KR820001931B1 - Process for preparing phthalazin-4-ylacetic acid derivatives - Google Patents

Abstract

The title compds.(I; R1 = optionally substitute C1-4 alkoxy; R2 = fluoro, methoxy; R3 = H, R4 = chloro, bromo, iodo; R5 = H, halogeno; R6,R7,R8 = H, halogeno, C1-4 alkyl, alkoxy) having enzyme inhibiting activities, were prepd. by the reaction of II and III(Hal = chloro, bromo, iodo). Thus, 2.0 g 1,2-dihydro-1-oxophthalazin-4-ylacetic acid was reacted with 0.9 g sodium hydroxide and 2.0 g 4-bromobenzyl bomide for 3 hr to give 0.6 g 2-(4-bromobenzyll)-1,2-dihydro-1-oxo-phthalazin-4-ylacetic acid(m.p. 179-181≰C).

Description

Method for preparing phthalazin-4-yl acetic acid derivative

The present invention relates to a method for preparing a novel phthalazin-4-ylacetic acid derivative having a function of inhibiting the enzyme aldose reductase in vivo.

The enzyme aldose reductase catalytically converts aldose, such as glucose and galactose, to the corresponding alditols such as sorbitol and galactitol, respectively. Alditol is so poorly penetrated by cell membranes that once formed it tends to be removed only by other metabolism. As a result, altitol tends to accumulate in the cells in which they are formed, creating an internal osmotic pressure sufficient to destroy or impair the function of the cells themselves. In addition, elevated levels of altitol may cause abnormal levels of metabolites that can impair cellular function on their own.

However, the enzyme aldose reductase has a relatively low substrate affinity. Ie effective only in the presence of relatively large aldose concentrations. Such large concentrations of aldose are present in clinical conditions of diabetes (excess glucose) and galactosemia (excess galactose). As a result, inhibitors of the enzyme aldos reductase are useful for reducing or preventing the progression of peripheral symptoms of diabetes or galactosemia, which may be due in part to the accumulation of sorbitol or galactitol respectively. Such peripheral symptoms are, for example, spots, edema, cataracts, retinopathy or damaged nerve conduits.

It is known from our previous studies that the 1-benzyl-2-oxoquinol-4-yl alkanoic acid derivative is an enzyme aldose reductase (British patent specification 1,502,312). The inventors also unexpectedly found that some of the benzyl 2-benzyl-1-oxophthalazin-4-yl acetic acid defined below is an inhibitor of the enzyme aldose reductase.

This finding is particularly surprising in view of the many differences between the 2-oxo-quinoline and 1-oxo phthalazine ring systems. Phthalazine derivatives, 2-benzyl- and 2- (2-pyrid-2-ylethyl) -1, 2-dihydro-1-oxophthalazine-4-ylacetic acid associated with their methyl and ethyl esters Are known and their action on the core of blood is reported (see sh. Feldeak et alia, Khim. Farm. Zh., 1970, 4, 22 26; Chemical abstracts, 1970, 73, 77173), as defined below. Unlike the compounds of the present invention, none of these known phthalazine derivatives are inhibitors of aldose ferductase in vivo at oral doses of 100 mg / kg or less.

According to the present invention, the compound of formula (3) is reacted with a halide of formula (4) in the presence of a suitable base, and the following formula (1) 2-benzyl-1, 2-dihydro-1-oxo Provided is a method for preparing a phthalazin-4-yl acetic acid derivative.

Wherein R ¹ is a C _1-4 alkoxy group optionally having a hydroxy or benzyloxy group, or an N-morpholino or di-C _1-4 alkylamino group, and a substituent R ² , R ³ , R ⁴ on the benzene ring A And R ⁵ is selected from any of the following combinations. In other words,

a) R ² is a fluoro or methoxy group, R ³ is hydrogen, R ⁴ is a chloro, bromo or iodine group, R ⁵ is hydrogen or a halogeno group,

b) R ² , R ³ and R ⁵ are hydrogen and R ⁴ is a bromo or iodine group,

C) R ² is hydrogen or a fluoro group, R ³ and R ⁵ are the same or different halogeno groups, R ⁴ is hydrogen,

d) R ² is hydrogen or a fluoro group, R ³ and R ⁴ are the same or different halogeno groups, R ⁵ is hydrogen,

e) R ² is hydrogen, R ³ and R ⁵ are each a fluoro or chloro group and R ⁴ is a chloro, bromo or iodine group.

