JPH013173A - Method for producing oxophthalazinyl acetic acids having a heterocyclic side chain such as benzothiazole - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing oxophthalazinyl acetic acids having a heterocyclic side chain such as benzodeazole. This type of compound has the function of inhibiting aldose reductase activity and is useful for treating various chronic complications derived from diabetes, such as diabetic cataract, retinopathy, and neuropathy. Such compounds are described in European Patent Application Publication No. Box 0222576 (Japanese Patent Laid-Open No. 62-114988).

The present invention relates to a method for producing a compound of formula VII, including: ? R3 and R4 are the same or different hydrogen, fluorine, chlorine,
Bromine, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl or nitro group, or R and R4 together are C1-4 R5 and R6 are the same or different hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkyl of cl-4, alkoxy of C1-4, alkylthio of C1-4, alkylsulfinyl of C1-4 , C1-4 alkylsulfonyl, nitro or benzo, or R and R6
are collectively C alkanedioxy; 2 is hydrogen or a methyl group; U is sulfur, methylene, or a covalent bond]; , R4 and Z are as defined above; W' is sulfur, methylene or a covalent bond; Q is -
C(-NH)-OR2 (wherein R2 is C-1-4 alkyl) or cyano] or an acid addition salt thereof; react with the compound or its acid addition salt (provided, however, that if neither of the compounds of formula (1) and formula VI is an acid addition salt at the time they are added to the other, the reaction is carried out in the presence of a strong acid. ), optionally hydrolyzing a formula VII in which R1 is not hydrogen to form a corresponding formula VII in which R1 is hydrogen.
The present invention relates to a method for producing oxophthalazinyl acetic acids having a heterocyclic side chain such as benzothiazole.

Among the compounds of formula VI, Q is -C(-NH)-0R(
R is C1-4 alkyl) and all compounds of formula VI are capable of forming acid addition salts. Although not wishing to be bound by the following inference, it is likely that adding a strong acid to the above reaction mixture will result in formulas
An acid addition salt will form in situ of at least one (possibly both) of the compounds, which will then react with the other. That is, at least one of the substances involved in the reaction is an acid addition salt that is either preformed or generated within the system.

The present invention also provides compounds of formula VI as described above, processes for preparing intermediates convenient for the synthesis of compounds of formula VI, intermediates convenient for the synthesis of compounds of formula VI, and other processes in which the intermediates can be utilized. It depends.

The intermediate according to the present invention includes a metal compound of the formula (1) described later, and also has the following formula M; R3 and R4 are the same or different hydrogen, fluorine, chlorine,
Bromine, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, or nitro group, or R and R together are C1 -4 alkanedioxy: Z is hydrogen or methyl: W' is sulfur, methylene or a covalent bond: Y is hydroxyl, chlorine, bromine, cyano or -C(-NH)-OR (R is C1-
(alkyl of 4) (however, when W' is sulfur, Y
cannot be hydroxyl, chlorine or bromine)] are also included.

More specifically, compounds of formula M are those in which OR1 is methyl or ethyl, R and R4 are hydrogen, W' is a covalent bond or methylene, Y is cyano, OR is methyl or ethyl, R3 and R4 is hydrogen, Y is cyano, W' is a covalent bond, Z is hydrogen, OR1 is ethyl,
W' is methylene, Y is cyano, 2 is hydrogen, OR1 is methyl or ethyl, R3 and R4 are water =
19 - element, Y is chlorine or bromine, or Z is hydrogen, OR1 is methyl or ethyl, R
and those in which R4 is hydrogen and Y is a hydroxyl group, or those in which Z is hydrogen, alkyl), and those in which OR and R4 are hydrogen and Y is -C(=NH)-OR2
(R2 is ethyl).

The compounds of the formula VI described above, in which Q is cyano, are the compounds of the following formula (1), the compounds of the following formula (U), in which R, R and R4 are as defined in Section 1], and the compounds of the following formula (1): -W' -CN [wherein, and the substituents on substituted naphthyl are C
1-4 alkyl, halogen or nitro] in the presence of an appropriate base. The base must be strong enough to catalyze the desired nucleophilic substitution; suitable examples of bases include:
Alkali metal hydrides (sodium hydride, etc.), alkali metal carbonates (potassium carbonate, etc.), alkali metal hydroxides (sodium hydroxide or potassium hydroxide), and alkali metal alkoxides (potassium tert-butoxide or sodium methoxide, etc.) ).

