)-피리다지논을 크림색 결정으로 얻는다. 융점 177˚~ 178℃A solution consisting of 38.0 g of the compound, 9.0 g hydrazine hydrate and 600 ml ethanol was refluxed for 24 hours. The solution is treated with activated charcoal and filtered to concentrate the filtrate. The residue was determined from methylene chloride / hexanes to give 6- (

,

,

-Trifluoro-p-tolyl) -4,5-dihydro-3 (2H) -pyridazinone is obtained as cream colored crystals. Melting Point 177˚ ~ 178 ℃

,

,

-트리플루오로-p-톨릴) -3(2H)피리다지논을 연한 회색 결정으로 얻는다. 융점 191˚~ 193℃A solution in which 14.5 g of the compound 10.4 g of bromine is dissolved in 150 ml of acetic acid is slowly heated in a steam bath until completely discolored. Heat for 30 minutes, then pour into crushed ice. Filter the resulting solid and wash it with water.

,

,

-Trifluoro-p-tolyl) -3 (2H) pyridazinone is obtained as light gray crystals. Melting Point 191˚ ~ 193 ℃

,

,

-트리플루오로-p-톨릴)피리다진을 백색 고체로 얻는다. 융점 186˚~ 188℃A mixture of 11.0 g of the compound and 150 ml of phosphorus oxychloride is heated in a steam bath for 5 hours. The solution is concentrated to remove the solvent, and the residue is washed with cold water, 3-chloro-6- (

,

,

Trifluoro-p-tolyl) pyridazine is obtained as a white solid. Melting Point 186˚ ~ 188 ℃

,

,

-트리플루오로-p-톨릴)피리다진, 2.09g의 포리밀히드라진 및 100ml n-의부타놀로된 혼합물을 교반하고 3일동안 환류시킨다. 용매를 제거하고, 잔여물을 염화메틸렌에 용해하여 마그네솔을 통과 시킨다음, 여액으로 부터의 고체를 염화메틸렌/헥산으로부터 재결정시키면 생성물을 백색 결정으로 얻는다. 융점 160˚~ 161℃4.50 g of 3-chloro-6- (

,

,

A mixture of -trifluoro-p-tolyl) pyridazine, 2.09 g of polymyridazine and 100 ml n-butanol is stirred and refluxed for 3 days. The solvent is removed, the residue is dissolved in methylene chloride and passed through magnesol, and the solid from the filtrate is recrystallized from methylene chloride / hexane to give the product as white crystals. Melting Point 160˚ ~ 161 ℃

Example 36

,

,

-트리플루오로-p-톨릴)-1,2,4-트리아졸로 [4,3-b] 피리다진의 제조3-methyl-6- (

,

,

Preparation of [4,3-b] pyridazine with -trifluoro-p-tolyl) -1,2,4-triazol

,

,

-트리플루오로-p-톨릴)피리다진 2.58g의 아세트히드라진 및 100ml의 n-부타놀로된 혼합물을 환류온도로 3일동안 가열한다.4.50 g of 3-chloro-6- (

,

,

A mixture of 2.58 g of acethydrazine and 100 ml of n-butanol is heated to reflux for 3 days -trifluoro-p-tolyl) pyridazine.

The solvent is removed and the residue is dissolved in ethylene chloride and passed through magnesol and the solid from the filtrate is recrystallized from methylene chloride / hexanes to give the product as brown crystals. Melting Point 199˚ ~ 201 ℃

Example 37

-(m-클로로페닐)-4-모르폴린 아세토니트릴의 제조

Preparation of-(m-chlorophenyl) -4-morpholine acetonitrile

To a cold solution of 76 g of p-toluenesulfonic acid in 500 ml of tetrahydrofuran are added 87 g of morpholine and 50.6 g of m-chlorobenzaldehyde. The mixture is refluxed for 2.5 hours, 100 ml of tetrahydroputane is distilled off, the mixture is cooled and a solution of 28.6 g of KCN dissolved in 100 ml of water is added. The mixture is refluxed for 5 hours, concentrated to dryness in vacuo. The residue is dissolved in methylene chloride and the solution is washed with sodium bisulfite solution, saturated NaCl solution and dried (Na ₂ So ₄ ). The solution is passed through a short column of hydrated magnesium silicate. The crystals are separated by adding hexane while refluxing the eluate. Incidence and filtration give 78.0 g of crystals. Melting Point 72˚ ~ 73 ℃

Example 38

Preparation of 3- (m-chlorobenzoyl) propionitrile

-(m-클로로페닐)-4-모르폴린아세토니트릴이 용해된 용액에, 메타놀내의 30% KOH 용액을 120방울 가한다. 혼합물에 4.1ml의 아클릴로니트릴을 가한다. (온도가 45℃로 오른다) 1시간동안 교반한 다음에 혼합물을 진공 건조하여 농축 시킨다. 잔여물을 염화메틸렌에 용해시키고 짧은 컬럼의 수화 마그네슘 실리케이트에 통과 시킨다.23.6 g in 100 ml tetrahydrofuran

To the solution in which-(m-chlorophenyl) -4-morpholine acetonitrile is dissolved, 120 drops of a 30% KOH solution in methanol are added. 4.1 ml of acrylonitrile is added to the mixture. After stirring for 1 hour, the mixture is concentrated to dryness in vacuo. The residue is dissolved in methylene chloride and passed through a short column of hydrated magnesium silicate.

Vacuuming the eluate yields 36.6 g of yellow oil. This oil is heated with 150 ml of acetic acid and 10 ml of water for 1 hour (steam bath). The solvent is removed in vacuo and the residue is treated with water. Filtration of the mixture gave 18.8 g of crystals. Melting Point 49˚ ~ 51 ℃

Example 39

3- (m-chlorobenzoyl) -2-methylpropionitrile

-(m-클로로페닐)-4-모르폴린아세토니트릴이 용해된 용액에, 메타놀내의 30% KOH 용액을 60방울 가한다. 이 용액에 4.62ml의 메타크릴로니로릴을 가한다. (온도가 42℃로 오른다)11.8 g in 50 ml tetrahydrofuran

To a solution in which-(m-chlorophenyl) -4-morpholine acetonitrile is dissolved, 60 drops of a 30% KOH solution in methanol are added. To this solution is added 4.62 ml of methacrylonitrile. (The temperature rises to 42 degrees Celsius)

After stirring for 1 hour, the mixture is dried to concentrate and the residue is dissolved in methylene chloride. The solution is passed through a short column of hydrated magnesium silicate and the eluate is concentrated to give 15.5 g of yellow oil. This oil is heated with 75 ml of acetic acid and 5 ml of water for 1 hour (steam bath). The solvent is dried in vacuo and water is added to the residue to give 11.2 g of crystals. Melting point 72˚-75 ℃. Recrystallization from methylene chloride-hexane yields 8.95 g of crystals. Melting Point 79.5˚ ~ 80.5 ℃

Example 40

Preparation of 3- (m-chlorobenzoyl) -2-methylpropionic acid

A mixture of 7.90 g of 3- (m-chlorobenzoyl) -2-methylpropionitrile and 75 ml of concentrated hydrochloric acid is refluxed for 1 hour. Cooling gives 8.5 g of crystals. Melting Point 102˚ ~ 105 ℃

The crystals are dissolved in 50 ml of 1N NaOH, the admixture is filtered and the filtrate is acidified with 1N HCl. Filtration yields 8.15 g of crystals. Melting Point 103˚ ~ 105 ℃

Example 41

Preparation of 6- (m-chlorophenyl) -4,5-dihydro-4-methyl-3 (2H) pyridazinone

A mixture of 7.11 g of 3- (m-chlorobenzoyl) -2-methylpropionic acid, 50 ml of ethanol and 3.0 ml of hydrazine hydrate is refluxed for 2 hours. Cooling and filtration give crystals (melting point 150 ° -151 ° C.), which is recrystallized from ethanol to give 5.72 g of crystals. Melting Point 152˚ ~ 153 ℃

Example 42

Preparation of 3- (m-chlorobenzoyl) propionic acid

A mixture of 8.1 g of 3- (m-chlorobenzoyl) propionitrile and 80 ml of concentrated hydrochloric acid is refluxed for 7 hours. Cooling yields oil, which when determined yields 8.8 g of crystals. Melting Point 105˚ ~ 107 ℃

The crystals are dissolved in 1N NaOH and the mixture is filtered.