R ⁶ , R ⁷ and R ⁸ in the benzene ring B are each selected from hydrogen, halogeno, C _1-4 alkyl and C _1-4 alkoxy groups, or R ⁶ and R ⁷ are each at least one of R ⁸ , Together constitute C _1-4 alkylenedioxy diradical in the presence of a suitable base.

Pharmaceutically acceptable base addition salts of compounds of formula (1) wherein R ¹ is a hydroxy group according to the invention or C _1-4 alkoxy having R ^{1 an} N-morpholino or di-C _1-4 alkylamino group Also provided are methods for preparing pharmaceutically acceptable acid addition salts of compounds of formula (1).

In the formula, Hal is a chloro, bromo or iodine group, and the substituents on R ¹ , benzene ring A and B, and benzene ring have the meanings mentioned above.

If a pharmaceutically acceptable salt is required, the compound of formula (1) wherein R ¹ is a hydroxy group is reacted with a base that produces a pharmaceutically acceptable cation, or R ¹ is N-morpholino or di-N The compound of formula (1), which is a C _1-4 alkoxy group optionally containing an, NC _1-4 -alkylamino group, is reacted with an acid giving a pharmaceutically acceptable anion.

The compound of general formula (1) is a derivative of 1,2-dihydro-1-oxo-phthalazin-4-ylacetic acid represented by general formula (2) throughout this specification.

It can be seen that the compound of the general formula (1) may be tautomer represented by the following general formula (1a), and the present invention is a tautomer (endo-tautomer) of the general formula (1) or an arc of the general formula (1a). Of course, it includes variants (exo-tautomers), or mixtures thereof.

When R ³ or R ⁵ are halogeno groups they are for example fluoro, bromo or iodine and in particular chloro or bromo groups.

When R ⁶ , R ⁷ or R ⁸ is a halogeno group, specific examples thereof are a fluoro, chloro, bromo, or iodine group, and in the case of a C _1-4 alkyl group, for example, a methyl group, C _1-4 alkoxy In the case of a group, for example, a methoxy or ethoxy group.

Specific examples of R ¹ when C _1-4 alkoxy group for example methoxy and ethoxy, or an ethoxy group, if blanket N- or di Reno -C _1-4 C _1-4 alkoxy group with the alkyl group for example 2- (N- Morpholino) ethoxy or 2- (N, N-dimethylamino) ethoxy group.

Specific examples for R ⁶ and R ⁷ are when they together form C _1-4 alkylenedioxy diradicals such as methylenedioxy, ethylenedioxy or isopropylidenedioxy diradical.

Of particular interest are particular combinations of R ² , R ³ , R ⁴ and R ^{5 where} the benzene ring A is for example 2-fluoro-4-bromo-, 2-fluoro-4-chloro-, 2-fluoro-4 -Iodine, 2-fluoro-4,5-dibromo-, 2-methoxy-4-chloro-, 4-bromo, 4-iodo, 3,5-dichloro-, 3-chloro-4- When the bromo-, 3,4-dichloro-, 3,4-dibromo- or 3,5-dichloro-4-bromo-phenyl group is used.

Particularly interesting combinations of R ⁶ , R ⁷ and R ⁸ are for example benzene ring B unsubstituted or 6-fluoro, 6-chloro, 6-methyl, 7-fluoro, 7-chloro, 7-methyl, When 7-methoxy, 8-fluoro, 8-methyl or 8-ethoxy group, or 6,7-dichloro or 6,7-methylenedioxy diradical.

