NO853732L - PROCEDURE FOR PREPARATION OF PYRAZOLONE DERIVATIVES. - Google Patents

Description

The invention relates to an improved preparation method for 1-substituted 3-amino-pyrazolone-(5), in that in a first step 4, a hydrazine derivative is condensed acidic with 8-amino-B-alkoxy-acrylic acid alkyl ester and the intermediate product is subjected in a second step to a strongly basic environment at temperatures below 10°C for a ring closure reaction.

3-amino-pyrazolone-(5)-derivatives and the process for their preparation are described in DE-OS 2 319 280. The compounds have a pronounced diuretic and antihypertensive effect, since 3-amino-1-methyl-4-chlorobenzyl)-pyrazolone -(5) ("Muzolimin") has proven valuable. With regard to the pharmacological effect of muzolimin, it shall e.g. refer to Recent Advances in Diuretic Therapy: Proe. of the Sec. Int. Edrul Symposium (1983), published by V.E. Andreucci, Excerpta Medica, Amsterdam, to Clin. Nephrol. 19 (1983): Suppl. 1, Loew et al in Eur. J. Clin. Pharmacol., 12 (1977), pp. 341-344 and the literature cited therein.

The amino-pyrazolones are obtained according to DE-OS 2 319 280 by reacting the corresponding hydrazine with a suitable acetic acid derivative, optionally in the presence of inert -:-. solvent and basic or acidic catalysts such as alkali and alkaline earth hydroxides and carbonates or as hydrohalic acids, sulfuric acid or sulphonic acids, at temperatures between 10 and 200°C. Muzolimin is obtained according to example 9 in DE-OS 2 319 280, whereby 6-amino-g-ethoxyacrylic acid ethyl ester and p-toluenesulfonic acids are mixed in absolute alcohol dropwise with α-methyl-3,4-dichlorobenzylhydrazine, the mixture is stirred, allowed to stand overnight and the alcohol evaporates. The residue is dissolved in 2n-NaOH and freed from impurities by extraction with ether. The aqueous phase is brought to pH 5 with acetic acid, the oil formed is taken up in methyl chloride, dried and the solvent is evaporated.

The method mentioned in DE-OS 2 319 280 has a number of disadvantages: The product formed is yellowish, and the yields are, above all when transferred on a technical scale, small (approx. 20-25%). It was thus the task of the present invention to find a technically simple synthesis method for amino-pyrazolones, which enables high yields of color-impeccable product also in large-scale technical mixtures. This task is solved with the method according to the invention.

The task of the invention is a method for the preparation of pyrazolone derivatives with the formula:

R means hydrogen, alkyl, alkenyl or optionally substituted aryl or aralkyl, 2 R means an alkyl residue, and R 3 means an optionally substituted aryl residue, which contains up to two identical or different substituents from the group hacogen, trifluoromethyl, alkyl, alkenyl, alkoxy or contains an alkylamino-, trifluoromethoxy-, nitro-, cyano-, carbonamino-, sulfonamido- or SO n-alkyl residue (n = 0-2), optionally together with one or two substituents from the group alkyl, alkenyl, alkoxy, halogen or trifluoromethyl, where optionally two substituents at the aryl residue together form a branched or unbranched, saturated or unsaturated 5- to 7 -membered isocyclic or heterocyclic ring, which in turn may contain 1-2 oxygen atoms or sulfur atoms, whereas a hydrazine of formula

in which R 2 and R 3 have the above meaning, is reacted with an acetic acid derivative of formula in which R"'" has the above meaning, X means a hydroxy, alkoxy, aralkyl, amino or alkylamino residue and Y means an alkoxy, aryloxy, aralkyloxy, alkylmercapto or aralkylmercapto residue or an amino group, in the presence of basic or acidic catalysts, as well as any inert solvent, in that the method is characterized by a) the acetic acid derivative (III) is used in the form of a salt with a strong acid, b) the salt of the acetic acid derivative (III) is condensed with the hydrazine (II) in a first step in the presence of 0.1-2.0 equivalents of a weak base in a preferably aqueous reaction medium, c) the intermediate product formed is further condensed with a concentrated aqueous solution of a strong base, keeping the reaction temperature below 10°C, and d) the reaction product is precipitated by setting a pH value from 0-3.5 using a strong aqueous acid.

Preferably, the intermediate product from the first step of the method according to the invention is also freed in an acidic environment by extraction using an organic solvent for contamination and by-products. Preferably, intermediate products are not isolated from the reaction mixture, but reacted directly further in the form of a one-pot reaction in the second step.