Acidification of the filtrate with 1N HCl afforded 8.7 g of crystals. Melting Point 103˚ ~ 105 ℃

Example 43

Preparation of 6- (m-chlorophenyl) -4-methyl-3 (2H) pyridazinone

A solution of 4.66 g of 6- (m-chlorophenyl) -4,5-dihydro-4-methyl) -3 (2H) pyridazinone dissolved in 60 ml of glacial acetic acid was heated in a steam bath, and added to 5 ml of acetic acid. Add 4.01 ml bromine dissolved solution by 1/4. After the bromine color disappears, the rest of the bromine solution is slowly added. The mixture is heated in a steam bath for 0.5 h and poured onto ice. Filtration yields crystals (melting point 243.5 ° to 245 ° C), which is recrystallized from ethanol to obtain 4.0 g of crystals. Melting Point 244˚ ~ 245 ℃

Example 44

Preparation of 6- (m-chlorophenyl) -4,5-dihydro-2 (2H) pyridazinone

A mixture of 7.70 g 3- (m-chlorobenzoyl) -propionic acid, 50 ml ethanol and 3.0 ml hydrazine hydrate is refluxed for 2 hours. The mixture is cooled and filtered, and the resulting crystals (6.30 g, melting point 146 ° to 147 ° C.) are recrystallized from ethanol to give 5.50 g of crystals. Melting Point 150˚ ~ 151 ℃

Example 45

Preparation of 6- (m-chlorophenyl) -3 (2H) pyridazinone

A mixture of 4.45 g of 6- (m-chlorophenyl) -4,5-dihydro-3 (2H) pyridazinone and 50 ml of glacial acetic acid is heated in a steam bath. To 15 ml of glacial acetic acid add a quarter of a solution containing 4.01 g of bromine. When bromine color disappears, add the rest of the bromine solution. The mixture is heated in the steam bath again for 0.5 h and the mixture is poured on ice. Filtration of the mixture gave 3.30 g of crystals. Melting Point 214˚ ~ 216 ℃

Example 46

Preparation of 3-chloro-6- (m-chlorophenyl) -4-methylpyridazine

A mixture of 25 ml of phosphorus oxychloride and 3.0 g of 6- (m-chlorophenyl) -4-methyl-3 (2H) -pyridazinone is refluxed for 6 hours. The mixture is concentrated to dryness in vacuo and water is added to the residue. Filtration yields 3.28 g of crystals. Melting point 138 DEG-140 DEG C. Recrystallization from ethanol yields 2.80 g of crystals.

Melting Point 138˚ ~ 141 ℃

Example 47

Preparation of 3-chloro-6- (m-chlorophenyl) pyridazine

A mixture of 25 ml of phosphorus oxychloride and 3.0 g of 6- (m-chlorophenyl) -3 (2H) -pyridazinic acid is refluxed for 6 hours. The mixture is concentrated in vacuo and water is added to the residue. Filtration yields 3.30 g of crystals. Melting point: 155 ° to 157 ° C Recrystallization from ethanol yields 2.75 g of crystals. Melting Point 157˚ ~ 158 ℃

Example 48

Preparation of [4,3-b] pyridazine with 6- (m-chlorophenyl) -8-methyl-1,2,4-triazol

A mixture of 2.0 g 3-chloro-6- (m-chlorophenyl) -4-pyripyridazine, 50 ml n-butanyl and 1.08 g formylhydrazine is refluxed for 18 hours. The mixture is concentrated to dryness in vacuo and the residue is dissolved in methylene chloride. The solution is passed through a short column of hydrated magnesium silicate. The hexane is slowly added while refluxing to separate the crystals. Cooling and filtration give 1.20 g of crystals. Melting point 173 DEG C ~ 176 DEG C. The crystals in methylene chloride are passed through a short column of hydrous magnesium silicate and the eluate is concentrated with hexane to obtain 0.83 g of crystals. Melting Point 181˚ ~ 182 ℃

Example 49

Preparation of [4,3-b] pyridazine with 6- (m-chlorophenyl) -3methyl-1,2,4-triazol

A mixture of 2.0 g 3-chloro-6- (m-chlorophenyl) -pyridazine, 50 ml n-butanol and 1.32 g acetylhydrazine is refluxed for 18 hours. The mixture is concentrated by vacuum drying and the residue is dissolved in methylene chloride. The solution is passed through a short column of hydrated magnesium silicate and hexane is slowly added while refluxing to separate the crystals. Cooling and filtration give 1.50 g of crystals. Melting Point 171˚ ~ 172.5 ℃

Example 50

Preparation of [4,3-b] pyridazine with 6- (m-chlorophenyl) -3,8-dimethyl-1,2,4-triazol

A mixture of 7.17 g 3-chloro-6- (m-chlorophenyl) -4methylpyridazine, 100 ml n-butanol and 6.96 g acetyl hydrazine is refluxed overnight. Cooling and filtration of the mixture give a solid. Dissolve in solid methylene chloride and pass the solution through a short column of hydrated magnesium silicate. The hexane is slowly added while refluxing to separate the crystals. Cooling and filtration give 3.30 g of crystals. Melting Point 193.5˚ ~ 195.5 ℃

Example 51

Preparation of 3- (m-chlorophenyl) -6-hydrazinopyridazine

A mixture of 6.85 g of 3-chloro-6- (m-chlorophenyl) pyridazine, 100 ml of n-butanol and 3.05 g of hydrazine hydrate was refluxed overnight. Removal of the solvent in vacuo yields a semisolid. The solid is dissolved in a minimum amount of hot nitromethane. Cooling gives 3.5 g of amorphous solid.

Example 52

Preparation of 6- (0-fluorophenyl) -1,2,4-triazolo- [4,3-b] pyridazine

-(0-플루오로페닐)-4-모르폴린아세토니트릴을 황색 기름으로 얻는다. 생성물인

-(0-플루오로페닐)-4-모르폴린아세토니트릴을 에틸 아크릴레이트와 반응시켜서 에틸

-시아노-

-(0-플루오로페닐)-4-모르폴렌부티레이트를 기름으로 얻는다. 에타놀내에 상기 화합물 및 히드라진 무수물이 용해된 용액을 환류시키면 6-(0-플루오로페닐)-4,5-디하이드로-3(2H)-피리다지논을 결정으로 얻는다. 융점 119˚~ 212℃The following reactions as in Example 35 were carried out. Reacting 0-fluoro benzaldehyde with P-toluenesulfonic acid, morpholine and KCN

-(0-fluorophenyl) -4-morpholine acetonitrile is obtained as a yellow oil. Product

Ethyl by reacting-(0-fluorophenyl) -4-morpholine acetonitrile with ethyl acrylate

-Cyano-

Obtain-(0-fluorophenyl) -4-morpholinbutyrate as oil. Reflux of a solution of the compound and hydrazine anhydride in ethanol yields 6- (0-fluorophenyl) -4,5-dihydro-3 (2H) -pyridazinone as crystals. Melting Point 119˚ ~ 212 ℃