Particular base addition salts of compounds of formula (1) wherein R ¹ is a hydroxy group are, for example, alkali or alkaline earth metal salts such as sodium, potassium, calcium, or magnesium salts, aluminum or ammonium salts, or pharmaceutically acceptable such as triethanolamine It is a salt of an organic base which gives a cation.

Specific examples of acid addition salts of compounds of formula (1) wherein R ¹ is a C _1-4 alkoxy group containing an N-morpholino or di-C _1-4 alkylamino group include a hydrohalide such as hydrochloride or hydrobromide, or sulfate to be.

A particular group of particularly preferred compounds is the compounds of formula (1) having the following groups and their pharmaceutically acceptable salts which depend on R ¹ . In other words,

(Iii) R ¹ is a hydroxy group;

(Ii) R ² is a fluoro group, R ³ and R ⁵ are hydrogen, R ⁴ is a chloro, bromo or iodine group;

(Iii) R ³ and R ⁴ are each a chloro, bromo or iodine group, and R ² and R ⁵ are hydrogen;

(Iii) R ⁶ , R ⁷ and R ⁸ are hydrogen;

The remainder of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ in each of the groups (i)-(iii) is defined in any of the above definitions or in other groups. It is.

Specific compounds obtainable by the present invention are described in the Examples, with the following compounds being preferred.

2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazine-4-ylacetic acid, 2- (2-fluoro-4-iodobenzyl) -1 , 2-dihydro-1-oxo phthalazine-4-ylacetic acid, and 2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxo-phthalazine-4- Monoacetic acid, and pharmaceutically acceptable base-addition salts thereof.

The process of the invention is preferably carried out in a solvent or diluent such as, for example, ethanol, dimethylformamide, dimethylsulfoxide or water, and is conveniently facilitated by heating, for example, in the temperature range of 40-110 ° C.

Particularly suitable bases are for example alkali metal hydrides, carbonate hydroxides or C _1-4 alkoxides such as sodium or potassium hydridecarbonates, hydroxides, methoxides, or ethoxides, for example dimethyl sulfoxide if hydrides are used Or a non-aqueous solvent such as dimethylformamide, and if alkoxide is used it is of course desirable that C _1-4 alkanols such as methanol or ethanol are used as the solvent.

It can be seen that at least 2 molar equivalents of base should be present when the compound of formula (3) wherein R ¹ is a hydroxy group is used in the present invention. This is because one molar equivalent reacts with the carboxylic acid group of such a compound. In addition, for such compounds of the general formula (3), it is preferable to use a hydroxy solvent to minimize the formation of by-products of the corresponding esters.

The starting material of formula (3) is reacted at a temperature of 40-110 ° C. in a water-soluble diluent or solvent such as hydrate roll, water-soluble dioxane, ethanol or dimethylformimide with a compound of formula (4) or its geometric isomer Can be obtained.

This process is particularly suitable for the production of compounds of formula (3) wherein R ¹ is a hydroxy or ethoxy group. Other starting materials of the general formula (3) in which R ¹ is not a hydroxy group include the free acid of phthalazin-4-ylacetic acid or chloride thereof produced in the process by a conventional esterification method of a known technique. Obtained by modifying with a suitable ester.

Some of the starting materials of formula (4) are conveniently prepared by condensing the corresponding substituted phthalic anhydride of formula (5) with anhydrous acid, for example in the presence of sodium or potassium acetate and in excess boiling acetic anhydride.

However, all of these can be reacted with a Witig reaction between a suitable phthalic anhydride of formula (5) and triphenylphosphorane of formula (5) in the presence of a suitable solvent such as 1,2-dimethoxyethane or tetrahydrofuran. Can be prepared and the reaction is conveniently facilitated, for example by heating to the boiling point of the reaction mixture. In some cases the product from the Wittig reaction may be a geometric isomer of the following general formula (4a) rather than one represented by general formula (4).

