CS241041B2 - Method of 2-benzyl-1,2-dihydro-1-oxophtalazine-4-ylacetic acid derivatives production - Google Patents

Description

The present invention provides a process for the production of novel phthalazin-4-ylacetic acid derivatives having the ability to inhibit the enzyme aldose reductase in vivo.

The aldose reductase enzyme is responsible for the catalytic conversion of aldoses, for example glucose and galactose, to the corresponding alditols, such as sorbitol, respectively. galactitol. Alditols poorly pass through the cell walls and, if formed, can be removed essentially only by further metabolism. As a result, alditols tend to accumulate in the cells in which they originate, causing an increase in osmotic pressure, which can then be so great that it can lead to disturbances or impaired function of the cells themselves.

In addition, elevated levels of aldithium may result in abnormal elevations in the levels of the corresponding metabolites, which may themselves impair or impair cellular function. However, the aldose reductase enzyme has a relatively low affinity for the substrate, meaning that it is only effective in the presence of relatively high concentrations of aldoey. Such high aldose concentrations occur in the clinical conditions of diabetes (excess glucose) and galactosemia (excess galactose). Accordingly, aldose reductase enzyme inhibitors are useful for reducing or preventing the onset of those peripheral effects of diabetes and galactosemia, which may be due in part to the accumulation of sorbitol, respectively. galactitol. Such peripheral effects are, for example, macular edema, cataract, retinopathy or impaired conduction of nerve impulses.

It is known from our earlier work that 1-benzyl-2-oxoquinol-4-ylalkanoic acid derivatives are inhibitors of the enzyme aldose reductase (see British Patent No. 1,502,312). It has now been found that certain 2-benzyl-1-oxophthalazin-4-ylacetic acid derivatives as defined below are unexpectedly also inhibitors of the enzyme aldose reductase. This finding is particularly surprising in view of the numerous differences between the 2-oxoquinoline and 1-oxophthalazine ring systems. Related phthalazine derivatives, namely 2-benzyl- and 2- (2-pyrid-2-ylethyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid and their methyl and ethyl esters are known and their effect has been described blood clotting (see Sh. Feldeak et al., Chim. Farm. Ž., 1970, 4, 22-26; Chemical Abstracts, 1970, 73, 77 173), but neither the compounds of the invention described below nor these The known phthalazine derivatives are not known to act as aldose reductase inhibitors in vivo when administered orally at doses of 100 mg / kg or less.

In accordance with the above, the present invention provides a process for the preparation of 2-benzyl-1,2-dihydro-1-oxophthalazin-4-ylacetic acid derivatives of the general formula I

wherein the substituents R ² , R ³ , R ⁴ and R ⁵ on the benzene ring A are selected from the following combinations

a) R ² represents a fluorine atom or a methoxy group,

R ³ represents hydrogen,

R ⁴ represents a chlorine, bromine or iodine atom;

R ⁵ represents a hydrogen or halogen atom,

b) R ² , R ³ and R ⁵ represent hydrogen atoms and ...... R ⁴ represents a bromine or iodine atom,

c) ^R2 is hydrogen or fluoro, R ³ and R ⁵ represent identical or different halogen atoms · and

R ⁴ is hydrogen,

d) R ² is hydrogen or fluorine,

R ³ and R ⁴ represent the same or different halogen atoms and

R 6 is a hydrogen atom, and f) R ² is an atom. hydrogen,

R ³ and R ⁵ independently represent fluorine or chlorine atoms and. '^; R 1 means 'chloro, bromo or yo.' · Dues ^; : · R® substituents, R ⁷ and R® on benzene ring B are independently selected from the group consisting of hydrogen, halogens, alkyl groups having 1 to 4 carbon atoms and alkoxy having 1 to 4 carbon atoms, .- or R ⁶ and R ⁷ together form a divalent alkylenedioxy radical having 1 to 4 carbon atoms, with at least one of R ⁶ , R ⁷ and R ^{6 being} hydrogen, and

X is oxygen or sulfur, and pharmaceutically acceptable base addition salts thereof, characterized in that the ester of formula (II) in which:

R ¹ is C 1 -C 4 alkoxy or a radical of formula III

where

R ² , R ³ , R ⁴ and R ⁵ are as defined above, and the remaining general symbols are as defined above, and the resulting free acid of formula I is optionally converted into a pharmaceutically acceptable salt thereof by treatment with a base providing a pharmaceutically acceptable cation. with base.

The hydrolysis according to the invention can be carried out in the presence of an acid or a base, for example in the presence of a mineral acid such as hydrochloric acid or an alkali metal hydroxide or carbonate, for example sodium or potassium hydroxide or carbonate. If the benzene ring B carries a labile substituent, for example a fluorine at the 8-position, an alkali metal carbonate is preferably used. The hydrolysis is carried out in the presence of water and optionally a solvent or diluent, for example acetic acid, methanol, ethanol or dioxane. The hydrolysis may be carried out at room temperature, for example at a temperature in the range of from 18 to 25 ° C, but is expediently accelerated by heating, for example to a temperature of 35 to 110 ° C.

The compounds of formula (I) are derivatives of 1,2-dihydro-1-oxo (or thioxo-phthalazin-4-ylacetic acid, the ring system of which is numbered throughout this text as in the following formula).

in which

X is oxygen or sulfur.

Obviously, the compounds of the general formula

I can tautomerize to a structure corresponding to formula la

and the invention includes both tautomer of formula I (endo-tautomer) and tautomer of formula Ia (exo-tautomer), as well as mixtures thereof.

Halogen represented by R ³ or R ⁵ is, for example, fluorine, chlorine, bromine or iodine, especially chlorine or bromine.

Halogen for R @, R @ ⁷ or R @ ⁸ is, for example, fluorine, chlorine, bromine or iodine, C1 -C4 -alkyl such as methyl and C1 -C4 -alkoxy. is, for example, a methoxy or ethoxy group.

The divalent C 1 -C 4 alkylenedioxy group, taken together with R ® and R ⁷ , is, for example, methylenedioxy, ethylenedioxy or Isopropylidenedioxy.

The benzene ring A bearing particularly interesting combinations of R ² , R ³ , R ⁴ and R ⁵ is, for example, 2-fluoro-4-bromo, 2-fluoro-4-chloro,

2-fluoro-4-iodo, 2-fluoro-4,5-dibromo, 2-methoxy-4-chloro, 4-bromo, 4-iodo, 3,5-dichloro, 3-chloro- A 4-bromo, 3,4-dichloro, 3,4-dibromo or 3,5-dichloro-4-bromophenyl residue.