The compound is heated with bromine in acetic acid to give 6- (0-fluorophenyl) -3 (2H) -pyridazinone as crystals. (CH ₂ Cl ₂ -hexanes). Melting Point 173˚ ~ 175 ℃

A mixture of the compound and phosphorus oxychloride is refluxed in a steam bath to give 3-chloro-6- (0-fluorophenyl) -pyridazine as crystals. Melting Point 95˚ ~ 96 ℃

A mixture containing 5.0 g of 3-chloro-6- (0-fluorophenyl) -pyridazine and 2.88 g of formylhydrazine in 75 ml of n-butanol was refluxed for 48 hours and worked as in Example 35. This gives 1.1 g of the product as cream colored crystals. Melting Point 161˚ ~ 163 ℃

Example 53

Preparation of 3-methyl-6- (0-fluorophenyl) -1,2,4-triazolo- [4,3-b] pyridazine

As in Example 36, a mixture of 2.5 g 3-chloro-6- (0-fluorophenyl) -pyridazine, 1.76 g acetylhydrazine and 50 ml n-butanol was refluxed for 48 hours to yield 2.0 g of product. Is obtained as a light gray crystal. Melting Point 147˚ ~ 149 ℃

Example 54

Preparation of 6- (m-fluorophenyl) -1,2,4-triazolo- [4,3-b] pyridazine

-(m-플루오로페닐)-4-모르폴린아세토니트릴을 결정으로 얻는다. (CH₂Cl₂-헥산으로부터). 융점 74˚~ 75℃The following reactions as in Example 35 were carried out. Reacting m-fluorobenzaldehyde with P-toluenesulfonic acid, morpholine and KCN

-(m-fluorophenyl) -4-morpholineacetonitrile is obtained as crystals. (From CH ₂ Cl ₂ -hexanes). Melting Point 74˚ ~ 75 ℃

-시아노-

-(m-플루오로페닐)-4-모르폴린부티레이트를 결정으로 얻는다(CH₂Cl₂-헥산으로부터). 융점 88˚~ 90℃When the compound is reacted with ethyl acrylate, ethyl

-Cyano-

-(m-fluorophenyl) -4-morpholinebutyrate is obtained as crystal (from CH ₂ Cl ₂ -hexane). Melting Point 88˚ ~ 90 ℃

Reflux of a solution of the compound and hydrazine hydrate in ethanol yields 6- (m-fluorophenyl) -4,5-dihydro-3 (2H) -pyridazinone as crystals (CH ₂ Cl ₂ -hexane From). Melting Point 132˚ ~ 134 ℃

Heating the compound with bromine in acetic acid yields 6- (m-fluorophenyl) -3 (2H) -pyridazinone as crystals. (From CH ₂ Cl ₂ -hexanes). Melting Point 207˚ ~ 209 ℃

Reflux of the mixture of the compound and phosphorus oxychloride affords 3-chloro-6- (m-fluorophenyl) -pyridazine as crystals. Melting Point 133˚ ~ 135 ℃

A mixture containing 3.6 g of 3-chloro-6- (m-fluorophenyl) pyridazine and 2.06 g of formylhydrazine in 50 ml of n-butanol was refluxed for 48 hours and worked as in Example 35. The product is obtained as cream colored crystals. Melting Point 150˚ ~ 161 ℃

Example 55

Preparation of 3-methyl-6- (m-fluorophenyl) -1,2,4-triazolo- [4,3-b] pyridazine

As in Example 36, a mixture of 3.0 g 3-chloro-6- (m-fluorophenyl) -pyridazine, 2.14 g acetylhydrazine, 50 ml n-butanol, and the like was refluxed for 48 hours at 2.0 g. The product of is obtained as crystals.

Melting Point 184˚ ~ 186 ℃

Example 56

Preparation of 6- (0-chlorophenyl) -1,2,4-triazolo- [4,3-b] pyridazine

-(0-클로로페닐)-4-모르폴린 아세토니트릴을 기름으로 얻는다(CH₂Cl₂-헥산으로부터). 융점 40˚~ 42℃The same reaction as in Example 35 was carried out. Reacting 0-chloro benzaldehyde with P-toluene sulfonic acid, morpholine and KCN

-(0-chlorophenyl) -4-morpholine acetonitrile is obtained as an oil (from CH ₂ Cl ₂ -hexane). Melting Point 40˚ ~ 42 ℃

-시아노-

-(0-클로로페닐)-4-모르폴린부티레이트를 기름으로 얻는다.When the compound is reacted with ethyl acrylate, ethyl

-Cyano-

Obtain-(0-chlorophenyl) -4-morpholinebutyrate as oil.

Reflux of a solution of the compound and hydrazine hydrate in ethanol yields 6- (0-chlorophenyl) -4,5-dihydro-3 (2H) pyridazinone as crystals. Melting Point 114˚ ~ 116 ℃

Heating the compound with bromine in acetic acid yields 6- (0-chlorophenyl) -3 (2H) -pyridazinone as crystals. Melting Point 214˚ ~ 216 ℃

Reflux of a mixture of the compound and phosphorus oxychloride affords 3-chloro-6- (0-chlorophenyl) -pyridazine as crystals. Melting Point 145˚ ~ 147 ℃

A mixture of 5.67 g of 3-chloro-6- (0-chlorophenyl) pyridazine 3.03 g of formylhydrazine and 50 ml of n-butanol and the like was refluxed for 48 hours to give 2.3 g of the product as ring yellow crystals. Melting Point 156˚ ~ 158 ℃

Example 57

Preparation of 3-methyl-6- (0-chlorophenyl) -1,2,4-triazolo [4,3-b] pyridazine

As in Example 36, a mixture of 5.5 g of 3-chloro-6- (0-chlorophenyl) -pyridazine, 3.6 g of acetylhydrazine and 75 ml of n-butanol was refluxed for 72 hours to give 2.2 g of The product is obtained as light gray crystals.

Melting Point 146˚ ~ 148 ℃

Example 58

,

,

-트리플루오로-m-톨릴)-4,5-디하이드로-3(2H) 피리다지논의 제조4-methyl-6- (

,

,

Preparation of -trifluoro-m-tolyl) -4,5-dihydro-3 (2H) pyridazinone

-(

,

,

-트리플루오로-m-톨릴) -4-모르폴린아세토니트릴이 용해된 용액에, 메타놀내의 30% 수산화 칼륨용액 5ml를 가한다. 이 혼합물에 22.0ml의 메타크릴로니트릴을 가하고, 혼합물을 밤새도록 교반한다. 혼합물을 진공건조하여 농축 시키고 잔여물을 클로로포름내에 용해시킨다. 용액을 수화마그네슘 실리케이트 컴럼에 통과 시킨다. 용출물을 농축하면 황색 기름으로 되고, 이것을 에테르-헥산으로 부터 결정시키면 47g의 크림색 결정으로 얻는다. 융점 88˚- 90℃ 상기 화합물(107g)을, 600ml의 초산 및 75ml의 물로된 혼합물과 함께 증기조에서 18시간동안 가열한다. 용매를 제거하면 기름을 얻는다. 500ml의 6 HCl에 상기 기름이 포함된 혼합물을 24시간동안 환류시킨다. 혼합물을 냉각하고 클로로포름으로 추출한다. 클로로포름층을 물 및 포화 NaCl 용액으로 씻고, 수화마그네슘 실리케이트 컬럼에 통과시킨다. 용매를 용출물로부터 제거하고 잔여물을 에테르-헥산으로부터 결정시키면 29.4g의 2-메틸-3-(m-트리플루오로메틸 벤조일)프로피온산을 연한 분홍색 결정으로얻는다. 융점 90˚~ 193℃60.0 g in 200 ml tetrahydrofuran