Alternatively, a mixture of two geometric isomers can be formed. Isomers or mixtures thereof may be reacted with hydrazine hydrate to give the starting material of formula (3). As can also be seen, when one of R ⁸ and R ⁷ and R ⁶ is hydrogen, the Witig reaction produces positional isomers as the two carbosyl groups of phthalic anhydride (5) react. If R ⁸ is not hydrogen, one positional isomer predominates. That is, the isomer formed by reaction of the carbonyl group furthest from R ⁸ is dominant.

Pharmaceutically acceptable salts as defined above may be prepared by reaction with appropriate bases or acids which impart pharmaceutically acceptable cations or anions, respectively, by conventional procedures.

Inhibitory properties of the enzyme aldose reductase can be demonstrated in the following standard laboratory tests. Therefore, streptocin was administered to the rats with diabetes and then administered daily as test compounds for 5 days. The test animals were killed and the eye lens and sciatic nerve removed. After the standard operating procedure, the remaining sorbitol concentration of each tissue was converted to polytrimethylsilyl derivative and measured by gas-liquid chromatography. Inhibition of aldose reductase in vivo was then evaluated in comparison to the concentrations of the rats in the diabetic group not administered and the rats in the normal group not administered the residual sorbitol concentration in the tissue from the rats of the diabetic group administered.

In contrast, a diabetic rat challenged with straptozotocin was tested daily for two days with test compounds. After 2-4 hours of final administration, the test animals were killed and the sciatic nerve was removed to evaluate the residual sorbitol concentration as described above.

The active compound in these tests reduces the residual sorbitol concentration to a concentration similar to that of normal non-administered rats. In general, however, compounds of formula (1) virtually inhibit the enzyme aldos reductase at oral administration of 100 mg / kg or less. Therefore, 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazine-4-ylacetic acid was orally administered at 10 mg / kg for 5 days in the sciatic nerve, This resulted in a residual sorbitol concentration, about 60% of the concentration obtained in the control diabetic rats that were not administered. No obvious toxicity and side effects were detected when the compound of Formula (1) was administered at 100 mg / kg in the above test.

In addition, the inhibitory properties of the enzyme aldose reductase can be measured in vitro.

Thus purified aldose reductase was isolated from bovine lens by known methods. The percent inhibition of this enzyme in vitro, in which aldose was reduced to polyhydric alcohols, and in particular, glucose was reduced to sorbitol by the test compound, was measured using standard spectrophotometric methods. In this test, compounds of formula (1) wherein R ¹ is a hydroxyl group show significant inhibition of the enzyme aldose reductase at concentrations of 10 ⁻⁸ −10 ⁻⁶ M or less. Thus, according to the examples, the 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid ki is 2.0x10 ^-8 M.

When the compound of the present invention is used to have an action against the enzyme aldose reductase in warm blooded animals, it can be administered orally mainly at a dose of 2-5 mg / kg daily, which is 20-750 mg per human. Corresponds to the daily total dose in the range. If necessary, it is dividedly administered.

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

Particularly preferred pharmaceutical compositions are those in a form suitable for oral administration such as, for example, tablets, capsules, suspensions or solutions. These types of compositions are prepared by known methods and may be admixed with conventional diluents, carriers or other excipients as needed.

Some of the compounds obtainable by the present invention have anti-inflammatory / analgesic effects in the form of nonsteroidal anti-inflammatory agents such as indomethacin, naproxen and ketoprofen in addition to aldose reductase inhibitory activity. Therefore, they are useful for the treatment of painful inflammatory arthritis such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In this regard, the compound may be administered orally mainly in the range of 10-50 mg / kg daily. Anti-inflammatory can be demonstrated in rats by known standard laboratory tests. Thus 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid and 2- (3-chloro-4-bromobenzyl) -1 Both, 2-dihydro-1-oxoprotalazin-4-yl acetic acid exhibited obvious toxic symptoms in a test by Winter et al. [Proceedinge of the Society of Experimental Biology (New York), 1962, 111, 554]. Significantly inhibited carrageenan-induced species.

The present invention will be described in detail based on examples.

