HK1055296B - Method for producing 4-(heteroaryl-methyl)-halogen-1(2h)-phthalazinones - Google Patents

Description

Process for preparing 4- (heteroaryl-methyl) -halogen-1 (2H) -2, 3-phthalazinone

Technical Field

The present invention relates to a process for the preparation of 4- (heteroaryl-methyl) -halogen-1 (2H) -2, 3-phthalazinone.

Background

4- (heteroaryl-methyl) -halogen-1 (2H) -2, 3-naphthyridinones, in particular 4- (4-pyridylmethyl) -1(2H) -2, 3-naphthyridinone, are particularly valuable intermediates in the preparation of 2, 3-naphthyridine derivatives, which are characterized by advantageous pharmacological properties, such as angiogenesis inhibition (WO 98/35958), cGMP phosphodiesterase inhibition (EP 0722936), inflammation inhibition and antihypertensive action (DE OS 2021195), and thus offer new therapeutic possibilities, in particular for the treatment of cancer and heart disease.

According to known methods, the preparation of, for example, 4- (4-pyridylmethyl) -1(2H) -2, 3-phthalazinone is carried out as follows: phthalic anhydride is reacted with 4-methylpyridine at about 20 ℃ and the condensation product obtained (gamma-pyrophthalone) is then reacted with excess hydrazine at 130 ℃ (DE AS 1061788). The disadvantages of these processes are the low yields (< 50%), the poor quality of the product and, above all, the very high temperatures required for the condensation reaction, which make their use difficult on an industrial scale.

As another alternative, 4- (4-pyridylmethyl) -1(2H) -2, 3-phthalazinone may be prepared as follows: 2-benzo [ c ] furanone is condensed with 4-pyridylaldehyde in the presence of methanol, and the resulting 2- (4(1H) -pyridylidine) -4, 5, 6, 7-tetrahydroindene-1, 3-dione is then reacted with a large excess (16 equivalents) of hydrazine at 130 deg.C (WO 98/35958). The overall yield of the two steps is about 40% of theory. In these processes, the handling of excess carcinogenic hydrazine at temperatures above the decomposition temperature of hydrazine (about 120 ℃) is a very serious problem in itself. In this case, it is almost impossible to maintain very low limits for hydrazine in air (MAK 0.008ppm) and waste water in the treatment and separation of the product.

However, a reaction in which hydrazine is present in an excess of about 100 times and the reaction temperature is close to the hydrazine decomposition temperature (about 120 ℃ C.) is known from WO 99/32456. On an industrial scale, these processes are very problematic in themselves. And the yield is relatively low.

It would therefore be desirable to have available a process for the preparation of 4- (heteroaryl-methyl) -halogen-1 (2H) -2, 3-phthalazinone, in particular 4- (4-pyridylmethyl) -1(2H) -2, 3-phthalazinone, which avoids the technical problems of the known processes (reaction at 200 ℃), the safety problems (heating of hydrazine to 130 ℃), and the environmental problems (large excess of hydrazine).

These known drawbacks can now be overcome with the method of the present invention.

Disclosure of Invention

The object of the present invention is to provide a process for the preparation of 4- (heteroaryl-methyl) -halogen-1 (2H) -2, 3-phthalazinone of the general formula I,

wherein: r₁Fluorine, chlorine, bromine or hydrogen, and

ar ═ pyridine, pyrazine or pyrimidine radical,

said method is characterized in that substituted 2-benzo [ c ] furanone-3-triphenylphosphine salts of the general formula II

Wherein: r₁Fluorine, chlorine, bromine or hydrogen,

with an aldehyde of the formula III in the presence of a base,

Ar-CHO III

wherein: ar ═ pyridine, pyrazine or pyrimidine radical,

then reacted with hydrazine hydrate and optionally treated under acidic conditions.

Detailed Description

If the radical R is₁Represents halogen, it can be in any position of the phenyl ring in the pyrazinone system, that is to say in the 1-, 2-, 3-, or 4-position. For a suitable Ar group, a pyridine, pyrimidine or pyrazine group may be mentioned. Suitable aldehydes are, for example, 2-, 3-, or 4-pyridine-aldehyde, 2-methyl-4-pyridine-aldehyde, 3-methyl-4-pyridine-aldehyde, 4-pyrimidine-aldehyde, 5-pyrimidine-aldehyde, 3-pyrazine-aldehyde or 4-pyrazine-aldehyde.