-(

,

,

-Trifluoro-m-tolyl) -4-ml of 30% potassium hydroxide solution in methanol is added to a solution of -4-morpholine acetonitrile. To this mixture is added 22.0 ml of methacrylonitrile and the mixture is stirred overnight. The mixture is concentrated to dryness in vacuo and the residue is dissolved in chloroform. The solution is passed through a hydrated magnesium silicate column. Concentrate the eluate to a yellow oil which is crystallized from ether-hexane to give 47 g of cream crystals. Melting Point 88 ° -90 ° C. The compound (107 g) is heated in a steam bath with a mixture of 600 ml of acetic acid and 75 ml of water for 18 hours. Removing the solvent gives oil. The mixture containing the oil is refluxed for 24 hours in 500 ml of 6 HCl. The mixture is cooled and extracted with chloroform. The chloroform layer is washed with water and saturated NaCl solution and passed through a hydrated magnesium silicate column. The solvent is removed from the eluate and the residue is determined from ether-hexane to give 29.4 g of 2-methyl-3- (m-trifluoromethyl benzoyl) propionic acid as light pink crystals. Melting Point 90˚ ~ 193 ℃

200 ml of ethanol was refluxed for 18 hours with the compound (25.4 g) and 5.0 ml of hydrazine hydrate. Cooling and filtering the mixture gave 21.8 g of the product as cream colored crystals. Melting Point 188˚ ~ 190 ℃ Recrystallized from CHCl ₃ -hexane to give light gray crystals. Melting Point 191˚ ~ 193 ℃

Example 59

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조8-methyl-6- (

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

,

,

-트리플루오로-n-톨릴)-4,5-디하이드로-3(2H) 피리다지논(20.5g)이 용해된 용액에, 25ml의 초산에 14.4g의 브롬이 용해된 용액을 한방울씩 가한다. 혼합물을 0.5시간동안 가열하고 용매를 진공하에 진공하에 제거한다. 잔여물에 얼음 및 물을 가하고, 혼합물을 여과하면 20.4g의 8-메틸-6-(

,

,

-트리플루오로-m-톨릴)-3(2H)피리다지논을 크림색 결정으로 얻는다. 융점 234˚~ 237℃To 200 ml of acetic acid 4-methyl-6- (

,

,

To a solution of -trifluoro-n-tolyl) -4,5-dihydro-3 (2H) pyridazinone (20.5 g), add 14.4 g of bromine dissolved in 25 ml of acetic acid dropwise. do. The mixture is heated for 0.5 h and the solvent is removed under vacuum. Ice and water were added to the residue, and the mixture was filtered to give 20.4 g of 8-methyl-6- (

,

,

-Trifluoro-m-tolyl) -3 (2H) pyridazinone is obtained as cream colored crystals. Melting Point 234˚ ~ 237 ℃

,

,

-트리플루오로-m-톨릴)피리다진을 크림색 결정으로 얻는다. 융점 123˚~ 126℃The compound (19.4 g) and 200 ml of phosphorus oxychloride are heated in a steam bath for 18 hours. The mixture is concentrated to dryness in vacuo and ice and water are added to the residue. The mixture was filtered and the solid was recrystallized from CHCl ₃ -hexanes to give 18.0 g of 3-chloro-4-methyl-6- (

,

,

Trifluoro-m-tolyl) pyridazine is obtained as cream colored crystals. Melting Point 123˚ ~ 126 ℃

A mixture of 8.0 g of the compound, 3.52 g of formylhydrazine, 125 ml of n-butanol and the like is refluxed for 48 hours and concentrated to dryness in vacuo. The residue in CHOl ₃ is passed through a hydrated magnesium silicate column and the eluate is concentrated to determine the residue from CH ₂ Cl ₂ -hexanes to give the product as crystals. Melting Point 181˚ ~ 183 ℃

Example 60

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조3,8-dimethyl-6- (

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

,

,

- 트리플루오로-m-톨릴) 피리다진, 4,34g의 아세틸히드라진 및 125ml의 n-부타놀등의 혼합물을 48시간 동안 환류시키면 3.9g의 생성물을 결정으로 얻는다. 융점 196˚~ 198℃8.0 g of 3-chloro-4-methyl-6- (as in Example 36

,

,

-A mixture of trifluoro-m-tolyl) pyridazine, 4,34 g of acetylhydrazine and 125 ml of n-butanol and the like is refluxed for 48 hours to obtain 3.9 g of the product as crystals. Melting Point 196˚ ~ 198 ℃

Example 61

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조7-methyl-6- (

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

-(

,

,

-트리플루오로-m-톨릴)-4-모르폴린아세토니트릴이 용해된 용액에, 1.0ml의 30% KOH-에타놀 용액을 가한다. 이 혼합물에 2.56g의 크로로니트릴을 가하고, 혼합물을 실온에서 18시간동안 교반한다. 혼합물을 진공건조로 농축시키고, 잔여물을 클로로포름 내에 용해시킨다. 용액을 수화마그네슘실리케이트 컬럼에 통과시킨다. 용출물을 농축하면 기름이 되고(17.3g), 이것을 헥산으로부터 결정시키고 다시 CHCl₃-헥산으로부터 재 결정시키면 3-메틸-2-모르폴리노-2-(

,

,

-트리플루오로-m-톨릴)글루타로니트릴을 결정으로 얻는다. 융점 115˚~ 118℃100 ml of tetrahydrofuran

-(

,

,

To a solution of -trifluoro-m-tolyl) -4-morpholine acetonitrile, 1.0 ml of 30% KOH-ethanol solution is added. To this mixture is added 2.56 g chloronitrile and the mixture is stirred for 18 hours at room temperature. The mixture is concentrated in vacuo to dryness and the residue is dissolved in chloroform. The solution is passed through a hydrated magnesium silicate column. Concentrate the eluate to an oil (17.3 g), which is crystallized from hexane and recrystallized from CHCl ₃ -hexane again to give 3-methyl-2-morpholino-2- (

,

,

-Trifluoro-m-tolyl) glutaronitrile is obtained as crystals. Melting Point 115˚ ~ 118 ℃

The mixture containing the compound (39 g) in 500 ml of 75% acetic acid is refluxed for 48 hours and the solvent is removed in vacuo. The residue is dissolved in CH ₂ Cl ₂ and the solution is washed with water, saturated sodium bicarbonate and saturated NaCl solution. The organic layer is dried (MgSO ₄ ) and passed through a hydrated magnesium silicate column. Concentration of the eluate yields 27.4 g of 3- (m-trifluoromethylbenzoyl) butyronitrile as a yellow oil.

The mixture of 26.4 g of the compound and 500 ml of 6N HCl is refluxed for 18 hours. The mixture is cooled and extracted with dichloromethane. The organic layer is extracted with saturated NaHCO ₃ solution. The basic aqueous extract is acidified with 6N HCl and extracted with ether. The ether layer was washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated to give 24.3 g-3- (m-trifluoromethyl benzoyl) -butyric acid as colorless oil.