A suitable solvent for this reaction is DMF (dimethylformamide). The reaction temperature is preferably about 20 to about 100°C, more preferably about 40°C.

Alternatively, in compounds of formula VI, W' is a covalent bond;
When Z is hydrogen and Q is cyano, the following formula v.

[wherein Y is chlorine or bromine; R1, R3 and R4
is defined for formula (1)] and an alkali metal or alkaline earth metal cyanide (cyanate). Suitable examples of cyanides include sodium cyanide or potassium cyanide. As a solvent, C1-4 alcohol, C1-
The alkanone of No. 4 and a polar neutral solvent such as DMF are preferable.

The reaction temperature may be about 0 to about 40°C, preferably about 20°C.

Of the compounds of formula VI, W' is sulfur, Z is hydrogen, and Q
is cyano, which can be obtained by reacting a compound of formula V, in which Y is chlorine or bromine and R1, R3 and R4 are as defined for formula (2), with an alkali metal or ammonium thiocyanate. can. As the solvent, polar neutral solvents such as C1-4 alcohol, C1,,4 alkanone, and DMF are preferable. The reaction temperature is approximately O
to about 40°C, preferably about 20°C.

The compound of formula (1) in which Y is chlorine or bromine required for the above reaction, the compound of formula (1) in which Y is a hydroxyl group,
It is obtained by reacting with phosphorus trichloride or phosphorus tribromide at about 0 to about 40°C, preferably about 20°C.

The above-mentioned compound of formula (1) is represented by formula (1) in which R1, etc. are as defined above. ] can be obtained by reacting the compound with hydrazine.

The above-mentioned compound of formula (1) can also be prepared by reacting the compound of formula (2) with a strong acid (such as sulfuric acid or p-toluenesulfonic acid) to form two (2)? It is also possible to obtain a compound of formula (2) by reacting it with hydrazine.

Compounds of formula V, where Z is hydrogen, W is a covalent bond, and Y is chlorine or bromine, have formula X? In formula 1, R1, R3 and R4 are as defined for formula ■; V is oxygen, sulfur or NH; Het is ■
Contains 1 nitrogen, oxygen or sulfur, or 2 nitrogen (of which 1
a five-membered heterocycle having three nitrogen atoms (one of which may be optionally substituted with oxygen or sulfur); or substituted with two fluorine, chlorine, C1-4 alkyl or phenyl, or fused with benzo, or substituted with one pyridyl, furyl or thienyl, and the phenyl or benzo is optionally one iodine or trifluoromethyldio or one or two fluorines,
Chlorine, bromine, C alkyl, C1-4 alkoxy, C
1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl or trifluoromethyl, and the pyridyl, furyl or thienyl may be substituted with fluorine, chlorine, or
6-membered, optionally substituted by bromine, C alkyl or C1-4 alkoxy, having from 1 to 3 nitrogen atoms, or having 1 or 2 nitrogen atoms and 1 oxygen or sulfur A compound ring, the ring having one or two
substituted with C1-4 alkyl or phenyl,
or fused with benzo, or substituted with one pyridyl, furyl or thienyl, where the phenyl or benzo is optionally one iodo or trifluoromethylthio or one or two fluorine, chlorine. , bromine, C
1-4 alkyl, C-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-
4 may be substituted with alkylsulfonyl or trifluoromethyl, and the pyridyl, furyl or thienyl is optionally substituted at the 3-position by fluorine, chlorine, C1-4 alkyl or C1-4 alkoxy. may be an oxazole or deazole fused with a six-membered aromatic ring containing one or two nitrogen atoms, or with thiophene or furan, which may optionally contain one fluorine, chlorine, bromine, one heli It is also useful for obtaining the following compounds which may be substituted with fluoromethyl, methylthio or methylsulfinyl and are: (1) imidazolopyridine, (2) naph-thiazole or (2) nano-1-xazole. Such compounds are described in the applicant's European Patent Application Publication No. 0222576 (JP 62-1.14988).

