GB2088376A - Process for Preparing 6-Amino- 3-hydrazinopyridazine Derivatives - Google Patents

Abstract

A process for preparing 6-amino- 3-hydrazinopyridazine derivatives which comprises reacting a 3,6- dihalogenopyridazine derivative with an amine, treating an acid addition salt of the obtained 6-halo-3- pyridazineamine with (C4-C13) alkylcarbazate to yield the corresponding aminopyridazinylcarbazate, which is in turn hydrolyzed to yield a 6-amino-3- hydrazinopyridazine derivative, The substituted amino-3-carb-t- butoxyhydrazinopyridazines are claimed per se.

Description

SPECIFICATION New Process for Preparing 6-amino-3-hydrazinopyridazine Derivatives The present invention refers to a new process for preparing compounds of the general formula

and the acid salts thereof, wherein the symbols R5 and R6 independently represents hydrogen, (C1- C6)al kyl, (C3-C6)-alkenyl, (C3-C6)a Ikynyl, hydroxy-(C1-C6)a Ikyl, (C14)-alkoxy-(C1-C6)alkyI, (C,-C,)alkanoyloxy-(C,-C,)alkyl, phenyl, phenyl substituted with 1 to 3 substituents independently selected from chloro, fluoro, bromo, (C1-C4)-alkyl, (C1-C4)alkoxy, phenyl substituted by methylenedioxy, phenyl(C1-C4)alkyl in which the phenyl ring may be substituted as above, or R5 and R6 taken together with the adjacent nitrogen atom may also represent a fully or partially hydrogenated 5 to 7 membered heterocyclic ring which may contain a further heteroatom selected from 0, N and S and bear 1 to 2 substituents selected from (ClC4)-alkyl, hydroxy, hydroxy(C,-C,)alkyl, phenyl, and phenyl substituted with 1 to 3 substituents independently selected from chloro, fluoro, bromo, hydroxy, (C14)alkyl, and (C1-C4)-alkoxy, R7 and Ra represent hydrogen atoms or, taken together, a 1,3butadienylene group forming a benzo system fused with the pyridazine ring. Examples of acid salts of the compound of the above formula I are the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, oxalate, tartrate, citrate, malate and the analogs. From these salts, the corresponding free bases may be obtained by treating the selected salt with an equimolecular amount of a suitable basic agent, such as, for instance, an alkali hydroxide. The acid addition salts of the compounds of formula I may be prepared by treating the free base with an equimolecular proportion of the predetermined acid.

The compounds of formula I, which chemically are 6-amino-3-hydrazinopyridazine derivatives, as well as their corresponding salts are useful as antihypertensive, as it is described for instance in Belgian Patent 687,855, British Patent 1,373,548, Belgian Patent 744,626, and in Progress in Drug Research, Vol. 20, pages 203-205, edited by E. Juker, Birkhauser Verlag, Basel 1976.

The compounds of formula I, besides their antihypertensive action are also usefully employed as intermediates in the synthesis of the compounds described in South African Patent 67/7803 and in the preparation of N-pyrrolyl-pyridazineamines of formula II

wherein: R5, R6, R7, Ra have the same meanings as above, R, R', R2, R3, may be the same or different and are independently selected from hydrogen and (C, < 4)alkyl, R4 represents hydrogen, (C,C4)alkyl, (C14)alkylamino-, bis-(C1C4)alkylamino-(C1- C4)alkanoyl, halo-(C1-C4)alkanoyl, carbo(C14)alkoxy, carbobenzyloxy.

The N-pyrrolyl-pyridazineamines of formula II are described in European Patent Application 0009655 as antihypertensive agents. The methods for preparing the compounds of formula I which are known from the chemical literature, (as an example those described in U.K. Patent 1,157,642 and in Belgian Patent 744,626), comprise as the first reaction step, the condensation of a 3,6dihalogenopyridazine with a suitable primary or secondary amine to afford the corresponding 6-amino3-halopyridazine derivative. These compounds are generally isolated and characterized, and are subsequently reacted with a large excess of highly concentrated hydrazine hydrate thus obtaining the desired 6-amino-3-hydrazinopyridazine derivatives.

The above mentioned procedures have several drawbacks which are essentially due to the use of large amounts of concentrated hydrazine hydrate as the reaction partner in the second reaction step.