,

,

-트리플루오로-m-톨릴)-4,5-디하이드로-3(2H) 피리다논을 백색 결정으로 얻는다. 융점 132˚~ 134℃. CH₂Cl₂-헥산으로부터 재 결정시키면 백색 결정으로 얻는다. 융점 142˚~ 144℃A mixture of the compound (24.3 g), 5.0 ml hydrazine hydrate, 200 ml ethanol and the like is refluxed for 18 hours and the solvent is removed in vacuo. The residue is dissolved in dichloromethane and the solution is passed through a hydrated magnesium silicate column. Concentrate the eluent to give 20.7 g of 5-methyl-6- (

,

,

-Trifluoro-m-tolyl) -4,5-dihydro-3 (2H) pyridanone is obtained as white crystals. Melting point 132˚ ~ 134 ℃. Recrystallization from CH ₂ Cl ₂ -hexanes results in white crystals. Melting Point 142˚ ~ 144 ℃

,

,

-트리플루오로-m-톨릴)-3(2H) 피리다지논을 백색 결정으로 얻는다. 융점 224˚~ 227℃.When the compound is heated with bromine in acetic acid, 5-methyl-6- (

,

,

-Trifluoro-m-tolyl) -3 (2H) pyridazinone is obtained as white crystals. Melting point 224 ° to 227 ° C.

Example 62

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조3,7-dimethyl-6- (

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

,

,

-트리플루오로 -m-톨릴) 피리다진, 4.34g의 아세틸히드라진 및 125ml의 n-부타놀등의 혼합물을 48시간 동안 환류시키면 6.2g의 크림색 결정을 얻는다. 융점 185˚~ 187℃8.0 g of 3-chloro-5-methyl-6- (as in Example 36

,

,

A mixture of -trifluoro-m-tolyl) pyridazine, 4.34 g of acetylhydrazine, 125 ml of n-butanol and the like was refluxed for 48 hours to obtain 6.2 g of creamy crystals. Melting Point 185˚ ~ 187 ℃

Example 63

Preparation of 6- (m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

-(m-톨릴)-4-모르폴린 아세토니트릴을 결정으로 얻는다. 융점 59˚~ 60℃As in Example 35, the following reaction was carried out. Reacting m-tolualdehyde with P-toluenesulfonic acid, morpholine and KCN

-(m-tolyl) -4-morpholine acetonitrile is obtained as crystals. Melting Point 59˚ ~ 60 ℃

-시아노-

-(m-톨릴)-4-모르폴린부티레이트를 기름으로 얻는다.When the compound is reacted with ethyl acrylate, ethyl

-Cyano-

Obtain-(m-tolyl) -4-morpholinebutyrate as oil.

Refluxing the solution of the compound and hydrazine hydrate in ethanol yields 6- (m-tolyl) -4,5-dihydro-3 (2H) pyridazinone as white crystals. Melting Point 130˚ ~ 132 ℃

Heating the compound with bromine in acetic acid gives 6- (m-tolyl) -3 (2H) -pyridazinone as white crystals. Melting Point 202˚ ~ 205 ℃

Reflux of the mixture of the compound and phosphorus oxychloride affords 3-chloro-6- (m-tolyl) -pyridazinone as light gray crystals. Melting Point 112˚ ~ 113 ℃

A mixture of 6.0 g 3-chloro-6- (m-tolyl) pyridazine, 3.52 g formylhydrazine and 100 ml n-butanol and the like was refluxed for 48 hours, working as in Example 35 and 2.0 g White crystals of (from CHCl ₃ -hexanes) are obtained. Melting Point 164˚ ~ 166 ℃

Example 64

Preparation of 3-methyl-6- (m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

As in Example 36, a mixture of 6.0 g of 3-chloro-6- (m-tolyl) pyridazine, 4.34 g of acetylhydrazine and 100 ml of n-butanol was refluxed for 48 hours to give 2.0 g of cream crystals. Get Melting Point 160˚ ~ 162 ℃

Example 65

,

,

-트리플루오로-P-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조3-propyl-6- (

,

,

Preparation of -trifluoro-P-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

,

,

-트리플루오로-P-톨릴) 피리다진, 3.94g의 부티트산 히드라지드 및 100ml의 n-부타놀등의 혼합물을 48시간 동안 환류시킨다. 용매를 진공제거하고 잔여물을 클로로포름에 용해시킨다. 용액을 수화 마그네슘 실리케이트 컬럼에통과시키고 용출물을 농축시키면 3.2g의 생성물을 얻는다. CHCl₃-헥산으로부터 재 결정시키면 결정을 얻는다. 융점 173˚~ 175℃5.0 g of 3-chloro-6- (

,

,

A mixture of -trifluoro-P-tolyl) pyridazine, 3.94 g butyric acid hydrazide and 100 ml n-butanol and the like is refluxed for 48 hours. The solvent is removed in vacuo and the residue is dissolved in chloroform. The solution is passed through a hydrated magnesium silicate column and the eluate is concentrated to give 3.2 g of product. Recrystallization from CHCl ₃ -hexanes gives crystals. Melting Point 173˚ ~ 175 ℃

Example 66

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조3-ethyl-6- (

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

,

,

-트리플루오로-m-톨릴) 피리다진, 3.40g의 프로피온산 히드라지드 및 100ml의 n-부타놀등의 혼합물을 48시간동안 환류시킨다. 용매를 진공제거하고 잔여물을 클로로포름에 용해시킨다. 용액을 수화마그네슘 실리케이트 컬럼에 통과시키고 용출물을 농축시키면 3.0g의 결정을 얻는다(CHCl₃-헥산으로부터). 융점 183˚~ 185℃5.0 g of 3-chloro-6- (

,

,

-Trifluoro-m-tolyl) pyridazine, 3.40 g propionic acid hydrazide and 100 ml n-butanol and the like are refluxed for 48 hours. The solvent is removed in vacuo and the residue is dissolved in chloroform. The solution is passed through a hydrated magnesium silicate column and the eluate is concentrated to give 3.0 g of crystals (from CHCl ₃ -hexanes). Melting Point 183˚ ~ 185 ℃

Example 67

,

,

-트리플루오로-P-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조3-ethyl-6- (

,

,

Preparation of -trifluoro-P-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

,

,

-트리플루오로-P-톨릴) 피리다진, 3.40g의 프로피온산 히드라지드 및 100ml의 n-부타놀등의 혼합물을 48시간 동안 환류시키면 3.1g의 백색 결정 얻는다(CHCl₃-헥산으로부터). 융점 194˚~ 196℃As in Example 65, 5.0 g of 3-chloro-6- (

,

,

A mixture of -trifluoro-P-tolyl) pyridazine, 3.40 g propionic acid hydrazide, 100 ml n-butanol and the like was refluxed for 48 hours to obtain 3.1 g of white crystals (from CHCl ₃ -hexane). Melting Point 194˚ ~ 196 ℃

Example 68

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로-[4,3-b] 피리다진의 제조6- (4-chloro-

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo- [4,3-b] pyridazine

-[4-클로로-3-(트리플루오로메틸)페닐]-4-모르폴린아세토니트릴을 백색 결정으로 얻는다. 융점 73˚~ 74℃5-amino-2-chlorobenzotrifluoride is converted to 4-chloro-3- (trifluoromethyl) benzaldehyde. As in Example 35, the following reaction was carried out. 4-chloro-3- (trifluoromethyl) benzaldehyde (13.9 g), 14.27 g of P-toluenesulfonic acid, 13.01 g of morpholine, and 4.88 g of potassium cyanide

-[4-Chloro-3- (trifluoromethyl) phenyl] -4-morpholine acetonitrile is obtained as white crystals. Melting Point 73˚ ~ 74 ℃

-시아노-

-[4-클로로-3-(트리플루오로메틸)페닐]-4-모르폴린 부티레이트를 황색 기름으로 얻는다(16.5g). 이 화합물(16.5g)을, 100ml의 에타놀내에서 2.11g의 히드라진과 반응시키면 6-[4-클로로-3-(트리플루오로메틸)페닐]-4,5-디하이드로-3(2H)피리다지논(4.2g)을 백색 결정으로 얻는다. 융점 195˚~ 198℃When this compound (14.0 g) is reacted with ethyl acrylate, ethyl