Particularly interesting combinations of R @, R @ ⁷ and R @ ⁸ are, for example, those in which the benzene ring B is either unsubstituted or carries the following substituents:

6-chloro, 6-methyl, 7-fluoro, 7-chloro, 7-methyl,

7-methoxy, 8-fluoro, 8-methyl, 8-ethoxy, 6,7-dichloro or 6,7-methylenedioxy.

Particularly suitable base addition salts of the compounds of formula I are, for example, alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts, or aluminum or ammonium salts, or salts with organic bases providing a pharmaceutically acceptable cation, e.g. with triethanolamine.

Particular groups of particularly preferred compounds of the invention are those compounds of formula (I) wherein (i) R ² is fluorine, R ³ and R ⁵ are hydrogen and R ⁴ is chlorine, bromine or iodine;

(11) R ³ and R ⁴ are each independently chlorine, bromine or iodine and R ² and R ⁵ are hydrogen;

(iii) R®, R ⁷ and R ⁸ are hydrogen; or (iv) X represents an oxygen atom, wherein in each of the above groups (i) to (iv), the remaining R ² , R ³ , R ⁴ , R ⁵ , R ®, R ⁷ , R ⁸ and X have the above said meaning or meaning given in any of the other groups above, and pharmaceutically acceptable base salts thereof.

Specific compounds produced by the process of the invention are those described in the Examples below, of which the following are preferred:

2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid,

2- (2-fluoro-4-iodobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid; and

2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid, and pharmaceutically acceptable base addition salts thereof.

The required starting materials of formula (II) may be prepared by general organic chemistry known in the art for the preparation of chemically analogous compounds. These procedures are described in the next section. In the following formulas, the symbols R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ®, R ⁷ , R ⁸ , X and the benzene rings A and B are as defined above, unless expressly stated otherwise.

(a) To produce compounds of formula II wherein X is oxygen, a compound of formula III is formed

241841 is reacted with a halide of formula IV

in which

Hal represents chlorine, thunder or iodine, in the presence of a suitable base.

This reaction is preferably carried out in a solvent or diluent, for example ethanol, dimethylformamide, dimethylsulfoxide or water. and is expediently accelerated by heating to a temperature in the range, for example, from 40 to 110 ° C. . A particularly suitable base is, for example, an alkali metal hydride, carbonate, hydroxide or alkoxide, for example, sodium or potassium hydride, carbonate, hydroxide, methoxide or ethoxide. If a hydride is used as the base, it is necessary to work in a non-aqueous solvent, for example dimethylformamide or dimethylsulfoxide; when ae uses an alkoxide as the base, preferably a C1 -C4 alkanol such as methanol or ethanol is used as the solvent.

(b) To produce compounds of formula II wherein X is oxygen, a compound of formula V is formed

or a geometric isomer thereof, is reacted with a hydrazine of formula VI

This reaction is preferably carried out in an aqueous diluent or solvent, for example aqueous dioxane, ethanol or dimethylformamide, and in the presence of a base, for example sodium or potassium bicarbonate. The reaction is also conveniently carried out under heating, for example to a temperature of 40 to 110 ° C.

(c) For a compound of formula II wherein X is oxygen and R ¹ is alkoxy having 1 to 4 carbon atoms, the diazoketone of the formula VII

subjected to catalytic decomposition in the presence of a compound of the general formula

Q.H where

Q is C 1 -C 4 alkoxy, for example methoxy or ethoxy.

The catalyst required may be, for example, colloidal silver or silver benzoate, the catalyst being preferably used in the presence of a base such as triethylamine, pyridine or s-collidine. The reaction is preferably carried out in the presence of a diluent or solvent, for example water, a C 1 -C 4 alkanol such as methanol or ethanol, tetrahydrofuran or dioxane, and is conveniently carried out using an excess of the compound of formula Q. H, optionally together with tetrahydrofuran or dioxane.

The reaction is expediently accelerated by heating, for example by heating to a temperature in the range of 40 to 110 ° C.

(d) To produce compounds of formula II wherein the benzene ring B carries a C 1 -C 4 alkoxy group, a compound of formula II wherein the benzene ring B carries a halogen atom such as fluorine is reacted with an alkali metal alkoxide with a 1-4 carbon atoms, for example with sodium methoxide or ethoxide.

The reaction is preferably carried out in a solvent or diluent, for example in an excess of the corresponding C 1 -C 4 alkanol such as methanol or ethanol, and can be accelerated by heating, for example to a temperature of 40 to 110 ° C or conveniently boiling the reaction mixture. .

(β) Κ The preparation of compounds of formula (II) in which X is a sulfur atom in the corresponding oxo compound of formula (II) in which X is an oxygen atom is exchanged into a sulfur atom using known procedures and conditions, e.g. phosphorus pentasulphide in boiling xylene or pyridine.

These well-known reactions are illustrated by the Examples below.

The starting materials of formulas III, VI and VII may be prepared by standard procedures known in the art of heterocyclic chemistry, for example as described in N. R '. Patel, "The Chemicals of Heterocyclic Compounds" Vol. 27, Interscience, New York. These processes are of an analogous type to those used to prepare the diazoketones of formula VII used for the process

c), illustrated by the following Scheme 1, in which the following reaction conditions and reagents are used:

(i) n-butyllithium, diethyl ether or dimethyl-

o ethylene glycol thylether, temperature from -10 ° C to (PC;

(il) diethyl oxalate, temperature from 0 to 5 ° C;

(iii) H ⁺ / water / dioxane, mp 90-100 ° ^C;

(iv) potassium carbonate / potassium permanganate / water, 100 ° C;

(v) hydrazine hydrate, temperature 90-100 ° C;

[vij as in procedure (a);

(vii) SO (Hal) 2, wherein Hal = chlorine bromine, or (COCl) 2;

(viii) an excess of diazomethane in ether, and wherein, for simplicity and clarity, the individual residues R ² to R ⁸ are not listed.

the individual abbreviations used in this scheme have the following meanings:

Me = methyl

Et = ethyl

řX

Vil

In many cases, it is expedient to convert an acid of formula XI prior to alkylation with a benzyl halide [step [vij] to its methyl ester, for example by reacting the sodium salt of this acid with methyl iodide in dimethylformamide. This modification. is described in Examples 7, 8, and 29 to 31 below and requires conventional hydrolysis after alkylation and prior to step (vii).

Depending on the nature of the substituents for. the benzene ring B may be the most preferred starting materials for either 2-acyltoluene of formula VIII or 2-phenyloxazoline of formula IV _; It will also be appreciated that it may be desirable not to isolate and purify some of the intermediates in Scheme 1, for example, the 11-aa oxalatoderivatives produced in steps (1j and (ii), respectively) and similarly to the process (c) described above. It is desirable to prepare a diazoketone of formula VII in situ from an acid halide of formula X.