As it is known from the chemical literature (see for instance the 8th Edition of the Merck Index, page 539, 1 968) and from the experimental practice, the hydrazine, both in the anhydrous as well as in the equally reactive hydrated form, is a very poisonous reactant, causes delayed eye irritation, and easily inflames. It corrodes glass, rubber and some stainless steels, and must be used under rigorously controlled reaction conditions, as an example in the absence of air and traces of some metal cations (as an example iron, molybdenum and the like) to avoid explosions. It is therefore clear that the use of highly concentrated hydrazine on industrial scale presents several difficult problems both from the technical and from the safety standpoint.All of the drawbacks connected with the prior art methods can be overcome following the process of the present invention.

One of the advantages of the process of the present invention, over the previously described ones, is therefore the replacement of hydrazine or highly concentrated hydrazine hydrate with a (C4- C,3)alkylcarbazate derivative, thus avoiding the above identified risks and drawbacks.

According to the prior art methods some of the products, depending on the meanings of R5 and R6, were obtained with low yields, while following this new process the yields are considerably increased.

A scheme of the process is the following: SCHEME I

wherein: R5, R8, R7, R8 are as defined above, R9, R'O, and R", are independently (C,C4) alkyl groups, X represents chloro, bromo, iodo, and HY represents a mineral acid, e.g. a hydrohalidic acid, sulphuric acid, phosphoric acid or the like.

The first step is the preparation of 3-halo-6-pyridazineamine derivatives, wherein halo represents chloro, bromo, iodo. According to U.K. Patent 1,115,642 the amine of formula HNR5R6, is allowed to react with the appropriate 3,6-dihalopyridazine of formula Ill at a temperature comprised between 900 and 1 500C in the presence of a solvent, or, with no solvent, at the melting temperature. The compounds of formula IV so obtained are recovered according to the usual procedures.

The second step is the preparation of the hydrohalogenide of the compound of formula IV by reacting the 3-halo-6-substituted-aminopyridazine derivative with an excess of an acid HY (as defined above) e.g. a halogenhydric acid HZ, wherein Z represent chloro, bromo or iodo.

The above obtained product of formula V is then reacted with (C4C,3)alkylcarbazate to give the 6-substituted-amino-3-pyridazinylcarbazate.

The specific feature of the alkylcarbazate derivatives that can be used in the process of the present invention is the easiness of hydrolysis under mild acidic conditions, so that, once they have reacted with the selected 6-halo-3-pyridazineamine, they are easily hydrolyzed to obtain the hydrazine derivative of formula I.

According to the process of the present invention, an excess (C4-C13)alkylcarbazate, preferably about 2-3 molar proportions, is added to a solution of the appropriate 6-halo-3-aminopyridazine hydrohalide in a suitable inert organic solvent, i.e. a solvent in which the reactants are sufficiently soluble to allow the reaction to proceed, but which does not itself react with the functional groups of the reactants or of the final products.Such solvents are advantageously selected from alkanols containing from 3 to 6 carbon atoms, such as, for instance, propanol, butanol, isobutanol, 1 -pentanol, 2-pentanol, 3-pentanol, 3-methyl-2-pentanol, 4-methyl-3-pentanol, 1 -hexanol, 2-hexanol, or 3hexanol, cycloalkanois containing from 5 to 7 carbon atoms, e.g. cyclopentanol, cyclohexanol or cycloheptanol, glycols containing from 2 to 4 carbon atoms and the corresponding mono- or di-(C1 C2)alkyl ethers or esters, e.g., ethylene glycol, bis-(2-methoxyethyl)ether, ethylene glycol monomethyl or monoethyl ether, ethyleneglycol monoisopropylether, ethylene glycol monoacetate; 1,2 propanediol, 1,3-propanediol, 1,3-propanediol monoacetate; 1,3-propanediol monoethylether, 1,2butanediol, 2,3-butanediol or 2,3-butanediol monomethylether, benzyl alcohol. Preferred solvents are the alkanols from 4 to 5 carbon atoms and the mono- and di-(C1C2)alkyl ethers of ethyleneglycol and 1 ,2-propanediol.

The reaction mixture is generally heated at a temperature higher than 500C and preferably at the reflux temperature of the reaction mixture.

The reaction is monitored by t.l.c. (thin layer chromatography) and it is generally completed in 24-36 hours or more.

It is not necessary to isolate the compounds of formula VI so obtained, but they can be hydrolyzed directly under mild acidic conditions.

Generally, inorganic acids are employed, and preferably halogenhydric acids.

According to a preferred embodiment, hydrochloric acid is employed in a concentration comprised between 5% and 12%.