In formula I means preferably

R1 hydrogen, an alkyl or alkenyl radical with up to 4 C atoms, a phenyl or benzyl group, which is optionally substituted with an alkoxy group with 1-2 C atoms, particularly preferably hydrogen,

R 2 an alkyl radical with 1-4 carbon atoms, particularly preferably methyl, and

R 3 a phenyl or naphthyl residue, especially a phenyl residue, which may be substituted with 1-2 straight or branched alkyl or alkenyl residues with up to 8 carbon atoms, especially with 1-2 alkyl residues with 1-4 carbon atoms, or preferably with 1-2 Alkoxide residues with up to 6 carbon atoms, especially with up to 4 carbon atoms, or with 1 cycloalkyl or cycloalkenyl residue with 5-7 carbon atoms, or with 1-2 halogen atoms such as fluorine, chlorine or bromine or with 1-2 trifluoromethyl residues or with a trifluoromethoxy-, nitro -, cyano group or a dialkylamino-, carbonamido- or sulfonamido group, whose nitrogen atom can be substituted by 1 or 2 linear or branched alkyl groups with respectively 1-4 C-atoms, and the above-mentioned alkyl groups together with the nitrogen atom can form a 5- to 7- membered heterocyclic ring which may contain an oxygen atom as an additional heteroatom, or is substituted with a SOn~alkyl group, where n means 0-2, especially 0 or 2, and the alkyl residue is linear or branched and contains 1-4 carbon atoms, and since 2 substituents at the phenyl or naphthyl ring together can form a branched or unbranched, saturated or unsaturated 5- to 7-membered isocyclic or heterocyclic ring, which can contain 1 sulfur or 1-2 oxygen atoms .

In formula III preferably means

X hydroxyl, an optionally branched alkoxy group with 1-6

C atoms, especially 1-3 C atoms, a benzyloxy, an amino, alkylamino or dialkylamino group with respectively 1-4 C atoms per alkyl group and

Y an alkoxy or alkylmercaptor residue with respectively 1-6 C atoms in the alkyl group, especially an alkoxy acid residue with 1-3 C atoms, or a benzyloxy, phenoxy, benzylmercaptor residue or an amino group.

Examples of compounds with formula I or starting compounds of formula II and III are disclosed in DE-OS 2 319 280.

Compound III, the following mentioned "Imido ester", is used in the method according to the invention as a salt of a strong acid, (K^>• 1), preferably a mineral acid (especially hydrochloric acid).

The salt of the imidoester is reacted in the first step of the process according to the invention with the hydrazine II, preferably in an aqueous reaction medium in the presence of 0.1-2.0 equivalents of a weak base, preferably with 0.4-0.6 equivalents. Suitable weak bases are e.g. salts of carboxylic acid or amines.

Salts of carboxylic acids, especially Na acetate, are preferred. The reaction temperature is between -20°C and +50°C, preferably between 10°C and 30°C.

The reaction mixture in the first step of the method according to the invention may optionally contain a water-miscible organic solvent.

Examples of this are methanol, ethanol, isopropanol, tetrahydrofuran or dioxane.

The alcohol or alcohols corresponding to the alkoxy residue or residues of the imidoester are preferred. The reaction mixture's first step of the method according to the invention is preferably freed at the above-mentioned slightly acidic pH by extraction with the aid of an organic solvent of by-products and unreacted starting products. Suitable solvents are e.g. petroleum ether, ether, methylene chloride or toluene.

Toluene is preferred.

After separation of the organic phase from the extraction step, the aqueous phase is preferably subjected directly, i.e. without isolation of the intermediate product for the alkaline condensation reaction. This takes place by adding a concentrated strong base (K<>>1), so that the reaction mixture contains 1-10% by weight, preferably 2-5% by weight of the strong base. Strong bases preferably include alkali and alkaline earth hydroxides, especially NaOH and KOH. During the alkaline condensation reaction, the temperature of the reaction mixture must be below 10°C, preferably between -15°C and 5°C, especially at approx. 0°C. The reaction duration is preferably less than 1 hour, particularly preferably 10-30 minutes.

The reaction mixture is then adjusted by adding a strong acid (e.g. the acids mentioned above for the imidoester salt) to a pH value of 0-3.5, preferably 1-2.5, especially approx. 1.5-2, as the reaction product precipitates out. The crude product can be further purified by recrystallization, e.g. from aqueous alcohol.

The synthesis method according to the invention has a number of advantages compared to the methods mentioned in DE-OS 2 319 280: 1) The imidoester is used directly as a salt of a strong acid, i.e. in the high-tech form, the imidoester thus does not need to be prepared pure, which saves a step. 2) After the acid condensation step, no organic solvent is distilled off, i.e. time and energy are saved, and the product is not subjected to thermal stress. 3) During the extraction at acidic pH after the acidic condensation step, by-products and unreacted starting material are removed. 4) The alkaline condensation (cyclization) proves to be more manageable and reproducible at temperatures below 10°C. 5) By setting a strongly acidic pH after the alkaline condensation, by-products such as e.g. 3-N(3,4-dichloro-a <-> methylbenzyl)-acetamidrazone IV this is not the case with acidification with acetic acid. 6) The reaction product has significantly better color quality and is obtained in yields of over 50%. 7) The overall manufacturing process is faster in terms of time and technically easier to implement.

