3-(o-Hydroxyphenyl)-5-formylhydrazino-.DELTA..sup.2 -pyrazolines

Abstract

New 3-(o-hydroxyphenyl)-5-formylhydrazino-.DELTA..sup.2 -pyrazolines useful in the preparation of 6-(2-hydrophenyl)-3-pyridazinones which are in turn important intermediates for preparing medicinally active compounds especially 3-[2-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine.

Description

The new process of this invention for preparing 6-(2-hydroxyphenyl)-3-pyridazionones comprises the reaction of 1,1 1-trichloro-2-hydroxy-4-(2-hydroxyphenyl)-4-butanones with hydrazine at elevated temperatures in an inert organic solvent.

PRIOR ART

6-(2-Hydroxyphenyl)-3-pyridaziones are important intermediates for preparing medically active compounds. As one example, one may use these intermediates for preparing the hypotensive agent, 3-[2-(3-t-butylamino-2-hydroxypropoxy)-phenyl]-6-hydrazino-pyridazine. Such 3-pyridazinone intermediates can be prepared by cycling the appropriate 3-benzoylpropionate ester with hydrazine followed by oxidation of the resulting phenyldihydropyridazinone appropriately protected or by reaction of an appropriate 3-benzoyl acrylic acid ester with hydrazine. Y. Y. Lee et al., J. Korean Chemical Society 17, 25 (1973) reported on the preparation of substituted 2,6-diphenyl-3-pyridazionones by reacting the corresponding trichloroethylideneacetophenones with phenylhydrazine. Of course, as stated, this gives the undesirable 2-phenyl-3-pyridazinone derivative. Lee reports, however, that only the pyrazoline derivative was obtained using hydrazine in place of phenylhydrazine. The present invention goes against the teaching of the art. Also pertinent to the presently claimed invention is F. G. Baddar et al., J. Chem. Soc. 3342: (1965) which discloses a number of 6-aryl-2,3-diphydropyridazin-3-ones which lack the essential hydroxyphenyl moiety.

We have now found that 1,1,1-trihalo-2-hydroxy-4-(2-hydroxyphenyl)-4-butanones (I, trihalocarbinols) react with hydrazine preferably in the presence of an elevated temperature to give the desired 6-(2-hydroxyphenyl)-3-pyridazinones (III) in good yields. ##STR1##

In the above exemplary sequence R may be hydrogen or any chemically inert substituent such as lower alkyl for example methyl or ethyl, lower alkoxy for example methoxy or ethoxy, lower alkylthio for example methylthio or ethylthio, halo for example fluoro, chloro or bromo or trifluoromethyl; X is bromo or preferably chloro.

Unexpectedly therefore the presence of a hydroxy substituent in the 2-position of the phenyl ring in compounds I above has been found critical to the reaction. When this hydroxy is absent or etherified as in a methoxy group, the reaction to form a pyridazone either fails completely or gives a very small quantity of the desired product. The reactions of this invention have now been demonstrated to proceed through a unique intermediate compound.

The claimed reaction (I.fwdarw.III) can be run in one step by reacting the trihalocarbinol with hydrazine, preferably as hydrazine hydrate and in excess, in an organic solvent in which the reactants are soluble and to which they are chemically inert at elevated temperatures, for example at above 150.degree. preferably from 150.degree.-175.degree.. Of course the solvent must have a boiling point at or above the reaction temperatured at which the process is carried out unless the reaction is carried out in a pressure reactor. At lower temperatures the pyrazoline derivative is formed in substantial amounts along with the desired pyridazinone (III). For example at about 120.degree. only 20-30% of III is obtained but at 165.degree.-170.degree. 60-70% of partially pure product is obtained.

The solvent is preferably ethylene glycol but similar products may be used such as propylene glycol or the common ether (methyl) or ester (acetate) derivatives of such glycols. Other high boiling inert solvents may be used such as water, dimethylsulfoxide, dimethylacetamide or dimethylformamide. The reaction is allowed to go to completion but reaction times of from about 2-25 preferably about 10 to 20 hours at 155.degree.-175.degree. may be used to best advantage.