The starting materials of formula (III) for the process of (a) may be analogous to (bj), i.e. by reacting a compound of formula (V) with hydrazine hydrate and then converting the resulting phthalazin-4-ylacetic acid in free acid or acid chloride form. in known manner to the corresponding ester.

Some of the starting materials of formula (V) may conveniently be prepared from an appropriately substituted phthalic anhydride of formula (XII)

(XII) condensation with acetic anhydride, for example in the presence of sodium or potassium acetate / and an excess of boiling acetic anhydride. However, all of these compounds can be obtained by a Wittig reaction between the appropriate phthalic anhydride (XII) and (ethoxycarbonylmethylene triphenylphosphate orange in a suitable solvent, for example 1,2-dimethoxyethane or tetrahydrofuran), expediently accelerating the reaction by heating, for example heating to boiling. It should be understood that in some cases, the product of the Wittig reaction may be a geometric isomer corresponding to the formula Va in place of the compound of formula V.

(IN*)

Alternatively, a mixture of both geometric isomers may be formed. Any of these isomers. and a mixture thereof may be used in the procedure (bj. It should also be noted that when R ⁸ and one of R ⁷ and R ⁶ are hydrogen, are formed in the Wittig reaction of positional isomers depending on which of the two carbonyl If R ³ has a meaning other than hydrogen, one of the possible positional isomers predominates, the one formed by the reaction of the carbonyl group furthest from R ⁸ .

The above-defined pharmaceutically acceptable base salts may be prepared by conventional methods of reacting the compound. with a corresponding base providing a pharmaceutically acceptable cation.

The properties of aldose reductase enzyme inhibitors can be demonstrated by the following standard laboratory test:

In rats, streptozotocin is induced by diabetes and the animals are then treated with the test compound for 5 days daily. The animals are sacrificed, their ocular lenses and sciatic nerves are removed, and after standard processing, residual sorbitol levels in each of these tissues are determined by gas chromatography (after conversion to poly-trimethylsilyl derivatives). In vivo inhibition of aldose reductase is then determined by comparing the residual levels of sorbitol in the tissues of the diabetic rat group receiving the test substance with the residual levels of sorbitol in the corresponding tissues of the non-administered diabetic rat group and the groups of normal rats not receiving the test compound. served.

Alternatively, a modified test may be used in which rats induced with diabetes by streptozotocin are administered the test compound daily for 2 days. After 2 to 4 hours after the last dose the animals are sacrificed and excised their sciatic nerves described above and ¹³ is thus determined residual sorbitol levels.

Substances that are effective reduce the residual sorbitol levels in both tests to a state similar to that in normal rats not receiving the test substance. In general, the compounds of formula I exert a marked inhibition of the aldose reductase enzyme when administered orally at a dose of 100 mg / kg or less. By way of illustration, 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid, after 5 days of oral administration at doses of 10 mg / kg, will reduce residual sorbitol levels in sciatic 60% of the condition in control diabetic rats to which the test compound was not administered. In the above tests, no marked signs of toxicity or other adverse effects were observed when the compounds of formula I were administered at doses of 100 mg / kg.

The ability to inhibit the enzyme aldose reductase can also be demonstrated in vitro. The procedure is to isolate purified aldose reductase from bovine eye lenses in a known manner and, using standard spectrophotometric methods, to determine in percent the inhibition of the ability of this enzyme to reduce aldoses to polyhydric alcohols, in particular to reduce glucose to sorbitol caused by the test compound. . In this test compounds of formula I produce significant inhibition of the enzyme aldose reductase at a concentration ranging from 10 ^"8 to 10 ^-8 M or lower in concentration. By way of illustration, 2- (2-fluoro-4-bromobenzyl] -1,2-dihydro-1-oxophthalazin-4-ylacetic acid has a K value of 2.0 X 10 ^-8 M.

When the compound produced by the method of the invention is used to affect the aldose reductase enzyme in warm-blooded animals, it can be administered orally at a daily dose of 2 to 50 mg / kg, which in humans corresponds to a total daily dose of 20 to 750 mg. can be applied in several sub-doses if necessary.

The compounds of the present invention may be administered in the form of pharmaceutical compositions.

Particularly suitable pharmaceutical compositions are those in a form suitable for oral administration, for example tablets, capsules, suspensions or solutions which can be prepared by conventional methods and which may optionally contain conventional diluents, carriers or other auxiliaries.

Some of the compounds produced by the process of the invention, in addition to the aldose reductase inhibitory effects, also have anti-inflammatory and / or analgesic properties of the type as non-steroidal anti-inflammatory agents such as indomethacin, sputum and ketoprofen. Thus, these agents may additionally be useful in the treatment of painful inflammatory joint diseases such as rheumatoid arthritis, osteoarthritis and ankyllotic spondylitis. In this context, it is contemplated that such agents will be administered primarily orally at a daily dose in the range of 10 to 50 mg / kg. The anti-inflammatory properties of the disclosed compounds can be demonstrated by known standard tests in rats. For example

2- (2-Fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid; and

2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid acts in a test developed by Winter et al. [Proceedings of the Society of Experimental Biology (New York), 1962, 111, 554], a marked inhibition of carrageenin-induced edera without any apparent signs of toxicity.

The invention is illustrated by the following non-limiting Examples

(a) all evaporations, unless otherwise indicated, shall be carried out under vacuum on a rotary evaporator;

(b) all operations, unless otherwise indicated, are carried out at room temperature, meaning a temperature in the range of 18 to 26 ° C;

cj the melting points of acetic acid derivatives are in many cases associated with decomposition;

d) all compounds of formula I and isolated intermediates are characterized by microanalysis and NMR and IR spectroscopy;

(e) yields, when given by way of illustration, do not necessarily represent the highest achievable yields;

f) Examples 4-6, 9, 10, 13-15, 34-50, 52 and 53 illustrate the process of the invention, the remaining examples describe the preparation of the required starting materials.

He did

A mixture of 11.5 g of ethyl 1,2-dihydro-1-oxophthalazin-4-ylacetate and 2.7 of sodium hydride [50% w / w dispersion in mineral oil] in 125 ml of dimethylformamide was stirred at nitrogen temperature for 1 hour. 60 ° C. The resulting solution was cooled to room temperature, 15.0 g of 4-bromo-3-chlorobenzyl bromide was added, and the mixture was stirred at 60 ° C for 2 hours. After cooling to 25 ° C, the reaction mixture was poured into 500 mL of water and extracted with 400 mL of ethyl acetate. The extracts were washed with water, dried (MgSO4) and evaporated. The solid residue yielded, after crystallization from 2-propanol, 7.3 g of ethyl 2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate, m.p. 142-145 ° C.