Example_l_£ifØl2§_2E£fiDD?i§erO

a) Preparation of the hydrazine (II):

1,2-dichloro-4-(1-chloroethyl)-benzene is reacted with hydrazine hydrate in a water-miscible solvent, e.g. ethanol, on heating to N-(1-(3,4-dichlorophenyl)-ethyl)-hydrazine. After separation of the hydrazine hydrochloride formed, the reaction mixture is washed with water. The hydrazine thus formed can be further processed directly, i.e. without further purification.

b) Production of muzolimin: 142 parts by weight of 2-methyl-3,4-dichlorobenzylhydrazine (raw material from step a) are mixed with 60 parts by volume of water. 69.5 parts by weight of sodium acetate trihydrate and 103.5 parts by weight of imidoester hydrochloride are then added within 10 minutes. Now stir for 25 minutes. 385 parts by volume of ethanol are then added, stirred for 10 minutes and filtered off from undissolved. The filtrate is stirred with 375 parts by volume of water and 600 parts by volume of toluene and the organic phase is separated. The aqueous phase is stirred again with 600 parts by volume of toluene and cooled after separation of the toluene to -5°C. A mixture of 82.8 parts by weight of 45% caustic soda and 128.1 parts by volume of water is now added during 10 minutes while cooling, and stirred further at 5°C. This solution is then adjusted with 140 parts by volume of a mixture of 154.7 parts by weight of hydrochloric acid (pure, 37% strength) and 46.5 parts by volume of water at pH 1.5, whereby 3-amine-1-(3,4-dichloro- α-methylbenzyl)-2-pyrazolin-5-one precipitates. A further 750 parts by volume of water are added and the crystallisate is isolated. The moist raw material is recrystallized from spirits/water and dried. 77 parts by weight of 3-amino-1-(3,4-dichloro-a-methylbenzyl)-2-pyrazolin-5-one of melting point 137°C (51.8% of the theoretical) are obtained.

Ek s emge 1 _2 Together equation)_

a) Preparation of imido ester Dissolve 109.2 g of sodium bicarbonate in 1.16 1 of water and pour over 280 ml of toluene. Now 195.7 g of imidoester hydrochloride are added in portions and stirred for 5 minutes until no more carbon dioxide evolution can be observed. The water phase is separated and extracted again with 140 ml. The combined toluene phases are dried with sodium sulphate, the sodium sulphate is sucked off and the toluene is evaporated on a rotary evaporator. 154.2 g (96.9% of the theoretical) of crude imidoester are obtained. The imido ester was distilled in high vacuum, 129.6 g (boiling point = 59-63°C, 81.4% of theory).

b) Production of muzolimin according to DE-OS 2 319 280:

To a solution of 31.8 g of imidoester and 1.5 g of para-toluenesulfonic acid in 150 ml of ethanol, 41 g of α-methyl-3,4-dichlorobenzyl-hydrazine (crude), dissolved in 50 ml, were added dropwise over the course of 18 minutes ethanol (temp

increased to 27°C, the solution became cloudy). The mixture was then stirred for another 2 hours and left to stand overnight (unclear solution, solid). The next morning, the solvent was evaporated in vacuo (bath 25°C, final pressure 16 mbar, time: 30 minutes, residue: orange-coloured oil, 73.5 g, contains solid), and the residue dissolved in 200 ml of 2 N caustic soda ( temperature increased to 30°C, again 'cooled to 20°C, stirred 10 minutes). The aqueous phase was extracted three times with 100 ml of diethyl ether each time and, after separation of the aqueous phase, adjusted to pH 5.0 with 30 ml of acetic acid. Now 100 ml of methylene chloride was added and the solid which does not dissolve was filtered off with suction.

The solid (24.5 g corresponding to 45% of the theoretical) was rinsed twice with 25 ml of methylene chloride and the combined, separated methylene chloride phases were dried with sodium sulfate. After separation of the sodium sulfate, the methylene chloride was removed in vacuo (residue: viscous oil, partially crystalline, 23.7 g) and the residue recrystallized with the previously aspirated solid from 35 ml of hot methanol. After cooling, suction, washing with methanol and drying, 22.8 g (40.5% of the theoretical) crystalline material could be isolated.

The product has a yellowish discoloration which could not be removed by recrystallization from ethanol/water either.