The reaction gives excellent yields if an inorganic base is present during the reaction such as an alkali metal carbonate, bicarbonate or hydroxide. Most useful are sodium or potassium carbonates and in about two mole equivalent quantities based on the carbinol starting material. The desired product is isolated by methods known to the art as will be apparent from the illustrative examples.

The starting material trihalocarbinol (I) is prepared by reacting the appropriate o-hydroxyacetophenone with chloral, bromal or a reactive derivative thereof such as the hydrate or alcoholate preferably in acetic acid in the presence of the advantageous ammonium acetate. In all the reactions described herein bromal or the tribromocarbinol derivative corresponding to I can be substituted. However chloral is preferred on a cost per gram basis.

For example, the trichlorocarbinal (I) is reacted with an excess of hydrazine hydrate at 90.degree. for one hour. The structure of the intermediate products assigned in the empirical formula C.sub.10 H.sub.12 N.sub.4 O.sub.2 from the analytical data on the parent compound is a hydrazide having the structural formula: ##STR2## in which R is as defined above but is usually hydrogen.

This compound (IV) is then reacted with an excess of hydrazine hydrate in ethylene glycol at 170.degree.-175.degree. for two hours. Working up the resulting product gives a good yield of the desired 6-(2-hydroxyphenyl)-3-pyridazinone (III).

On the other hand reacting trichlorocarbinols without the necessary 2-hydroxy phenyl substitutent yield mostly the expected hydrazone (V):

The following examples are intended to illustrate the practice of this invention to those skilled in the art. All temperatures are on the Centigrade scale.

EXAMPLE 1

(A) To a solution of o-hydroxyacetophenone (20.4 g, 0.150 m) and ammonium acetate (13 g, 0.17 m) in acetic acid (90 cc) was added chloral hydrate (32 g, 0.19 m) and the solution stirred at 115.degree.-120.degree. overnight. The heat was removed and water (100 cc) was added and the solution stirred while cooling to 15.degree.. A brown-precipitate formed and after 1 hour of stirring it was collected and washed with dilute acetic acid. On drying the light brown solid weighed 33.7 g (79%), m.p. 111.degree.-114.degree.. The thin layer chromatogram (toluene: cyclohexane: acetonitrile: acetic acid--10:10:5:1) on silica gel showed 1 minor and 3 trace components as well as the major component, 1,1,1-trichloro-2-hydroxy-4-(o-hydroxyphenyl)-4-butanone. This is a new compound to the best of our knowledge and is part of this invention.

An identical reaction was run using 90 cc of propionic acid in place of acetic acid. The yield of tan solid was 32.4 g (7%) after drying. A portion of this sample (5 g) was recrystallized from 70% ethanol with a bone carbon treatment with 80% recovery. The thin layer shows essentially 1 spot with a trace at the origin, m.p. 122-124.5.degree..

______________________________________Assay Calc'd Found______________________________________ C 42.36 41.77 H 3.20 3.26 Cl 37.51 38.98______________________________________ Use of catalysts such as pyridine or sodium acetate in place of ammonium acetate resulted in very sluggish reactions with yields only 20-30%.

(B) A solution of o-hydroxyacetophenone (6.8 g, 50 mm), anhydrous chloral 8.25 g (5.5 cc, 56 mm), acetic acid (30 cc) amd pyrrolidone (2.7 cc) was stirred and heated 15 hours at 110.degree.. The gas chromatogram indicated the presence of o-hydroxyacetophenone and the reaction was treated with 1 cc of chloral and 0.2 cc of pyrrolidine and the reaction heated at 120.degree. for 5 hours. On slow addition of water and cooling a dark precipitate formed. The dark product was filtered, washed with water and dried. The product was crystallized from benzene-petroleum ether to give 6.4 g of trichlorocarbinol (45%), m.p. 120.degree.-124.degree..