-Cyano-

Obtain [[4-Chloro-3- (trifluoromethyl) phenyl] -4-morpholine butyrate as yellow oil (16.5 g). This compound (16.5 g) was reacted with 2.11 g hydrazine in 100 ml of ethanol to give 6- [4-chloro-3- (trifluoromethyl) phenyl] -4,5-dihydro-3 (2H) pyridine. Dazinon (4.2 g) is obtained as white crystals. Melting Point 195˚ ~ 198 ℃

This intermediate is heated with bromine in acetic acid to give 6- [4-chloro-3- (trifluoromethyl) phenyl] -3 (2H) pyridazinone as white crystals. Melting Point 249˚ ~ 251 ℃

The mixture of 5 g of this compound and 60 ml of phosphoric oxychloride was refluxed for 18 hours to obtain 3-chloro-6- [4-chloro-3- (trifluoromethyl) phenyl] -pyridazine as cream crystals. Melting point 145 ° to 147 ° C. A mixture of 2.2 g of the compound, 0.9 g of formylhydrazine, 50 ml of n-butanol, and the like was refluxed for 48 hours to obtain 2.1 g of the product. Melting Point 211˚ ~ 214 ℃

Recrystallization from n-propanol yields cream colored crystals. Melting Point 217˚ ~ 218 ℃

Example 69

,

,

-트리플루오로-m-톨릴)-1,2,4-트리아졸로[4,3-b] 피리다진의 제조3-methyl-6- (4-chloro-

,

,

Preparation of -trifluoro-m-tolyl) -1,2,4-triazolo [4,3-b] pyridazine

A mixture of 2.2 g 3-chloro-6- [4-chloro-3- (trifluoromethyl) phenyl] pyridazine, 1.11 g acetylhydrazine and 50 ml n-butanol was prepared as in Example 36. Reflux over time gives the product as crystals. Melting Point 267˚ ~ 269 ℃

Example 70

Preparation of 6- (3,4-dichlorophenyl) -1,2,4-triazolo [4,3-b] pyridazine

-(3,4-디클로로페닐)-4-모르폴린아세토니트릴을 크림색 결정으로 얻는다. 융점 69˚~ 71℃ . 이 화합물(136.9g)을 600ml의 테트라하이드로푸란내에서 50ml의 에틸 아크릴레이트와 반응시켜서 132.6g의 갈색기름을 얻는다. 이 기름(132.6g) 및 36ml의 히드라진 수화물을 500ml의 에타놀내에서 환류시키면 63.5g의 6-(3,4-디클로로페닐)-4,5-디하이드로-3(2H)피리다지논을 황색결정으로 얻는다. 융점 168˚~ 182℃. 이 중간 생성물(63.45g), 67.5g의 나트륨 m-니트로 벤젠 설포네이트 및 52.0g의 수산화나트륨을 2ℓ의 물속에서 밤새도록 증기조상에서 가열하면 26.4g의 6-(3,4-디클로로페닐)-3(2H)-피리다지논을 갈색 결정으로 얻는다 . 융점 215˚~ 218℃. 상기 화합물(10g) 및 100ml의 포스포러스 옥시클로라이드를 증기조에서 가열하면 8.9g의 3-클로로-6-(3,4-디클로로페닐)피리다진을 얻는다. 실리카겔상에서 클로로포름-메타놀(95.5)로 칼럼 크로마토그라피하면 5.5g의 생성물을 결정으로 얻는다. 융점 188˚~ 189℃The following reactions are carried out as in Example 35. Reacting 3,4-dichlorobenzaldehyde (106.3 g) with 124 g of P-toluenesulfonic acid, 122 g of morpholine and 45 g of potassium cyanide in 50 ml of tetrahydrofuran

-(3,4-dichlorophenyl) -4-morpholine acetonitrile is obtained as cream colored crystals. Melting point 69˚ ~ 71 ℃. This compound (136.9 g) is reacted with 50 ml of ethyl acrylate in 600 ml of tetrahydrofuran to give 132.6 g of brown oil. This oil (132.6 g) and 36 ml of hydrazine hydrate were refluxed in 500 ml of ethanol to give 63.5 g of 6- (3,4-dichlorophenyl) -4,5-dihydro-3 (2H) pyridazinone as yellow crystals. Get Melting point 168 ° ~ 182 ° C. This intermediate product (63.45 g), 67.5 g sodium m-nitrobenzene sulfonate and 52.0 g sodium hydroxide in 2 liters of water overnight were heated in a steam bath to give 26.4 g of 6- (3,4-dichlorophenyl)- 3 (2H) -pyridazinone is obtained as brown crystals. Melting point 215 ° to 218 ° C. The compound (10 g) and 100 ml of phosphorus oxychloride were heated in a steam bath to obtain 8.9 g of 3-chloro-6- (3,4-dichlorophenyl) pyridazine. Column chromatography on chloroform-methanol (95.5) on silica gel yields 5.5 g of product as crystals. Melting Point 188˚ ~ 189 ℃

Example 71

Preparation of 3-methyl-6- (3,4-dichlorophenyl) -1,2,4-triazole [4,3-b] pyridazine

A mixture of 2.6 g of 3-chloro-6- (3,4-dichlorophenyl) pyridazine and 1.8 g of hydrazide acetate is heated in 50 ml of n-butanol for 24 hours to give the product. Melting Point 267 ℃

Example 72

Preparation of 50mg Tablets

3,7,8-triethyl-6-phenyl-1,2,4-triazole is mixed together with [4,3-b] pyridazine, lactose and corn starch (for mixing).

Corn starch (adhesive) is suspended in 600 ml of water and heated with stirring to form a pool. This pool is used to make mixed powders. Add more water as needed. Pass the wet litter in eight cages and dry at 120˚F. Pass the dry seedlings through 16 houses. The mixture is lubricated with 1% magnesium stearate and compressed into a suitable tablet maker to make tablets.

Example 73

Preparation of Oral Suspension

Sorbitol solution is added to 40 ml of distilled water and [4,3-b] pyridazine is suspended in 3,8-di-n-butyl-6-phenyl-1,2,4-triazole. Saccharin, sodium benzoate, flavors and dyes are added to dissolve. The volume is adjusted to 100 ml with distilled water. 5 mg of 3,8-di-n-butyl-6-phenyl-1,2,4-triazole is contained [4,3-b] pyridazine in 1 ml of syrup.

Example 74

Preparation of topical solution

To a solution of 700 ml propylene glycol and 200 ml water while stirring 20.0 g of 7,8-di-n-propyl-6-phenyl-1,2,4-triazolo [4,3-b] pyridazine monohydrochloride Suspend. Once the suspension is complete, adjust the pH to 5.5 with hydrochloric acid and bring the volume to 1000 ml with water. This preparation is sterilized and filled in 5.0 ml ampoules each containing 2.0 ml (labeled 40 mg of drug) and sealed under nitrogen.