The hydrolytic step produces also hydrazine hydrohalide because of the hydrolysis of the (C4 C13)alkylcarbazate excess, and other by-products. The hydrazine hydrohaiide is insoluble in concentrated hydrohalidic acid, while the main product is still soluble in these conditions, and could be separated by filtration.

Sometimes it is difficult to separate completely the main product from the by-products simply following the above procedures.

When it occurs, it may be useful to prepare the hydrazone of t e 3 the 3-hydrazino-6-substituted- amino pyridazine using benzaldehyde or other suitable aromatic aldehydes. This reaction- is preferably carried out under alkaline conditions such as those provided by alkali metal carbonate and bicarbonate water solutions, and the like. The hydrazone of the desired product generally is insoluble in many organic solvents in which, on the contrary, the reaction byproducts are soluble. This fact can be used for purification purposes; the main product is separated from the undesired by-products by adding one or a mixture of said organic solvents. The recovery is easily carried out by filtration. Examples of such solvents are lower alkanols of at least 3 carbon atoms, alkyl ethers, and the like. Preferred solvents are isopropyl alcohol and ethyl ether.

The hydrazone of the 3-hydrazino-6-substituted amino pyridazine derivative is then hydrolyzed under acidic conditions to give the 3-hydrazino-6-substituted amino pyridazine derivative in a pure and solid form.

A preferred hydrolytic agent is a hydrogen halide, HZ (preferably HX) defined as above. According to a further preferred embodiment 5-10% hydrochloric acid is employed in this hydrolysis.

The separation step involving benzaldehyde is described in Journal of Medicinal Chemistry 1975, 18, 741-746, by Pifferi et al.

The final products of formula I so obtained may be used per se, as antihypertensive agents, or may be used to prepare N-pyrrolyl pyridazineamines of formula II, through the reaction with an appropriate diketone (as described in EPA 0009655), or used as intermediates for preparing the compounds of South African Patent 67/7803.

The intermediate products of formula VI are new and represent further specific object of the present invention. However, substituted amino-3-carbethoxyhydrazino pyridazines of formula

(where R1 and R2 represent (C16)alkyl, allyl, 2-hydroxyethyl, 2-hydroxypropyl), are described as antihypertensive agents in Belgian Patent 811,847 and British patent 1,470,747. These compounds however could not usefully be employed as intermediates in the process of the present invention because, unlike the (C4-C13)alkoxycarbonyl group, the ethoxycarbonyl group does not easily hydrolyze under the mild acidic conditions, employed in the process of the present invention.

The following examples are intended to better describe the process of the present invention, but are not to be considered as limitative of its scope.

Example 1 6-Hydrazino-3-[N,N-bis(methoxyethyl)]amino pyridazine dihydrochloride A) 149 g (1 mole) of 3,6-dichloropyridazine are slowly added to 266.4 g (2 mole) of bis(2 methoxyethyl)amine heated at 140aC.

Heating is continued with stirring for further 5 hours, then the reaction mixture is allowed to reach room temperature, dissolved in 600 ml of ethyl acetate and washed twice with water (300 ml).

The organic solvent is distilled under vacuum and the residue is purified by distillation under vacuum, (b.p. 115-11 80C/0.4 mmHg). 100 g of 3-chloro-6-bis(2-methoxyethyl)amino pyridazine are obtained, yielding about 40.7%.

Mp. 33340 C.

B) 1 00 g of the product obtained as above are dissolved in ethanol (200 ml) and acidified adding a solution of hydrogen chloride in ethyl either. The solvent is boiled off under vacuum and the residue is crystallized from acetonitrile.

Yield 84 g (83%) of 3-chloro-6-bis-(2-methoxyethyl) amino pyridazine hydrochloride.

Mp. 130-1320C.

C) t.-Butylcarbazate (72 g, 0.545 mole) is added to a solution of 3-chloro-6-bis(2 methoxyethyl)aminopyridazine hydrochloride (65 g, 0.23 mole) in 2-methoxyethylenglycol (900 ml).

After boiling at the reflux temperature for 26 hours, the mixture is allowed to reach room temperature and the solvent is evaporated off under vacuum.

The residue is dissolved in 10% hydrochloric acid heating for few minutes at 50--800C, dried again under vacuum, added with 37% hydrochloric acid, and then filtered.

The hydrazine hydrochloride is recovered on the filter, the filtrate is distilled under vacuum and tha obtained residue is dissolved in water, alkalinized vvith sodium carbonate, and extracted with toluene (300 minx3).