EXAMPLE 2

A solution of hydrazine hydrate (4.0 g, 80 mm) in ethylene glycol (50 cc) was stirred at 100.degree.. The trichlorocarbinol (5.0 g, 17.6 mm) was added in one portion and the reaction heated rapidly to 165.degree.-170.degree. (bath temperature). After16 hours the reaction was cooled to 100.degree. and 3N hydrochloric acid was added, pH=1.2. Stirring and heating at this temperature was continued for 1.2 hours.

The reaction was poured into ice water and the tan solid collected. The solid was washed free of color with an acetone-ether mixture and dried for 12 hours at 60.degree. in vacuo. Yield 2.26 g (68%) m.p. 280.degree.(d), of impure 6-(2-hydroxyphenyl)-3-(2H)-pyridazinone.

______________________________________ Calc'd Found______________________________________ C 63.83 62.30 H 4.56 4.29 N 14.89 17.69______________________________________

The infrared spectrum and NMR were identical to a sample of authentic pyridazinone. However the high pressure liquid chromatogram indicated an impurity of 30-40% was present. The product was purified by crystallization from aqueous dimethylacetamide. Yield 1.0 g (31%).

EXAMPLE 3

A solution of thr trichlorocarbinol (15 g, 0.053 m) in 98% hydrazine hydrate (90 cc) was heated to 90.degree. for 1 hour. The reaction was cooled at 20.degree. and the solid product filtered and washed with cold aqueous alcohol. The white solid weighed 6.35 (55% based on molecular weight 220); m.p. 194.degree.-198.degree..

______________________________________Assay - Mass Spectrum M/e 220. Calc'd Found______________________________________ C 54.54 53.97 H 5.49 5.51 N 25.44 26.41______________________________________

The material contains 1.1% chloride due to ammonium chloride admixture. It reacts with 2 moles of acetone.

To a solution of hdyrazine hydrate (2.0 g, 80 mm) in ethylene glycol (20 cc) at 100.degree. was added the above compound (2 g, 9.1 mm). The solution was heated at 5 minutes at 120.degree. then a hot solution of potassium hydroxide (85%, 2.5 g) in ethylene glycol (15 cc) was added. The reaction was stirred and rapidly heated to 170.degree.-175.degree. then stirred at that temperature for 2 hours. The reaction was cooled and poured into water, and the pH was adjusted from 12 to 8.0 with 3N hydrochloric acid. A thick white precipitate formed and the solution was placed in the icebox overnight. The solid was collected and dried. Yield 0.7 g (3.72 mm, 41%) m.p. 275.degree.-280.degree.(d). The pyridazinone was identical to the product formed in Example 2.

EXAMPLE 4

The deshydroxy trichlorocarbinol (1.22 g, 4.56 mm) was added to a solution of anhydrous hydrazine (0.72 g, 22.8 mm) in ethylene glycol (8 cc) stirred at 95.degree.-100.degree. . After two hours at 110.degree., the solution was heated to 120.degree. and a hot solution of potassium hydroxide (85%, 1.42 g) in the ethylene glycol (8 cc) was added in 2 portions. The reaction was rapidly heated at 170.degree.-175.degree. for 3 hours. On cooling the reaction was poured into cold water and the pH adjusted from 11.4 to 8.0 with 3N hydrochloric acid. No product could be isolated on standing or cooling this solution. An authentic sample of the desired product was prepared by known methods and shown to be completely insoluble in a water-ethylene glycol solution at pH 8. Using this reference pyridazinone, it was determined that the solution contained 0-5% of the desired product by quantitative thin layer chromatography (Silica Gel G.F., chloroform-methanol 95-5). The chromatogram showed no starting material in a complex mixture.

EXAMPLE 5

Under conditions where the o-hydroxy compound is converted to a C.sub.10 H.sub.12 N.sub.4 O.sub.2 compound, the unsubstituted phenyl compound is simply converted to the corresponding hydrazone V.