Examples 2 and 3

In an analogous manner to that described in Example 1, ethyl 1,2-dihydro-2-oxophthalazin-4-yl acetate and the corresponding bromide of formula XIV

1S

(IV) prepare compounds corresponding to formula XIII wherein ring B is not substituted. These compounds are summarized in the following overview:

example substituents on benzene ring number A yield (%) crystallization melting point solvent (C · 3,4-dichloro * *), 40 139-141 isopropanol

2-fluoro-4-bromo 60 114 ethanol

Legend:

*) 3,4-dichlorobenzyl chloride was used as starting material

Example 4

A solution of 7.0 g of ethyl 2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate in 70 ml of ethanol containing 7.0 g of potassium hydroxide is heated to reflux for 30 minutes under reflux. The resulting solution was poured into 250 ml of water and extracted twice with 150 ml of ether each time. The aqueous phase is acidified to pH 2 with concentrated hydrochloric acid, the precipitated solid is separated, washed with water, dried in vacuo and then recrystallized from a mixture of toluene, 2-propanol and petroleum ether (b.p. 60-80 ° C). : 2: 3. There were obtained 3.9 g of 2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid, melting at 186 ° C.

example substituents on the benzene ring enumeration A% (%)

5- 3,4-dichloro 60

2-fluoro-4-bromo 64

Examples 5 and 6

Analogous to the procedure of Example 4, compounds of formula XV were prepared by hydrolysis of the corresponding ethyl esters

wherein ring B is not substituted. The obtained compounds are summarized as follows:

start temperature krystalitání extended (C ^J j thinners

175-176 toluene-isopropanol (2: 1)

184—185 * ´ methanol

Legend:

This compound can crystallize in polymorphic forms, i.e. in the form melting after crystallization from methanol containing a small amount of water at 184-185 ° C and in the form melting after double crystallization from dry methanol at 180-182 ° C

241341

Example 7

A mixture of 1.9 g of 2- (3,4-dichlorobenzyl) -7-methyl-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid and 10 ml of thionyl chloride containing 0.1 ml of dimethylformamide was stirred and stirred for 3 hours. reflux. The resulting solution was evaporated, the residue was dissolved in dry toluene and the solution was evaporated again. This treatment is performed three times. 2- (3-dichloro-benzyl) -7-methoxy-1,2-dihydro-1-oxo-phthalazin-4-yl-carboxylic acid chloride is obtained in a practically quantitative yield as a solid with a satisfactory IR spectrum.

A solution of the above acid chloride in 50 ml of dry tetrahydrofuran is added dropwise with stirring to a solution of diazomethane in 200 ml of dry ether [prepared as described by JA Moore in Organic Syntheses 1961, 41, 16 out of 10 g of bis (N-methyl-N-nitrosojterephthalamide) ], cooled to 0 ^DEG C. After complete addition the mixture with stirring was allowed to warm over 2 hours to room temperature and filtered. the solid residue was washed with 20 ml of dry tetrahydrofuran, the filtrate combined with the washings and evaporated. to give 2- (3,4-dichlorobenzyl) -4- (α-diazoacetyl-7-methoxy-1,2-dihydro-1-oxophthalazine) as a solid which is used without further purification or characterization.

A solution of 0.2 g of silver benzoate in 1 ml of triethylamine is slowly added dropwise to a solution of the above 4- (α-diazo) acetylderivative in 50 ml of absolute ethanol and 30 ml of tetrahydrofuran. During the addition, the mixture foams and the foaming is allowed to subside before the addition of the next solution. After the addition was complete, the reaction mixture was heated to reflux for 30 minutes with stirring. then filtered while still hot. The filtrate was evaporated and the residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water (3.times.100 ml), dried (MgSO4) and evaporated. The residue was purified by chromatography on 100 g of silica gel using a solution of ethyl acetate in toluene with increasing ethyl acetate as eluent. 0.9 g of ethyl 2- (3,4-dichlorobenzyl) -7-methoxy-1 was obtained from the appropriate fractions (as checked by thin layer chromatography on silica gel using a 1: 3 by volume mixture of acetate and toluene as the solvent system). Of 2-dihydro-1-oxophthalazin-4-yl acetate melting at 129-130 ° C.

The required starting material is prepared as follows:

(a) A mixture of 10.0 g of 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid, 15.0 g of sodium bicarbonate and 15.0 ml of methyl iodide in 200 ml of dry dimethylformamide was stirred at room temperature for 16 hours. room temperature. The reaction mixture is poured into 600 ml of water, the precipitated solid material is separated off, washed first with water and then with cold methanol and then recrystallized from methanol. There was obtained S, Qg of methyl 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate, m.p. 122-225 ° C.

(bj To a solution of 3.29 g of the methyl ester prepared in (a) in 200 ml of dry dimethylformamide was added 1.75 g of sodium hydride [50% (w / w) dispersion in mineral oil]. The reaction mixture was stirred at room temperature for 2 hours and then poured into 600 ml of water. Water, dried under vacuum and recrystallized from 2-propanol / petroleum ether (bp 60-80 degrees Celsius) 1: 3 to give 9.0 g of methyl 2- (3,4-dichlorobenzyl). 144-148 ° C: 1- (2-dihydro-1,2-dihydro-1-O-phthalazin-4-ylcarboxylate), m.p.

(c) A solution of 9.0 g of the methyl ester prepared in (b) above, in 100 ml of ethanol and 100 ml of water containing 10.0 g of potassium hydroxide, was heated under reflux for 4 hours. The resulting solution was diluted with 200 mL of water and acidified to pH 2 with concentrated hydrochloric acid. The precipitated solid was collected, washed with water, dried in vacuo and recrystallized from a mixture of equal volumes of 2-propanol and dimethylformamide. 6.1 g of 2- (3,4-dichlorobenzyl) -7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid of melting point 238 DEG-240 DEG C. are obtained. [Note: 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid was prepared as a solid melting at 229-230C by the procedure described by Vaughan et al. in J. Amer. Chem. Soc. 1946, 83, 1314).

Example 8

Using the procedure analogous to Example 7, starting from 2- [3,4-dichlorobenzyl) -7-chloro-1,2-dihydro-1-Ophthalazin-4-ylcarboxylic acid (A), ethyl-2- (3,4-dichlorobenzyl) -7-chloro-1,2-dihydro-1-oxophthalazin-4-yl acetate as a solid with a satisfactory NMR spectrum.