D) Benzaldehyde (60 g) is added to the alkaline water solution and the reaction mixture is kept warm in waterbath for 1 5 minutes and then filtered. The filtrate is discarded, the solid on the filter is dissolved in methanol, then the methanol is distilled under vacuum, and the residue is taken up with isopropanol and precipitated with ethyl ether.

Benza I-6-[N,N-bis(2-methoxyethyl)amino]-3-pyridazinyl hydrazone is recovered and crystallized from 95% ethanol, yielding 34.5 g, (45.6%).

Mp. 138--1390C.

E) The above product (32.5 g) is dissolved in 37% hydrochloric acid (100 ml) and water (400 ml), and then dried under vacuum. This operation is repeated till there is no reaction with 2,4-diphenylhydrazine.

The residue is dissolved in boiling isopropanol and precipitated with ethyl ether.

Obtained 29.9 g (96.5%) of the compound of the title.

Mp. 1 950C (dec.).

Example 2 6-Hydrazino-3-[N,N-bis(ethyl)amino]pyridazine dihydrochloride A) 3-Chloro-6-bis(ethyl-aminopyridazine is known from Schonback and Klamstein Monatsh.

Chem. 99,15(1968) B) The 3-chloro-6-bis(ethyl)amino pyridazine chloridrate is formed bubbling hydrogen chloride in a solution of 3-chloro-6-bis-ethylaminpyridazine in 2-propanol.

Mp. 134-1 350C (from 2-propanol/Ethyl Ether), yield about 90%.

C) 55.5 g (0.25 mole) of the above product and 82.5 g (0.625 mole) of the t.-butylcarbazate are reacted according to Example 1C) and the obtained 2-[6-diethylamino)-3 pyridazinyl]hydrazinecarboxylic acid t.butyl ester is in turn hydrolyzed following the second part of the same Example 1 C).

D) Then 62.5 g of benzaldehyde are added to the product of the above reaction following Example 1, D) obtaining 20.9 g of benzal-2-[6-bis(ethyl)amino pyridazinyl]-hydrazone. Yield 31.2%, Mp. 200-2050C.

The same compound is obtained also by Pifferi et al. J. of Medicinal Chemistry, 18, 741 746.

The yields starting from the 3-chloro-6-bis-ethylaminopyridazine reported in the above quoted paper is 15%, [see No. 26 Table IV, page 744] while with our new process about 28% is obtained, starting from the same product.

E) The product of the title is obtained from the above compound according to Example 1, E.

(Yield 99 ,6) Mp. 235-2380C (dec.).

Example 3 6-Hydrazino-3-[(4-morpholinyl)amino]pyridazine di hydrochloride A) The 3-chloro-6-(4-morpholinyl)pyridazine is known from E. Bellasio et al. "II Farmaco" Ed.

Sc. 24,912(1962).

B) 30 g (0.15 mole) of the above product are dissolved in methanol and acidified adding a solution of hydrogen chloride in ethyl ether.

Adding new ethyl ether (1 50 ml) a precipitate is recovered, and crystallized from isopropanol obtaining 27 g (Yield 76%) of 3-chloro-6-(4-morpholinyl)pyridazine hydrochloride.

Mp. 197-2080C.

C) 23.6 g (0.1 mole) of the above product and 33.4 g (0.25 mole) of t.-butylcarbazate are reacted as described in Example 1, C).

D) 25 g benzaldehyde are added to the product of the above reaction following the procedures described in Example 1, D), yielding 11.6 g of benzal-6-(4-morpholinyl)-3-pyridazinyl) hydrazone.

(41%), Mp. 278-2800C.

E) 9.1 g of the product of the title are obtained starting from 10 g of the above product (Example 3, D) following the procedures described in Example 1, E).

Yield 96%, 231-2330C.

Claims (10)