A solution of the deshydroxy trichlorocarbinol (5.0 g, 18.7 mm) and 98% hydrazine (1:87 g, 37.4 mm) in ethanol 13 cc) was heated at 70.degree. for 3.5 hours and stirred overnight at room temperature. The reaction (precipitate present) was poured into icewater and the solid yellow, 4.9 was collected. The product (V) was crystallized from isopropyl alcohol and dried overnight--m.p. 141.degree.; there was a single spot on this layer chromatogram (silica gel, chloroform-methanol: 90-10).

______________________________________Assay (V) Calc'd Found______________________________________ C 42.66 42.65 H 3.94 4.03 N 9.95 10.09 Cl 37.77 38.01______________________________________

EXAMPLE 6

A solution of o-methoxyacetophenone (22.5 g, 150 m), chloral hydrate (32 g, 193 m), ammonium acetate and propionic acid (90 cc) is heated at 120.degree. for 4 hours. Water (120 cc) was added dropwise and the heating was removed. On cooling, a dark precipitate formed and the product was collected and washed with water. On drying the product weighed 36 g (81%) m.p. 80.degree.-84.degree.. the tan-brown product was recrystallized from benzene-petroleum ether; m.p. 82.degree.-84.degree..

______________________________________Assay Calc'd Found______________________________________ C 44.40 44.39 H 3.73 3.71 Cl 35.74 35.80______________________________________

To a solution of hydrazine hydrate (98%, 4.0 g, 80 mm) in 30 cc ethylene glycol at 110.degree. was added the above 1,1,1-trichloro-2-hydroxy-4-(o-methoxyphenyl)-4-butanone (5.24 g, 17.6 mm). After 2 hours at that temperature a hot solution of potassium hydroxide (85%, 5.28 g, 80 mm) in 30 cc of ethylene glycol was added, and the temperature rapidly raised to 170.degree.-175.degree.. After 2 hours the reaction was cooled, and quenched in 150 cc of ice water (pH=11). The pH of the solution wad adjusted to 8 bit no ppt formed on cooling or standing overnight. The pH was then adjusted to pH-2. No precipitate formed on standing or cooling.

A portion of the above solution was neutralized and extracted with chloroform. Only a small amount of organic soluble material was present.

EXAMPLE 7

The trichlorocarbinol 5.0 g (17.6 mm) was added to a stirred solution of hydrazine hydrate (98-99%, 3.0 g 60 mm) in ethylene glycol (50 cc) at 80.degree.. After 2 hours at 80.degree., the reaction mixture was removed from the heat and finely powdered potassium carbonate (4.69 g, 34 mm) was added in one portion. No evaluation of gas was noted.

This reaction mixture was placed in an oil bath preheated to 175.degree.-180.degree.; and stirred for 3-4 hours. The reaction was cooled to about 80.degree.-90.degree. and poured into cold water containing 2 cc of 1N sodium hydroxide.

The pH was adjusted for 8 and the solid was collected and washed with water and acetone and dried. The yield, corrected for purity was 44% of 6-(2-hydroxyphenyl)-3-(2H)-pyridazinone.

EXAMPLE 8

Substituting a molar equivalent quantity of bromal in the procedures of Examples 1(A) and 2 gives 6-(2-hydroxyphenyl)-3-pyridazinone.

Claims

1. The compound of the formula: ##STR4## in which R is hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, halo or trifluoromethyl.

2. The compound of claim 1 in which R is hydrogen.

3. The method of preparing a compound of the formula: ##STR5## in which R is hydrogen, methyl ethyl, methoxy, ethoxy, methylthio, halo or trifluoromethyl in which a compound of claim 1 is heated at about 170.degree.-175.degree. with one mole equivalent of hydrazine hydrate in the presence of base in ethylene-glycol until the reaction is complete.

4. The method of claim 3 in which R is hydrogen and the base is an alkali metal.

5. The method of claim 3 in which the base is potassium hydroxide.

6. The method of claim 3 in which the base is hydrazine hydrate in excess of one mole equivalent.