Example 75

Preparation of [4,3-b] pyridazine with 3,7,8-trimethyl-6-phenyl-1,2,4-triazol

200 g of 3-benzoyl-2,3-dimethyl-propionic acid and 60 g of hydrazine hydrate are added to 1 L of ethyl alcohol and stirred at reflux for 18 hours. The reaction mixture is cooled in an ice bath and collected by conventional methods to give 4,5-dihydro-4,5-dimethyl-6-phenyl-3 (2H) -pyridazinone as a cream solid. This product is partially dissolved in 600 ml of glacial acetic acid. Here, 50 ml of bromine is dissolved in 100 ml of glacial acetic acid, and heated in a steam bath. (Approximately 15% bromine solution is added before heating starts, and it takes about 1 hour to add hydrogen bromide gas during this time) When the addition is complete, the reaction mixture is heated in a steam bath for 1 hour and the mixture Pour into crushed ice. The resulting solid is vacuum filtered, washed well with water and air dried to afford 4,5-dimethyl-6-phenyl-3 (2H) -pyridazinone as a cream solid. This material is added to 800 ml of phosphorus oxychloride and heated in a steam bath for 5 hours. The reaction mixture is concentrated to remove excess phosphorus oxychloride and diluted with cold water. Vacuum the resulting solids, wash well with water and air dry to afford 3-chloro-4,5-dimethyl-6-phenylpyridazine as a pink solid 10 g of the above product, 8 g of N-acetylhydrazine and 100 ml of n-butyl The alcohol is allowed to stir at reflux for 48 hours. The reaction mixture is cooled in an ice bath, the resulting solid is vacuum filtered, washed sequentially with petroleum ether and water and air dried. After treatment with activated charcoal, the solid was recrystallized from ethyl alcohol and dried in vacuo to afford [4,3-b] pyridazine as a white solid with 3,7,8-trimethyl-6-phenyl-1,2,4-triazole Get into.

Example 76

Preparation of [4,3-b] pyridazine with 7-methyl-6-phenyl-1,2,4-triazol

10 g of 6- (P-bromophenyl) -5-methyl-3 (2H) pyradazinone and 100 ml of phosphorus oxychloride are heated to steam bath temperature for 3 hours. The mixture is added dropwise while stirring in cold water. The resulting solid is filtered and washed with water to give 3- (P-bromophenyl) -6-chloro-4-methylpyridazine as a gray solid. A mixture of 1.5 g of the compound, 0.64 g of formylhydrazine and 25 ml of n-butalcohol is stirred at reflux for 18 hours. The reaction mixture was cooled in an ice bath and filtered, and the solid was recrystallized from methylalcohol to give 6- (P-bromophenyl) -7-methyl-1,2,4-triazolo [4,3-b] pyridazine Get

A mixture of 10 g of the material, 30 ml of ammonium hydroxide, 250 ml of ethyl alcohol and a catalytic amount of charcoal palladium and the like is shaken for 18 hours. After two hours you'll get 35 pounds of hydrogen. The reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to give a white solid which is triturated with petroleum ether. The solid is collected by filtration, air dried, recrystallized from methylol-ethyl acetate and [4,3-b] pyridazine is obtained as white crystals with 7-methyl-6-phenyl-1,2,4-triazole. Melting Point 188˚ ~ 190 ℃

Example 77

Preparation of [4,3-b] pyridazine with 3-methyl-6-phenyl-1,2,4-triazol

The title compound is prepared by known methods.

Example 78

Preparation of [4,3-b] pyridazine with 3,8-dimethyl-6-phenyl-1,2,4-triazol

The title compound is prepared by known methods.

Example 79

Preparation of [4,3-b] pyridazine with 7-isopropyl-6-phenyl-1,2,4-triazol

The method of Example 4 was repeated using equimolar amounts of 3-benzoyl-3-isopropyl-propionic acid and N-propylhydrazine in place of 3-benzoyl-2,3-dimethyl-propionic acid and N-acetylhydrazine. The compound is obtained in the same yield.

Example 80

Preparation of [4,3-b] pyridazine with 8-isobutyn-6-phenyl-1,2,4-triazol

According to the general method of example 4 3-benzoyl-2-isobutyl-propionic acid is converted to 3-chloro-4-isobutylpyridazine, which is treated with N-propylhydrazine to give the title compound.

Example 81

Preparation of [4,3-b] pyridazine with 3-ethyl-7-methyl-6-phenyl-1,2,4-triazol

The general procedure of Example 4 is repeated using 3-benzoyl-3-methyl-propionic acid and N-propionylhydrazine instead of 3-benzoyl-2,3-dimethyl-propionic acid and N-acetylhydrazine.

Example 82

Preparation of [4,3-b] pyridazine with 6-phenyl-1,2,4-triazol

10 g of 3-chloro-6-phenylpyridazine, 6.6 g of formylhydrazine and 100 ml of n-butanol are refluxed for 48 hours. The reaction mixture is cooled in an ice bath. The resulting solid was filtered, washed with petroleum ether and water and air dried to give 6-phenyl-1,2,4-triazole [4,3-b] pyridazine as brown crystals. Melting Point 138˚ ~ 139 ℃

Example 83

Preparation of [4,3-b] pyridazine with 8-methyl-6-phenyl-1,2,4-triazol

A mixture of 13.2 g of 4-methyl-6-phenyl-3 (2H) pyridazinone and 200 ml of phosphorus oxychloride is heated in a steam bath for 18 hours. The reaction mixture is filtered. The filtrate is concentrated to remove excess phosphorus oxychloride. The residue is stirred with ice and filtered. The solid is washed with water and air dried to afford 3-chloro-4-methyl-6-phenylpyridazine as a cream solid.

A mixture of 2.05 g of the product, 1.2 g of formylhydrazine and 50 ml of n-butanol and the like is stirred and refluxed for 48 hours. The reaction mixture is concentrated to remove the solvent and the residue is stirred with diethyl ether. Filtration of the mixture gives a cream solid. This solid is treated with activated charcoal and then recrystallized from methanol. Allowing the methanol methanol to evaporate at room temperature results in white needles and a dark yellow oil. The oil is removed and the needles are washed with a small amount of diethyl ether and poured out. Recrystallization of the needle-like material from methanol-diethyl ether-petroleum ether yields [4,3-b] pyridazine as white crystals with 8-methyl-6-phenyl-1,2,4-triazole. Melting Point 150˚ ~ 151 ℃

Example 84

Preparation of [4,3-b] pyridazine with 3-n-propyl-6-phenyl-1,2,4-triazol

A mixture of 10 g 3-chloro-6-phenylpyridazine, 11.2 g butyric acid hydrazine, 100 ml n-butanol and the like is stirred at reflux for 40 hours. The solution is cooled and the precipitate is filtered off and washed with petroleum ether and water. The filtrate is concentrated to an oil, and petroleum ether is added to this oil to form a precipitate. The precipitate is collected and washed with petroleum ether and water. The solids are combined and recrystallized from 30 ml of ethanol to give [4,3-b] pyridazine as crystals with 3-n-propyl-6-phenyl-1,2,4-triazole. Melting Point 123˚ ~ 125 ℃

Example 85

Preparation of [4,3-b] pyridazine with 3-ethyl-6-phenyl-1,2,4-triazol

A mixture of 7.6 g 3-chloro-6-phenylpyridazine, 7.4 g propionic acid hydrazide, 60 ml n-butanol and the like is stirred at reflux for 48 hours. The solution is cooled in air cooling, concentrated to remove the solvent, and then triturated with water to obtain crystals. The mixture is filtered, washed with petroleum ether and water and dried. The product is recrystallized from 20 ml of ethanol to give [4,3-b] pyridazine with 3-ethyl-6-phenyl-1,2,4-triazole. Melting Point 133˚ ~ 135 ℃

The mixture containing the compound and formylhydrazine in n-butanol was refluxed for 24 hours for 6- (3,4-dichlorophenyl) -1,2,4-triazolo [4,3-b] -pyridazine Get

Example 86

Preparation of [4,3-b] pyridazine with 3-methyl-6- (3,4-dichlorophenyl) -1,2,4-triazol

A mixture of 2.6 g of 3-chloro-6- (3,4-dichlorophenyl) pyrazine and 1.8 g of hydrazide acetate was heated in 50 ml of n-butanol for 24 hours to afford the title product.