Thus, for example, 2-benzo [ c ] furanone-3-triphenylphosphine salt is reacted with 4-pyridylaldehyde in the presence of a base (basic auxiliary) and subsequently with hydrazine hydrate, and the reaction mixture is then subjected to an acid treatment. The method is realized specifically as follows: 2-benzo [ c ] furanone-3-triphenylphosphine salt is reacted with 4-pyridylaldehyde in a solvent in the presence of a base (basic auxiliary), then with 1-1.1 equivalents of hydrazine hydrate, and the reaction mixture is then treated with 0.1-0.3 equivalents of acetic anhydride.

To isolate the product, the reaction mixture is mixed with an aqueous acid, the solvent is distilled off, the precipitated triphenylphosphine is filtered off and the filtrate is then basified. In this case, the desired product precipitates out and, after filtration and drying, has a very high purity and excellent yields (95-98% of theory).

As the solvent in the reaction, an organic solvent is suitable, such as tetrahydrofuran, dimethoxyethane, methanol, ethanol, or dimethylformamide. Bases which can be used are organic bases, such as amines, for example triethylamine, ethyldiisopropylamine, or inorganic bases, such as potassium carbonate, sodium carbonate, magnesium carbonate or alkali metal hydroxides or alkaline earth metal hydroxides, such as magnesium hydroxide. The reaction time for the reaction of 2-benzo [ c ] furanone-3-triphenylphosphine salt is 1 hour at 40 ℃ and the reaction with hydrazine is 7-14 hours at 50-70 ℃.

The 2-benzo [ c ] furanone-3-triphenyl phosphonium salts (bromides and chlorides) used as educts are readily available according to methods known in the literature (J.organometallic chem.1972, 391; J.org.chem.1973, 4164).

The advantage of the process according to the invention compared to the processes known from the prior art is that the reaction conditions are not harsh, that a significantly higher yield (> 90%) is obtained, and that in particular a stoichiometric amount of hydrazine can be used. The reaction was complete and in a closed system, no hydrazine was detected in the reaction mixture prior to work-up (single site reaction). Thus, the carcinogenic risk of hydrazine can be avoided.

Examples

Preparation of 4- (4-pyridylmethyl) -2, 3-phthalazinone

500g of 2-benzo [ c ] furanone-3-triphenylphosphonium chloride (1.160mol) were suspended in 2250ml of Tetrahydrofuran (THF). At 5 ℃ 110.7ml of pyridine-4-aldehyde (124.2g, 1.160mol) are added, and 161.7ml of triethylamine (117.4g, 1.160mol) are then metered into the white suspension. After the addition was complete, the reaction mixture was stirred at 40 ℃ for 1 hour, then mixed with 62.0ml of hydrazine hydrate (63.9g, 1.276mol) and stirred at 70 ℃ for 8 hours. 32.7ml of acetic anhydride (35.5g, 0.348mol) were then added and stirring was continued for 2.5 h at 20 ℃. The reaction mixture was then mixed with 1500ml of water and then 367ml of a 4M sulfuric acid solution. About 2500ml of THF/water were distilled off from the reaction mixture in vacuo. The resulting suspension was filtered from the frit. The filtrate was mixed with 50% sodium hydroxide solution until the pH was 8.0 (about 185 ml). The precipitated product was filtered off, washed with 450ml of water and then dried at 60 ℃. 264.2g of a pale yellow solid are obtained (96% of theory).

Melting point: 193 ℃ and 194 ℃. EI-MS (M + H)⁺242。

Other derivatives can be prepared analogously to this example.

Claims (4)

1. A process for the preparation of 4- (heteroaryl-methyl) -1(2H) -2, 3-phthalazinone of the general formula I,

wherein: r₁Fluorine, chlorine, bromine or hydrogen, and

ar ═ pyridine, pyrazine or pyrimidine radical,

said method is characterized in that substituted 2-benzo [ c ] furanone-3-triphenylphosphine salts of the general formula II

Wherein: r₁Fluorine, chlorine, bromine or hydrogen,

with an aldehyde of the general formula III in the presence of an organic or inorganic base,

Ar-CHO III

wherein: ar ═ pyridine, pyrazine or pyrimidine radical,

then reacting with 1-1.1 equivalent of hydrazine hydrate and optionally treating under acidic conditions.

2. The process of claim 1, wherein the base is an amine or an alkali metal hydroxide or an alkaline earth metal hydroxide.

3. A process as claimed in claim 1, wherein the reaction mixture after the reaction with hydrazine hydrate is treated with acetic anhydride or acetic acid.

4. A process according to any one of claims 1 to 3 wherein the reaction mixture after reaction with hydrazine hydrate is treated with from 0.1 to 0.3 equivalents of acetic anhydride.