The necessary starting carboxylic acid (Aj is prepared in a manner analogous to that described in paragraphs (aj to (c) of Example 7, starting from 7-chloro-1,1-dihydro-1-oxophthalazin-4-ylcarboxylic acid (Bj). The intermediates obtained have the following melting points:

degree (also:

methyl 7-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate; mp 255-257 ° C (after crystallization from a 2: 1 by volume mixture of methanol and dimethylformamide);

410-41 degree (b):

methyl 2- (3,4-dichlorobenzyl) -7-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate; m.p. 178-180 ° C (after recrystallization from a mixture of 2-propanol and petroleum ether (b.p. 60-80 ° C) in a 1: v / v ratio)

step (c):

2- (3,4-dichlorobenzyl) -7-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid; mp 260 DEG-262 DEG C. (after recrystallization from a mixture of equal volumes of methanol and dimethylformamide).

[Note: the carboxylic acid (B) is obtained as a solid melting at 241-243 degrees Celsius in a manner analogous to that described by Vaughan et al. (J. Amer. Cnem. Soc. 1946, 83, 1314), but using 4-chloro-2-methylacetophenone as the starting material].

Examples 9 and 10

The following acids are obtained in an analogous manner to that of Example 4 using the corresponding ethyl ester as starting material:

Example 9

2- (3,4-dichlorobenzyl) -7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylacetic acid, m.p. after recrystallization from 2-propanol at 198 DEG-200 DEG C., yield: 50%.

Example 10

2- (3,4-Dichlorobenzyl) -7-chloro-1,2-dihydro-1-oxophslazin-4-ylacetic acid melting after recrystallization from a mixture of equal volumes of 2-propanol and petroleum ether (b.p. 60-80 ° C) at 203-205 ° C, yield 43%.

Examples 11 and 12

The following esters are prepared from the corresponding benzyl bromide or chloride in an analogous manner to that described in Example 1: Example 11

Ethyl 2- (2-fluoro-4-chlorobenzyl] -l, 2-dihydro-lo ^x 'oítalazin 4-yIacetát first recrystallised from petroleum ether (b.p. 60-80 ° C] and then from ethanol at 102 ° C. The yield was 45%.

Example 12 ro-1-oxophthalazin-4-yl acetate melting after recrystallization from petroleum ether (b.p. 60-80 ° C) at 113 ° C; the yield is 50%. Examples 13 to 15

The following acids were obtained in an analogous manner to that of Example 4 using the corresponding ethyl esters as starting materials:

Example 13

2- (2-Fluoro-4-chlorobenzyl) -1,2-dihydro-1-oxo-thiaziazin-4-ylacetic acid, melting after recrystallization from ethanol / water (3: 1, v / v) at 193-194 ° C; %.

Example 14

2- (2-Fluoro-4-iodobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid, melting after recrystallization from ethanol / water (3: 1 v / v) at 189 ° C, yield 55% .

Example 15 * '

2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-dioxophthalazin-4-ylacetic acid, melting after recrystallization from 2-propanol at 197 DEG-199 DEG C., yield 25%.

The hydrolysis is carried out under reflux for 10 minutes with aqueous methanolic sodium hydroxide solution].

Example 16

A mixture of 1.8 g of ethyl 2- (3-chloro-4-bromobenzyl) -1,2-dihydro-4-naphthalazin-4-yl acetate and 2.5 g of phosphorus sulfides in 100 ml of xylene is heated under stirring for 1 hour. boiling under reflux Chl controller. The reaction solution was cooled to room temperature, 25 mL of ethyl acetate was added thereto, and the mixture was filtered through 20 g of silica gel for chromatography. The filtrate was concentrated and the solid residue was recrystallized from ethanol to give 1.1 g of ethyl 2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-thioxophthalazin-4-yl acetate, melting at 124-126. ° C. Examples 17-22

In analogy to Example 1, the following compounds corresponding to the above general formula (XIII), wherein ring B is not substituted, are obtained from the corresponding bonzyl bromides of the above formula (XIV):

Ethyl 2- [2-fluoro-4-iodobenzyl] -1,2-dihyd 241041

21 example number substituents on the benzene ring 17 3.4-dibromo 18 2-fluoro-4,5-dibromo 19 Dec 3,5-dichloro 20 May 3,5-dichloro-4-bromo; 21 2-methoxy-4-chloro 22nd 4-iodo

yield (%) temperature thaw AFTER 22nd crystallization solution, solvent 44 140-142 isopropanol 21 129—130 ethyl acetate 36 100—101 ethyl acetate 19 Dec 146—147 ethanol 22nd 133 isopropanol 43 106—107 isopropanol / petroleum ether (60-80 ° C) 13

Examples23 to 25

Κ 2.29 g of ethyl 4-methyl-3-oxo-N- -ftalanacetátu ^To 200 ml of toluene under stirring and reflux a solution of 1.9 g of 3,4-dichlorbenzylhydrazinu in 50 ml of toluene. The mixture was refluxed for 3 hours, then cooled and evaporated. After recrystallization from a mixture of isopropanol and petroleum ether (b.p. 60-80 ° C), the solid residue gave 1.4 g of ethyl 2- (3,4-dichlorobenzyl) -8-methyl-1,2-dihydro- 1-oxophthalazin-4-yl acetate (Example 23), m.p. 134-137 ° C.

In an analogous manner starting from ethyl-4-fluoro-3-oxo-A ^lK -ftalanacetátu as starting material to give 37% yield of ethyl 2- (3,4-dichlorobenzyl) -8-fluoro-l, 2-dihydro- 1-Oxophthalazin-4-yl acetate (Example 24) melting after recrystallization from isopropanol / petroleum ether (b.p. 60-80 ° C) 1: 2 v / v at 117-178 ° C.

By analogy to a mixture of equal parts of 5-methyl- and 6-methyl-3-oxo-N ^, N-phthalate acetate a 33% yield of a mixture of equal parts of ethyl 6-methyl- and 7-methyl-2- (3, 6-methyl-) was obtained. 4-dichlorobenzyl) -1,1-dihydro-1-oxophthalazin-4-yl acetate (Example 25) melting after recrystallization from isopropanol at 110 to 122 degrees Celsius.

The necessary starting materials are prepared as follows:

A solution of 7.35 g of 3-fluorophthalic anhydride and 17.5 g of (ethoxycarbonylmethylene) triphenylphosphorane in 200 ml of dry 1,2-dimethoxyethane was stirred and heated under reflux for 16 hours under a nitrogen atmosphere, and the solvent was evaporated. This silica gel was applied to a column of 300 g of the same type of silica gel and eluted with toluene, and the eluate was monitored by thin layer chromatography [silica gel, toluene-ethyl acetate (9: 1) v / v]. The solid residue was recrystallized from isopropanol to give 2.3 g of ethyl 4-fluoro-3-oxo- ^1a- phthalate acetate melting at 101-103 ° C (starting material for the work-up procedure). according to Example 24).