Example 87

Preparation of 6- [2-chloro-5- (trifluoromethyl) phenyl] triazolo [4,3-b] pyridazine

3-amino-4-chlorobenzo trifluoride is converted to 2-chloro-5- (trifluoromethyl) benzaldehyde as in Example 68, which in turn is 3-chloro-6- [2-chloro-5- Conversion to (trifluoromethyl) phenyl] pyridazine yields cream colored crystals. 2.2 g of the compound, 0.9 g of formyl hydrazine and 50 ml of n-butanol were refluxed for 48 hours to afford the title product.

Example 88

Preparation of [4,3-b] pyridazine with 3-methyl-6- [2-chloro-5- (trifluoromethyl) phenyl] 1,2,4-triazol

2.2 g of 3-chloro-6- [2-chloro-5- (trifluoromethyl) phenyl] pyridazine and 1.11 g of acetylhydrazine were refluxed in 50 ml of n-butanol for 48 hours as in Example 36. To get the title product.

Example 89

Preparation of 6- [4-nitro-3- (trifluoromethyl) phenyl] -3 (2H) -pyridazine

2.0 g of 6- [3- (trifluoromethyl) phenyl] -3 (2H) -pyridazinone and 10 ml of fuming nitric acid are heated in a steam bath for 30 minutes. The mixture is poured into crushed ice and filtered, and the solid is washed with water. A yellow solid (2.2 g) is dissolved in 20 ml 5N NaOH. The mixture is cooled (ice bath) and filtered. The solid is dissolved in water and the solution is acidified with hydrochloric acid. The solid was filtered off and washed with water to yield 1.0 g of creamy crystals. Melting point 235 ° to 238 ° C Recrystallization from dimethylformamide-water gives the product as crystals. Melting Point 238˚ ~ 241 ℃

Example 90

Preparation of 6- [4-nitro-3- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

A mixture of 7.0 g of 6- [4-nitro-3- (trifluoromethyl) phenyl] -3 (2H) -pyridazinone and 80 ml of phosphorus oxychloride is heated in a steam bath for 18 hours. Remove the solvent and add ice water to the residue. Filtration yields 7.2 g of 3-chloro-6- [4-nitro-3- (trifluoromethyl) phenyl] -pyridazine as brown crystals. Melting point 129˚ ~ 135 ℃ Recrystallized with dichloromethane-hexane to give a creamy crystal. Melting point 151 DEG-155 DEG C. The compound is reacted with formylhydrazine in reflux n-butanol for 24 hours to obtain the title product.

Example 91

Preparation of 3-methyl-6- [4-nitro-3- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

Reflux of 4.0 g of 3-chloro-6- [4-nitro-3- (trifluoromethyl) phenyl] pyridazine and 1.95 g of acetylhydrazine for 18 hours in 40 ml of n-butanol yielded the product as crystals. Get Melting Point 293-295 ℃

Example 92

Preparation of 6- [4-fluoro-3- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

A mixture containing 10 g of 6- [4-nitro-3- (trifluoromethyl) phenyl] -3 (2H) -pyridazinone in 50 ml of trifluoroacetic acid is reduced to 6- by hydrogen and palladium on carbon. [4-amino-3- (trifluoromethyl) phenyl] -3 (2H) -pyridazinone is obtained. The compound is converted to 6- [4-fluoro-3- (trifluoromethyl) phenyl] -3 (2H) -pyridazinone. Reaction of the compound with phosphorus oxychloride as in Example 47 affords 3-chloro-6- [4-fluoro-3- (trifluoromethyl) phenyl] -pyridazine, which is carried out with formyl hydrazine. Reaction as in example 48 gives the title compound.

Example 93

Preparation of 3-methyl- [4-fluoro-3- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

As in Example 36, 3-chloro-6- [4-fluoro-3- (trifluoromethyl) phenyl] pyrazine is reacted with acetic acid hydrazide in n-butanol to give the title product.

Example 94

Preparation of 3-methyl- [4-chloro-3- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

6- [4-Amino-3- (trifluoromethyl) phenyl] -3 (2H) -pyridazinone to 6- [3-chloro-5- (trifluoromethyl) phenyl] -3 (2H)- Convert to pyridazinone. Reaction of the compound with phosphorus oxychloride affords 3-chloro-6- [4-chloro-3- (trifluoromethyl) phenyl] -pyridazine, which is reacted with hydrazide acetate as in Example 36. Obtain the product. Melting Point 267˚ ~ 269 ℃

Example 95

Preparation of 3-methyl-6- [4-amino-3- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

75 g of trifluoroacetic acid contained 5 g of 3-methyl-6- [3-nitro-5- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine The reduced mixture with hydrogen and a palladium on carbon catalyst to give the title product. Recrystallization from metasol gives a cream color. Melting Point 240˚ ~ 242 ℃

Example 96

Preparation of [4,3-b] pyridazine with 3-methyl-6- (2-chloro-5-methylphenyl) -1,2,4-triazol

As in Example 35, reacting 2-chloro-5-methyl-benzaldehyde with morpholine and potassium cyanide yields Y- (2-chloro-5-methylphenyl) -4-morpholine acetonitrile. In a similar manner as in Example 35, the compound was converted to 3-chloro-6- (2-chloro-5-methylphenyl) pyridazine, which was reacted with hydrazide acetate in reflux n-butanol for 24 hours to give the title To get the product.

Example 97

Preparation of 3-methyl-6- (2,3-dichlorophenyl) -1,2,4-triazolo [4,3-b] pyridazine

As in Example 35, 2,3-dichlorobenzaldehyde is converted to 3-chloro-6- (2,3-dichlorophenyl) pyrazine. A mixture of this compound and hydrazide acetate was refluxed in n-butanol for 24 hours to afford the title product.

Example 98

Preparation of 6- (2-methyl-5-chlorophenyl) -1,2,4-triazolo [4,3-b] pyridazine

As in Example 35, 2-methyl-5-chlorobenzaldehyde is converted to 3-chloro-6- (2-methyl-5-chlorophenyl) pyrazine. Reflux of the compound and formyl hydrazine in reflux for 24 hours in n-butanol affords the title product.

Example 99

Preparation of [4,3-b] pyridazine with 6- [3-chloro-5- (trifluoromethyl) phenyl] -1,2,4-triazol

As in Example 35, 3-chloro-5- (trifluoromethyl) benzaldehyde is converted to 3-chloro-6- (3-chloro-5- (trifluoromethyl) phenyl] pyridazine. The mixture is reacted with formylhydrazine for 24 hours in reflux n-butanol to give the title product.

Example 100

Preparation of 3-methyl-6- [3-chloro-5- (trifluoromethyl) phenyl] -1,2,4-triazolo [4,3-b] pyridazine

The mixture of 3-chloro-6- [3-chloro-5- (trifluoromethyl) phenyl] pyridazine and this hydrazide acetate in reflux for 24 hours in n-butanol affords the title product.

Claims (1)

The following compound of formula (IV) is reacted with the following compound of formula (V) at reflux in a lower alkanol solvent to substitute 6-phenyl-12,4-triazole [4,3-b] pyri of formula (VI) How to prepare chopped.

Wherein R ₁ , R ₂ , R ₃ are each hydrogen or alkyl having up to 3 carbon atoms, R ₄ is hydrogen, fluoro, chloro, bromo, cyano, trifluoromethyl, nitro, amino, Acetamido, carabamoyl, thiocarabamoyl or alkyl having up to 4 carbon atoms, where at least one of R ₁ and R ₂ is hydrogen and when R ₁ , R ₂ and R ₄ are all hydrogen R ₃ may not be methyl, and R ₁ and R ₄ may not be hydrogen when both R ₂ and R ₃ are methyl.