Claims

1. A process for preparing 3-hydrazino-6-pyridazineamine derivatives of formula

and the acid salts thereof, wherein the symbols R5 and Ra independently represent hydrogen, (C1- C6)alkyl, (C3C6)alkenYl; (C3-C8)alkynyl, hydroxy-(C,-C,)alkyl, (C1C4)alkoxy(C1C6)alkyl (C2- C4)alkanoyloxy-(C1-C6)alkyl, phenyl, phenyl substituted with 1 to 3 substituents independently selected from chloro, fluoro, bromo, (C1C4)alkyl, (C1C4)alkoxy, phenyl substituted by methylenedioxy, phenyl (C1-C4)alkyl in which the phenyl ring may be substituted as above, or R5 and R6 taken together with the adjacent nitrogen atom may also represent a fully or partially hydrogenated 5 to 7 membered heterocyclic ring which may contain a further heteroatom selected from 0, N and S and bear 1 to 2 substituents selected from (C1-C4)alkyl, hydroxy, hydroxy (C1-C4)alkyl, phenyl, and phenyl substituted with 1 to 3 substituents independently selected from chloro, fluoro, bromo, hydroxy, (C1-C4)alkyl, and (C1-C4)alkoxy. R7 and R8 represent hydrogen atoms or, taken together, a 1,3 butadienylene radical forming a benzo system fused with the pyridazine ring, which comprises, reacting a derivative of formula

wherein X represents Cl, Br, I, and HY represents an inorganic acid, with (C4C13) alkylcarbazate of formula H2N-NH-COOC(R9R10R11) wherein R9, R10, and R11 independently represent (C1-C4)alkyl groups in a suitable inert organic solvent, heating at a temperature higher than 500C, and hydrolysing the obtained intermediate under mild acidic conditions.

2. A process as in claim 1 wherein from 2 to 3 moles of t.-butylcarbazate are employed per mole of pyridazineamine derivative.

3. A process as in claim 1 in which the organic solvent is selected from alkanols containing from 3 to 6 carbon atoms, such as, propanol, butanol, isobutanol, 1 -pentanol, 2-pentanol, 3-pentanol, 3- methyl-2-pentanol, 4-methyl-3-pentanol, 1 -hexanol, 2-hexanol or 3-hexanol, cycloalcanols containing from 5 to 7 carbon atoms, e.g. cyclopentanol, cyclohexanol or cycloheptanol, glycols containing from 2 to 4 carbon atoms and the corresponding mono- or di-(C1C2)alkyl ethers or esters e.g., ethylene glycol, ethylene glycol monomethyl or monoethyl ether, ethyleneglycol monoisopropylether, ethylene glycol monoacetate; 1,2-propanediol, 1,3-propanediol, 1,3-propanediol monoacetate; 1,3-propanediol monoethylether, 1 ,3-butanediol, 2,3-butanediol or 2,3-butanediol monomethylether, benzyl alcohol, dioxane or dimethylformamide.

4. A process as in claim 1 in which the temperature is the reflux temperature of the reaction mixture.

5. A process as in claim 1 in which the hydrolysis is carried out with 5-12% HCI.

6. A process as in claim 1 wherein the final product is conveniently separated from the reaction mixture by conversion into the corresponding hydrazone of benzaldehyde or other suitable aromatic aldehyde.

7. A process as in claim 1 for preparing a compound of formula I wherein R7 and R8 are hydrogen and R5 and R8 represent(C1C6)alkyl, (C1--C4)alkoxy(C1--C6)alkyl or R5 and R8 taken together with the adjacent nitrogen group represent a fully or partially hydrogenated 5-7 membered heterocyclic ring which may contain a further heteroatom selected from 0, N and S and bear 1 to 2 substituents selected from (C1-C4)alkyl, hydroxy and hydroxy-(C1C4)alkyl, phenyl, and phenyl substituted with 1 to 3 substituents independently selected from chloro, fluoro, bromo, hydroxy, (C1- Clkyl, (C1C4)-alkoxy.

8. A process for preparing a compound of formula I wherein R7 and R8 are hydrogen and R5 and R6 represent (C1 C6)alkyl, (C1--C4)alkoxy(C1--C6)alkyl or R5 and R6 taken together with the adjacent nitrogen group represent a fully or partially hydrogenated 5-7 membered heterocyclic ring which may contain a further heteroatom selected from 0, N and S and bear 1 to 2 substituents selected from (C1-C4)alkyl, hydroxy and hydroxy-(C1C4)alkyí, phenyl, and phenyl substituted with 1 to 3 substituents independently selected from chloro, fluoro, bromo, hydroxy, (C1C4)alkyl, (C1-C4)alkoxy in which the solvent is 2-methoxyethanol, the temperature of the reaction mixture is the reflux temperature, the hydrolysis is performed in 512% HCI, and the final product is conveniently reacted with benzaldehyde or other aromatic aldehydes to form the hydrazone derivative which is separated and in turn hydrolyzed under mild acidic conditions.

9. A process as in claims 1 to 8 further characterized in that the (C4C13)alkylcarbazate reactant is tbutylcarbazate.

10. A compound of formula

wherein R5, R6, R7, R8 have the same meanings as in claim 1.