In an analogous manner, ethyl 4-methyl-3-oxo- ^1α -phthalaneacetate was obtained from 4-methylthalic anhydride in a yield of .40 56% as a solid melting after recrystallization from isopropanol at 84-86 ° C (starting material for work). according to Example 23).

In an analogous manner, a mixture of equal parts of ethyl 5-methyl-6-methyl-3-oxo-A1 ^{, K-} phthalalacetate as a solid melting after recrystallization from isopropanol at 84% was obtained from 4-methyl anhydride in 40% yield. to 86 ^° C (starting material for the procedure of Example 25)

The following compounds are obtained in an analogous manner to Example 1, in each case from the appropriately substituted 1,2-dihydro-1-oxo-phthalazin-4-yl acetate and 2-fluoro-4-biobenzylhydrazine:

Example 26

Ethyl 2- (2-fluoro-4-bromobenzyl) -8-fluoro-1,2-dihydro-1-oxophthalazin-4-yl acetate melting after recrystallization from isopropanol / petroleum ether (b.p. 60-80 ° C) v / v ratio 1: 3 at 128-130 ° C, yield 36%.

Example '27

Ethyl 2- (2-fluoro-4-bromobenzyl) -8-methyl-1,2-dihydro-1-oxophthalazin-4-yl acetate melting after recrystallization from a mixture of isopropanol and petroleum ether (b.p. 60-80 ° C) in m.p. volume ratio of 1: 3 at from 120 to 122 ³ C; the yield is 43%.

Example 28

Ethyl 2- (2-fluoro-4-bromobenzyl) -6,7-methylenedioxy-1,2-dihydro-1-oxophthalazin-4-yl acetate, melting after recrystallization from ethyl acetate at 163-165 ° C; the yield is 56%.

The necessary starting materials are prepared as follows:

(i) Ethyl-8-methyl-1,2-dihydro-1-oxophthala241041 zin-4-yl acetate starting material according to Example 27)

To a solution of 3.5 g of ethyl 4-methyl-3-oxo-A "'- ftalanacetátu in 100 ml of ethanol under stirring and reflux _přika-: PE 15 ml of a 1M solution of hydrazine hydrate in ethanol. After the addition was complete, the mixture was stirred at reflux for a further 3 hours and then allowed to cool to room temperature. The precipitated solid product is collected, washed thoroughly with petroleum ether (b.p. 60-80 ° C) and recrystallized from a mixture of isopropanol and petroleum ether (bp 60-80 ° C). 1.0 g of ethyl 8-methyl-1,2-dihydro-1-oxophthalazin-4-yl acetate of melting point 197 DEG-199 DEG C. is obtained.

(ii) Ethyl-8-fluoro-1,2-dihydro-1-oxophthalizin-4-yl acetate (starting material according to the procedure of Example 26)

This ester is obtained as described in (i) above from ethyl 4-fluoro-3-oxo-N '- phthalate acetate and hydrazine hydrate. For-

the product results in a yield of 51% example number substituents on ring B . substituents on ring A 29 7-fluoro 3,4-dichloro 30 6,7-dichloro 3,4-dichloro 31 6-chloro 3,4-dichloro 32 6-fluoro 2-fluoro-4-bromo Legend:

*) Dlazomethane was prepared from bis (N-methyl-N-nitroso) terephthalamide according to the improved procedure described by Moore and Reed (Organic Syntheses, Collected Vol. 5, pp. 351-355).

The necessary starting phthalazin-4-ylcarboxylic acids can be prepared as follows:

(i) 2- (3,4-dichlorobenzyl) -7-fluoro-1,2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid

7-fluoro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid [prepared in 52% yield as a solid melting at 241-243 degrees Celsius, analogously to Vaughan et al. in J. Amer. Chem. Soc. 1946, 68, 1314] was converted to the sodium salt and reacted with iodomethane as described in Example (a) of Example 7 to give the corresponding methyl ester as a solid in 68% yield after recrystallization from methanol / dimethylformamide in a volume ratio 3: 1 at 234-237 ° C.

as a solid melting after recrystallization from ethyl acetate at 207-210 ° C.

(iii) Ethyl-6,7-methylenedioxy-1,2-dihydro-1-oxophthalazin-a-ylacetate (starting from the procedure of Example 28)

This ester is obtained from ethyl-5,6-methylenedioxy-3-o: -OAl ^; Phthalate acetate (A) and hydrazine hydrate. The desired product resulted in a yield of 70% as a solid melting at 226-228 ° C. The starting phthalate acetate (A) is prepared in a yield of 64% in an analogous manner to that described for the preparation of the corresponding starting materials for the procedures of Examples 23-25 (this method is based on that described by Knight and Porter, Tetrahedron Letters, 1977, 4543). 4547], The product melts after recrystallization from ethanol at 189-191 ° C.

Examples 29 to 32

By analogy to Example 7, the following compounds corresponding to formula XIII are obtained from the appropriate starting materials:

yield temperature crystallization (%) melting (° C) solvent

26 160—162 isopropanol 70 *) 204—205 chloroform / ethyl acetate (1: 2) 10 143—146 ethanol 60 *) 121—123 ethanol This ester is alkylated with 3,4-dichlorobenzyl- chloride using the procedure described in

Part (b of Example 7) to give methyl 2- (3,4-dichlorobenzyl) -7-fluoro-1,2-dihydro-1-oxophthalizin-4-ylcarboxylate, melting after recrystallization from a mixture of equal volumes of toluene and petroleum ether (bp 60-80 ° C) at 147-149 ° C (68% yield) The ester was then hydrolyzed using a mixture of aqueous potassium carbonate and dioxane as described in Example 34 below to give 2- (3,4-dichlorobenzyl). -7-fluoro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid as a solid melting after recrystallization from isopropanol at 222 DEG-224 DEG C. The yield is 87 DEG.

(ii) 2- (3,4-dichlorobenzyl) -6,7-dichloro-1,2-dihydro-1-oxophthalizin-4-ylcarboxylic acid

This acid is obtained in a manner analogous to (i) above. The appropriate intermediates and resulting product, melting points, crystallization solvents and yields are listed below:

241841

6,7-dichloro-1,2-dihydro-1-oxo-phthalazin-4-yl-carboxylic acid; mp 294-296 ^; C (after recrystallization from dimethylformamide); yield 42%. The corresponding methyl ester melts after recrystallization from dimethylformamide at 234-236 ° C (51% yield).

Methyl 2- (3,4-dichlorobenzyl) -6,7-dichloro-1,2-dihydrp-1-oxophthalazin-4-ylcarboxylate; mp 155-156 ° C (after recrystallization from dimethylformamide); yield 85 ° / o.