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Claims (10)

1. Process for the preparation of pyrazolone derivatives with formula R"^ means hydrogen, alkyl, alkenyl or optionally substituted aryl or aralkyl, 2 R means an alkyl residue and R^ means an optionally substituted aryl residue, which contains up to two identical or different substituents from the group halogen, trifluoromethyl, alkyl, alkenyl, alkoxy or contains an alkylamino-, trifluoromethoxy-, nitro-, cyano-, carbonamino-, sulfonamido- or S0n~ alkyl residue (n = o-2), optionally together with 1 or 2 substituents from the group alkyl, alkenyl, alkoxy, halogen or trifluromethyl, with optionally two substituents at the aryl residue together forming a branched or unbranched, saturated or unsaturated, 5- to 7- membered isocyclic or heterocyclic ring, which in turn may contain 1-2 oxygen or sulfur atoms, whereby a hydrazine of formula 2 3 in which R and R have the above meaning is reacted with an acetic acid derivative of formula in which R has the above meaning, X means a hydroxy, alkoxy, aralkyl, amino or alkylamino residue and Y means an alkoxy, aryloxy, aralkoxy, alkyl mercapto or aralkyl mercapto residue or an amino group, in the presence of basic or acidic catalysts as well as any inert solvent, characterized by a) the acetic acid derivative (III) is used in the form of its salt with a strong acid, b) the acetic acid derivative (III) is condensed with the hydrazine (II) in a first step in the presence of a weak base in a preferably aqueous reaction medium, c) the intermediate product formed is further condensed with a concentrated aqueous solution of a strong base, keeping the reaction temperature below 10°C, and d) the reaction product is precipitated by setting a pH value from 0-3.5 using a strong aqueous acid. 2. Method according to claim 1, characterized in that R <1> means hydrogen, an alkyl or alkenyl residue with up to 4 C atoms, a phenyl or benzyl group, which is optionally substituted with an alkoxy group with 1-2 C atoms, especially hydrogen. 3. Process according to claim 1 or 2, characterized in that R 2 means an alkyl radical with 1-4 C atoms, preferably a methyl radical. 4. Method according to claims 1-3, characterized in that R means a phenyl or naphthyl residue, especially a phenyl residue, which can be substituted with 1-2 straight or branched alkyl or alkenyl residues with up to 8 carbon atoms, especially with 1-2 alkyl residues with 1-4 carbon atoms, or preferably with 1-2 alkoxy residues with up to 6 carbon atoms, especially with up to 4 carbon atoms, or with a cycloalkyl or cycloalkenyl residue with 5-7 carbon atoms or with 1-2 halogen atoms such as fluorine, chlorine or bromine, or with 1-2 trifluoromethyl residues or with a trifluoromethoxy, nitro, cyano group or a dialkylamino, carbonamido or sulfonamide group, whose nitrogen atom may be substituted by one or two linear or branched alkyl groups with respectively 1-4 C atoms, and since the above-mentioned alkyl group together with the nitrogen atom can form a 5- to 7-membered heterocyclic ring, which can contain an oxygen atom as an additional heteroatom, or with a SOn~ alkyl group, where n means 0-2, especially 0 or 2, and the alkyl residue is linear or branched, and contains 1-4 carbon atoms, and since two substituents on the phenyl or naphthyl ring together can form a branched or unbranched, saturated or unsaturated 5- to 7-membered, isocyclic after heterocyclic ring, which can contain 1 sulfur or 1-2 oxygen atoms. 5. Method according to claims 1-4, characterized in that X ■ means hydroxyl, an optionally branched alkoxy group with 1-6 C atoms, a benzyloxy group, an amino, alkylamino or dialkylamino group with respectively 1-4 C atoms per alkyl group, especially an alkoxy group with 1-3 C atoms , and Y means an alkoxy or alkylmercaptor residue with respectively 1-6 C atoms in the alkyl group, a benzyloxy, phenoxy, benzylmercaptor residue or an amino group, especially an alkoxy acid residue with 1-3 C atoms. 6. Process according to claims 1-5, characterized in that the product from the first process step is also freed from impurities in an acidic environment by extraction with an organic solvent and is preferably further converted without isolation directly in the form of a one-pot reaction in the second process step. 7. Method according to claims 1-6, characterized in that the compound (III) is used as a salt of a mineral acid, preferably hydrochloric acid. 8. Method according to claims 1-7, characterized in that the temperature during the first method step is kept between -20°C and +50°C, preferably between 10 and 30°C. 9. Process according to claims 1-8, characterized in that the reaction mixture in the second method step contains 2-5% by weight of an alkali or alkaline earth hydroxide, preferably NaOH or KOH. 10. Method according to claims 1-9, characterized in that the reaction mixture during the second method step is kept at -15°C to +5°C, preferably approx. 0°C, and the reaction time is less than 1 hour.