In this embodiment,

(Iii) All evaporations were carried out by rotary evaporation in vacuo unless otherwise noted.

(Ii) All operations were performed at room temperature, ie 18-26 ° C., unless otherwise noted.

(Iii) Petroleum ether (boiling point: 60-80 ° C) is referred to as "petrol (60-80)".

(Iii) The melting point of acetic acid is in most cases related to degradation.

(Iii) All compounds of formula (1) and isolated intermediates are based on microanalysis and NMR and IR spectroscopy.

(Iii) Given yields are exemplary and do not necessarily represent the maximum achievable.

Example 1

1,2-dihydro-1-oxophthalazine-4-yl acetic acid (2.0 g) was added to a solution of sodium hydroxide (0.9 g) dissolved in methanol (50 ml). Obtained by slightly heating the clear solution, which was treated with 4-bromobenzyl bromide (2.0 g). The mixture was heated to reflux for 3 hours and then evaporated. The residue was treated with water (60 ml) and the resulting solution was extracted with ether (3 × 60 ml).

The aqueous layer was treated with concentrated hydrochloric acid to acidify the pH to 2 and then the acid mixture was extracted with ethyl acetate (150 ml). The extract was washed with water (50 ml), dried (MgSo ₄ ) and evaporated. The resulting solid was recrystallized from a 1: 4v / v mixture of ethyl acetate and petrol (60-80) as a result of 2- (4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl Acetic acid (0.6 g) was obtained. Melting point: 179-181 ° C.

Example 2

Of ethyl 1,2-dihydro-1-oxophthalazine-4-ylacetate (11.5 g) and sodium hydride (2.7 g: 50% W / W suspension suspended in mineral oil) in dimethylformamide (125 ml) The mixture was stirred at 60 ° C. for 1 hour under a nitrogen stream. The resulting solution was cooled to room temperature, then 4-bromo-3-chlorobenzylbromide (15.0 g) was added and the mixture was stirred at 60 ° C. for 2 hours. The resulting aqueous mixture was extracted with ethyl acetate (400 ml). The extract was washed with water, dried (MgSO ₄ ) and evaporated to give a solid, which was recrystallized from propan-2-ol to give ethyl 2- (3-chloro-4-bromobenzyl) -1,2-di Hydro-1-oxophthalazine-4-yl acetate (7.3 g) was obtained. Melting point: 142-145 ° C.

Example 3-4

A process similar to the one described in Example 2 was used, wherein ring B was unsubstituted and then the compound of formula (6) was substituted with ethyl-1,2-dihydro-2-oxophthalazine-4-yl acetate and Obtained from the appropriate bromide of following General formula (7).

[* Note: 3,4-dichlorobenzyl chloride was used as starting material.]

Example 5-6

The following ester was prepared using a process similar to the process described in Example 2 and using the appropriate benzyl bromide or chloride.

Example 5 Ethyl 2- (2-fluoro-4-chlorobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate, Melting point: 102 캜

[Recrystallized from petrol (60-80) and then recrystallized from ethanol], yield: 45%

Example 6 ethyl 2- (2-fluoro-4-iodobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate, melting point: 113 占 폚

[Recrystallization yield from petrol (60-80): 50%].

Example 7

Using the process analogous to the process described in Example 2, using the appropriate benzyl bromide of formula (7), the following compound of formula (6) with ring B unsubstituted was prepared.

Example 13-15

The following compounds are prepared from suitable substituted 1,2-dihydro-1-oxophthalazin-4-ylacetic acid and 2-fluoro-4-bromobenzyl hydrazine using a process similar to the process described in Example 2 It was.

Example 13

Ethyl 2- (2-fluoro-4-bromobenzyl) -8-fluoro-1,2-dihydro-1-oxophthalazin-4-yl acetate, melting point: 128-130 ° C

[1: recrystallized from 3v / v isopropanol / petrol (60-80)] yield: 36%

Example 14

Ethyl 2- (2-fluoro-4-bromobenzyl) -8-methyl-1,2-dihydro-1-oxophthalazine-4-yl acetate, melting point: 120-122 ° C

[1: recrystallized from 3v / v isopropanol / petrol (60-80)] yield: 43%.