2- (3,4-dichlorobenzyl) -6,7-dichloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid; mp 240-242 ° C (after recrystallization from ethanol); 62% yield.

(ii) 2- (3,4-dichlorobenzyl) -6-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid

To a solution of 50.0 g of 2- (4-chlorophenyl) -4,4-dimethyl-2-oxazoline (prepared as described by Meyers et al., J. Org. Chem., 1974, 39, 2787) in 600 ml of ether dried over sodium, 165 ml of 1.6 M butyllithium in hexane are slowly added while stirring under a dry argon atmosphere while maintaining the temperature between -5 and 0 ° C. After the addition was complete, the mixture was stirred at the above temperature for 30 minutes, then added slowly to a solution of 326 ml of diethyl oxalate in 500 ml of ether while stirring and maintaining the temperature at 0 ° C. All manipulations are carried out in a dry argon atmosphere to exclude air and water. After the addition was complete, the reaction mixture was stirred for 1 hour while allowing to warm to room temperature, then washed twice with 150 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure (1333 Pa) until all excess diethyl oxalate was removed.

The residue is dissolved in 500 ml of dioxane and the solution is added to 500 ml of 5 N hydrochloric acid. The resulting mixture was refluxed for 18 hours, then evaporated to half volume and the remaining solution was filtered. The filtrate is basified to pH 8 by the addition of hydrazine hydrate. The solution is heated to 90 ° C for 30 minutes, then acidified to pH 4 with concentrated hydrochloric acid. The mixture is cooled, the precipitated solid is filtered off, washed twice with 500 ml of water. in vacuum over phosphorus pentoxide. 21.0 g of 6-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid are obtained.

This acid is suspended in 250 ml of dimethylformamide and 21.0 g of sodium bicarbonate and 40 ml of iodomethane are added. The resulting mixture is stirred overnight, then diluted with 250 ml of water, the precipitated solid product is collected, washed twice with 200 ml of water each time and recrystallized from a 2: 1 mixture of isopropanol and dimethylformamide to give 17.0 g of methyl- 628

chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate melting at 248-250 ° C.

This ester was treated with 3,4-dichlorobenzyl chloride in a manner analogous to (i) and (ii) above to give methyl-2- (3,4-dichlorobenzyl) -6-chloro-1 in 45% yield. 2-dihydro-1-oxophthalazin-4-ylcarboxylate melting after recrystallization from toluene at 168-170 ° C. This ester provides hydrolysis by a procedure analogous to (i) above (i) 2- (3,4-dichlorobenzyl) -6-chloro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid, melting after recrystallization from ethanol at 222 to 223 ° C. The yield was 60 percent.

(iv) 2- (2-fluoro-4-bromobenzyl) -6-fluoro-1,2-dihydro-1-oxophthalazine-4-carboxylic acid

This acid is prepared in an analogous manner to that described in (iii) above, with the appropriate intermediates and the resulting product, melting points, solvents used for crystallization and yields as follows:

Methyl 6-fluoro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate melting after recrystallization from methanol / dimethylformamide 2: 1 (v / v) at 221-223 ° C; yield 15%.

Methyl 2- (2-fluoro-4-bromobenzyl) -6-fluoro-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate melting after recrystallization from methanol at 131-134 ° ^C ; yield 51%.

2- (2-fluoro-4-bromobenzyl) -6-fluoro-1,2-dihydro-1-oxo-thiazol-4-ylcarboxylic acid melting after recrystallization from isopropanol at 210-211 ° C; 70% yield.

Example J 3 3

By proceeding as in Example 16, substituting the oxygen atom in ethyl 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate for the sulfur atom yielded ethyl 2- 2- in a yield of 22%. (2-Fluoro-4-bromobenzyl) -1,2-dihydro-1-thioxophthalazin-4-yl acetate melting after recrystallization from ethanol at 97-99 ° C. Examples 34 to 37

A mixture of 1.5 potassium carbonate, 16 ml of water, 50 ml of dioxane and 1.0 g of ethyl 2- (2-fluoro-4-bromobenzyl) -8-fluoro-1,2-dihydro-1-oxophthalazin-4-yl acetate was added for 24 hours The mixture is heated to reflux, then evaporated, the residue is dissolved in 100 ml of water and the solution is washed twice with 100 ml of ether each time. The aqueous phase is acidified to pH 2 with concentrated hydrochloric acid, the precipitated solid is filtered off, washed with water and recrystallized from a toluene / isopropanol / petroleum ether mixture (b.p. 60-80 ° C) 7: 1: 5 by volume. 0.5 g of 2- (2-fluoro-4-bromobenzyl) -8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (Example 34), melting at 173-175 ° C, is obtained.

The following acetic acid derivatives are prepared in an analogous manner from the corresponding ethyl esters:

Example 35

2- (3,4-dichlorobenzyl) -7-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetic acid, melting after recrystallization from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C) in a volume ratio of 1: 2 at 201-202 ° C; yield 90%.

EXAMPLE 36 Hydro-1-oxophthalazin-4-ylacetic acid, melting after recrystallization from a 5: 1 by volume mixture of methanol and dimethylformamide at 204-205 ° C; yield 76%.

Example 1 7

2- (3,4-dichlorobenzyl) -6-chloro-1,1-dihydro-1-oxophthalazin-4-ylacetic acid, melting after recrystallization from isopropanol at 208-209 ° C; yield 55%.

Examples 38 to 50

By analogy to Example 4, hydrolysis of the corresponding ethyl esters with potassium hydroxide gives the following acetic acid derivatives, corresponding to the above general formula (XV).

2- (3,4-dichlorobenzyl) -6,7-dichloro-1,2-di-

example substituents substituents yield temperature crystallization number Circle B Circle A (%) melting point (° C) solvent 38 - 4-iodo 64 178—180 isopropanol / petroleum ether (60-80) 1: 2 39 - 3,4-dibromo 61 187—189 isopropanol 40 - 2-fluoro-4,5-dibromo 71 184—186 isopropanol 41 - 3,5-dichloro-4-bromo 60 219—220 isopropanol 42 - 2-methoxy-4-chloro 55 183-184 isopropanol 43 8-fluoro 3,4-dichloro 68 143—145 ethyl acetate / toluene (1: 1) (6-methyl *) 3,4-dichloro 44 | + 43 - 182—184 isopropanol (7-methyl) 3,4-dichloro 45 8-methyl 2-fluoro-4-bromo 37 195—197 isopropanol / petroleum ether (60-80) 1: 2 46 8-methyl 3,4-dichloro 44 203-205 isopropanol / petroleum ether (60-80) 1: 2 47 6,7-methylenedioxy 2-fluoro-4-bromo 70 209—210 isopropanol 48 6-fluoro 2-fluoro-4-bromo 72 137—188 isopropanol 49 3-ethoxy **) 3,4-dichloro 85 204—206 isopropanol

Example 51

Legend:

*) 1: 2 mixture of 6-methyl and 7-methyl derivative **) exo-tutomer (by NMR spectroscopy)

By analogy to hydrolysis of the corresponding ethyl esters with aqueous methanolic sodium hydroxide solution, 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-thioxophthalazin-4-ylacetic acid (Example 50) is obtained in the form of 30%. solids melting after recrystallization from methanol at 194-196 degrees Celsius.