Example 15

Ethyl 2- (2-fluoro-4-bromobenzyl) -6,7-methylenedioxy-1,2-dihydro-1-oxophthalazin-4-yl acetate, melting point: 163-165 ° C

(Recrystallized from ethyl acetate), Yield: 56%

The required starting material was prepared by the following method.

(Iii) Ethyl 8-methyl-1,2--dihydro-1-oxophthalazine-4-yl acetate (Example 14)

A solution of ethyl 4-methyl-3-oxo-Δ1α-phthalane acetate (3,5 g) dissolved in ethanol (100 ml) was stirred and heated to reflux with dropwise addition of hydrazine hydrate (15 ml of 1 M solution in ethanol). After the addition was complete, the mixture was further stirred and heated at reflux for 3 hours and then left to cool to room temperature. The precipitated solid was collected and washed well with petrol (60-80) and then recrystallized from isopropanol / petrol (60-80) to yield ethyl 8-methyl-1,2-dihydro-1-oxophthalazine-4- One acetate (1.0 g) was obtained. Melting point: 197-199 캜.

(Ii) ethyl 8-fluoro-1,2-dihydro-1-oxophthalazine-4-yl acetate (Example 13)

This ester was prepared as a solid from ethyl 4-fluoro-3-oxo-Δ, 1α-phthalane acetate and hydrazine hydrate using the process described above (iii). Melting: 207-210 degreeC.

(Recrystallized from ethyl acetate), Yield: 51%.

(Iii) Ethyl 6,7-methylenedioxy-1,2-dihydro-1-oxophthalazin-4-yl acetate (for Example 15)

This ester was prepared as a solid from ethyl 5,6-methylenedioxy-3-oxo-Δ, 1α-phthalane acetate (A) and hydrazine hydrate. Melting point: 226-228 ° C., yield: 70%. Phthalan acetate (A) itself was prepared as a solid from 4,5-methylene dioxyphthalic anhydride using a process similar to that described for the corresponding intermediates in Examples 25-27. Melting point: 189-191 ° C (recrystallized from ethanol), yield: 64%. This process is based on the process of Knight and Porter's Tetrahedron Letters, 1977, 4543-4547.

Example 16

A solution of sodium methoxide (25 ml of 1.0 M solution in methanol) was added 2- (2-fluorobrom-4-benzyl) -1,2-dihydro-1-oxophthalazin-4-yl in methanol (300 ml). To a solution of acetic acid (9.87 g) was added and the mixture was heated to its boiling point. Methanol was left to boil off until the volume of the mixture was approximately 100 ml. Isopropanol (150 ml) was added followed by petrol (60-80) until the mixture became opaque. The mixture was left to cool to room temperature. The solid formed was isolated by filtration, evaporated with toluene (2 × 400 ml) and washed with ether (300 ml) as a result of sodium 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1- Oxophthalazin-4-yl acetate (6.5 g) was obtained. Melting point: 244-247 ° C.

Example 17

1,2-dihydro-2-oxophthalazin-4-ylacetic acid (2.0 g) was added to a solution of potassium carbonate (3.5 g) dissolved in water (40 ml) and dimethylformamide (60 ml). The mixture was stirred and heated to 60 ° C. for 30 minutes. 2-fluoro-4-bromobenzyl bromide (2.8 g) was added and the mixture was stirred at 60 ° C. for 2 hours, followed by water (30 ml). The obtained aqueous mixture was extracted with ethyl acetate (2 x 300 ml) and the extract was discarded. Treatment of the aqueous layer with concentrated hydrochloric acid to acidify to pH 2 yields 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid, Recrystallization with ethanol gave pure substance (0.5 g) as a solid. Melting point: 180-182 ° C.