To a solution of 1.5 g of sodium in 150 ml of dry ethanol was added 1.8 g of ethyl 2- (3,4-dichlorobenzyl) -8-fluoro-1,2-dihydro-1-oxophthalazin-4-yl acetate. The resulting solution was heated at reflux for 3 hours, then evaporated, 100 ml of water were added to the residue and the precipitated solid was filtered off. After drying, 0.5 g of ethyl 2- (3,4-dichlorobenzyl) -8-ethoxy-1,2-dihydro-1-oxophthalazin-4-yl acetate is obtained.

Example 1 a d 5 2

To a solution of 9.87 g of 2- (2-fluoro-4-bromobenzyl) 241041

-1,2-Dihydro-1-oxophthalazin-4-ylacetic acid in 300 ml of methanol was added a solution of sodium methoxide (25 ml of 1.0 M solution in methanol) and the resulting mixture was heated to boiling. The methanol is distilled off until the volume of the mixture is about 100 ml. 150 ml of isopropanol are added to the residue, and then petroleum ether (b.p. 60-80 degrees Celsius) is added until the turbidity begins. The resulting mixture was allowed to cool to room temperature, the precipitated solid was filtered off, evaporated twice with 400 ml of toluene and then washed with 300 ml of ether. 6.5 g of sodium 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-phthalazin-oxof-4-ylacetate, m.p. 244-247 ° C ^Q

Example 53

0.9 g of 2-fluoro-4-bromobenzyl-2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate are dissolved in 40 ml of ethanol containing 2.0 g of potassium hydroxide. . The mixture was heated at reflux for 90 minutes, then the solvent was evaporated. 100 ml of water were added to the residue, and the resulting clear solution was acidified to pH 2 with concentrated hydrochloric acid. The precipitated solid was filtered off and washed thoroughly with water and dried in vacuo. 0.35 g of 2- (2-fluoro-4-bromobenzyl-1,2-dihydro-

Claims (5)

SUBJECT A process for the preparation of 2-benzyl-1,2-dihydro-1-oxophthalazin-4-ylacetic acid derivatives of the general formula I by substituents R ² , R ³ , R ⁴ and R ⁵ on the benzene ring A are selected from the following combinations a) R ² represents a fluorine atom or a methoxy group, R ³ represents hydrogen, R ⁴ represents a chlorine, bromine or iodine atom; ^R represents a hydrogen or halogen atom, b) R ² , R ³ and R ⁵ are hydrogen atoms and R ⁴ represents a bromine or iodine atom, 1-oxophthalazin-4-ylacetic acid melting after recrystallization twice from methanol at 181-183 ° C. The starting material is obtained as follows: To a solution of 4.0 g of potassium carbonate in 50 ml of dimethylformamide was added 2.0 g of 1,2-dihydro-1-oxophthalazin-4-ylacetic acid, to which 6.0 g of 2-fluoro-4-bromobenzyl bromide was added. and the mixture was stirred at 60-70 ° C for 15 hours. The reaction solution is poured into 400 ml of water, the precipitated solid material is separated, washed thoroughly with water and, after drying in vacuo, dissolved in ethyl acetate. The solution was filtered through a column (50 g) of dry silica gel for chromatography and the eluate collected as fractions. The column is then eluted with additional ethyl acetate and the fractions which, according to thin layer chromatography [silica gel, toluene-ethyl acetate 3: 1 (v / v)], contain the major non-polar component, are combined and evaporated. Recrystallization of the solid residue from 2-propanol twice gave 1.1 g of 2-fluoro-4-bromobenzyl-2- (2-fluoro-4-bromobenzyl) 1,2-dihydro-1-oxophthalazin-4-yl acetate, m.p. 125-127 ° C (softens at 85 degrees Celsius). c) ^R2 is hydrogen or fluoro, R ³ and R ⁵ represent identical or different halogen atoms and R ⁴ is hydrogen, d) ^R2 is hydrogen or fluoro, R ³ and R ⁴ represent identical or different halogen atoms and R ⁵ represents a hydrogen atom, and e) R ² is hydrogen, R ³ and R ³ independently represent fluorine or chlorine atoms and R ⁴ represents chlorine, bromine or iodine, the substituents R ⁶ , R ⁷ and R ⁸ on the benzene ring B are independently selected from the group consisting of hydrogen, halogen atoms , (C 1 -C 4) alkyl and (C 1 -C 4) alkoxy, or R ⁶ and R ⁷ together form a divalent C 1 -C 4 alkylenedioxy radical, provided that at least one of R ⁶ , R ⁷ and R ³ represents a hydrogen atom, and X is oxygen or sulfur, and pharmaceutically acceptable base addition salts thereof, characterized in that the ester of formula (II) in which: R1 is C1 -C4 alkoxy or a radical of formula III (III) wherein R ^2, R ^3, R ⁴ and R ⁵ are as defined above and the remaining symbols have the above meanings, and the resulting free acid of formula I or by reacting with a base affording a pharmaceutically acceptable cation converted to its pharmaceutically-acceptable base addition salt thereof . 2. A method according to claim 1, characterized by hydrolyzing the ester of the formula II wherein R ¹ is alkoxy having 1 to 4 carbon atoms and the other symbols are as defined in claim 1, and the resulting free acid of formula Alternatively, by reaction with a base providing a pharmaceutically acceptable cation, it is converted to its pharmaceutically acceptable base addition salt. 3. The method according to claim 1 or 2, characterized by. The process according to claim 1, wherein the hydrolysis is carried out in the presence of an aqueous mineral acid at a temperature of 18 to 110 ° C. 4. Process according to claim 1 or 2, characterized in that the hydrolysis is carried out in the presence of an alkali metal hydroxide or carbonate at a temperature of 18 to 110 ° C. 5. Process according to claims 1 to 4, characterized in that starting materials are used the above formula II wherein benzene ring B is unsubstituted, R ¹ is as defined in claim 1; R ² represents a fluorine atom, R ^3, and R ⁵ are hydrogen and R ⁴ is chlorine, bromine or iodine, or R ² and R ⁵ are hydrogen and R ³ and R ^{4 are each} independently chlorine, bromine or iodine.