Example 18-40

Using a process similar to the process of Example 7 described above, with the appropriate compound of formula (3) (R ¹ = OH) as starting material, the following general formula acetic acid was obtained in 25-55% yield.

Example 41-44

Use a process similar to the process described in Example 2, wherein Formula (3), (Formula, R ¹ is methoxy, 2- (2N-morpholino) -ethoxy, 2- (N, N-dimethyl) A compound of the general formula (1) (wherein the benzene ring A is 2-) using a suitable 1,2-dihydro-1-oxophthalazine-4-ylacetic acid derivative of amino) ethoxy or benzyloxy group as a starting material Fluoro-4-bromo phenyl group, and benzene ring B is unsubstituted). (Yield: 20-60%)

Example 45

1,2-dihydro-2-oxophthalazin-4-ylacetic acid (2.0 g) was added to a solution of sodium hydroxide (0.9 g) in methanol (70 ml) containing water (10 ml). The mixture was left until a clear solution was obtained, then treated with 4-bromo-2fluorobenzyl bromide (3.0 g) and heated at reflux for 3 hours. The solution was then evaporated and the residue was treated with water and extracted with ether (3 x 80 ml). The aqueous layer was treated with concentrated hydrochloric acid to acidify to pH 2. The precipitated solid was collected by filtration, washed twice with water and then recrystallized with methanol to give 2- (4-bromo-2-fluorobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl Acetic acid * (0.45 g) was obtained.

Melting point 183-185 ° C.

Note: This compound crystallizes in polymorphic form and has a melting point of 184-185 ° C.

Phosphorus form (methanol with some water) and melting point 180-182 ° C (second crystal from anhydrous methanol).

Example 46

Sodium hydride (0.5 g; 50% w / w in mineral oil) in a solution of ethyl 1,2-dihydro-1-oxophthalazin-4-yl acetate (2.32 g) in dimethylformamide (50 ml) was stirred. Suspension). When boiling stops, the mixture is stirred at room temperature for 90 minutes.

A 3,4-dichlorobenzyl chloride (2.0 g) solution dissolved in dimethylformamide (5 ml) was added again and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (400 ml) and the precipitated solid was collected by filtration, washed with water and dried in air and recrystallized twice from propan-2-ol to give ethyl 2- (3,4-dichlorobenzyl)- 1,2-dihydro-1-oxophthalazin-4-ylacetate (2.1 g) was produced. Melting point 139-141 ° C.

Claims (1)

As described above in the text, 2-benzyl-1,2-dihydro-1- of formula (1) characterized by reacting a compound of formula (3) with a halide of formula (4): Method for preparing oxophthalazine-monoacetic acid derivative.

Food, R ¹ is a C _1-4 alkoxy group optionally having a hydroxy or benzyloxy group or an N-morpholino or di-C _1-4 alkylamino group; Substituents R ² , R ³ _and R ⁴ on the benzene ring A are selected from any of the following combinations. In other words (a) R ² is a fluoro or methoxy group, R ³ is hydrogen, R ⁴ is a chloro, bromo or iodine group, R ⁵ is hydrogen or a halogeno group; (b) R ² , R ³ and R ⁵ are hydrogen, R ⁴ is a bromo or iodine group; (C) R ² is hydrogen or fluoro, R ³ and R ⁵ are the same or different halogeno groups, R ⁴ is hydrogen, (d) R ² is hydrogen or fluoro, R ³ and R ⁴ are the same or different halogeno groups, R ⁵ is hydrogen, (e) R ² is hydrogen, R ³ and R ⁵ are each a fluoro or chloro group, R ⁴ is a chloro, bromo or iodine group; R ⁶ , R ⁷ and R ⁸ on the benzene ring B are each hydrogen, halogeno, C _1-4 alkyl and C _1-4 alkoxy group; Or R ⁶ and R ⁷ together form a C _1-4 alkyl dioxy diradical when at least one of R ⁶ , R ⁷ and R ⁸ is hydrogen; Hal is a chloro, bromo or iodine group.