The above-mentioned compound of formula It is obtained by reacting with a ring compound in an aqueous, alcoholic, or polar neutral solvent. Suitable solvents include ethanol and DMF. The reaction can be carried out under the catalysis of a suitable base. The base must be strong enough to catalyze the desired nucleophilic substitution. Suitable examples of bases include alkali metal hydrides (
sodium hydride, etc.), alkali metal carbonates (potassium carbonate, etc.), alkali metal hydroxides (sodium hydroxide or potassium hydroxide), and alkali metal alkoxides (potassium tajaribe oxide or sulfurium hydroxide). methoxide, etc.). The reaction temperature is preferably about 30 to about 100°C, more preferably about 40°C.

Each operation related to the present invention is shown in the reaction pattern in the figure.

Compounds of formula ■ can be prepared by standard RefOrlatSky reaction conditions using zinc or zinc-copper conjugates or by Tetrahedron Letters, 2569
(1984) etc., various applications of the same reaction lead to the compound of formula (2). Suitable solvents for the conversion of a compound of formula (1) to a compound of formula (2) include aromatic hydrocarbons such as benzene, dialkyl ethers, and cyclic ethers such as THF. The reaction temperature is preferably about 35 to about 100°C, more preferably reflux temperature.

The compound of formula (1) is converted into the compound of formula (2) in the presence of a strong acid, in an appropriate solvent, or without a solvent. When a solvent is used, a hydrocarbon solvent such as benzene or 1.luene is preferred, and an organic acid such as p-toluenesulfonic acid is preferred as the acid. In such cases, the temperature is at least about 9
The temperature should be 0°C, preferably about 90 to about 100°C. It is convenient to maintain the reaction mixture at its reflux temperature.

When converting the compound of formula (1) to the compound of formula (2) without a solvent, sulfuric acid is used as the acid, and the reaction temperature is preferably about 0 to about 30°C, more preferably about 0 to about 30°C. The temperature is approximately 20°C.

Compounds of Formulas (1) to (2) are converted to compounds of Formula IV by reacting with anhydrous or aqueous hydrazine in an alcoholic solvent such as ethanol at a temperature of about 20 to about 80°C, preferably about 60°C. That is, the temperature may be room temperature or the reflux temperature of the solvent.

The compound of formula ■ is then converted into Tetrahedron, 5
31 (1964) to the compounds of 2V, where Y is OH. The reaction temperature is about 20 to about 100°C, more preferably about 30 to 40°C.

To synthesize a compound of formula (■) in which R1 is C1-4 alkyl, a compound of formula (1) in which Q is CN may be reacted with a previously prepared acid addition salt (hydrochloride, etc.) of a compound of formula VI. ,
Alternatively, it may be reacted with an acid addition salt prepared in situ by addition of a strong acid such as hydrochloric acid.

From a practical standpoint, it is more convenient to prepare the acid addition salt in advance. Although 01-4 alkanol solvents such as ethanol are preferred, mixtures of at least equimolar 01-4 alkanol and hydrocarbon or hydrogen halide solvents may also be used. An example of the former is benzene and an example of the latter is chloroform. The temperature should be at least about 60°C. It is convenient to maintain the reaction mixture at 3 ta flow temperature.

When the reaction is carried out in a C1-4 alkanol solvent such as ethanol, the resulting compound of formula VII has R1
can be immediately hydrolyzed to compounds of formula VII where R1 is hydrogen.

For hydrolysis, an aqueous base solution such as thorium hydroxide or potassium hydroxide may be added. The temperature is about 20 to about 100°C, preferably about 60°C.

The compound of formula VII is dissolved in a C1-4 non-alkanol.
30 - When preparing in a medium, the compound is isolated and dissolved in a C1-4 alkanol, and the hydrolysis shift is good as described above.

The compound of formula VII may be synthesized by eutecticizing the compound of formula VI with a previously prepared acid addition salt (such as a hydrochloride) of the compound of formula VII at a temperature of about 110 to about 180°C.

Alternatively, a compound of formula VI in which Q is -C(-NH)10R (wherein R is C1-4 alkyl, hereinafter referred to as a compound of formula can also be reacted with an acid addition salt thereof (such as the hydrochloride) to give a compound of formula VII. This reaction is carried out in alcoholic, hydrocarbon, or halogenated hydrocarbon solvents, each of which is typified by ethanol, toluene, and chloroform. The reaction temperature is desirably at least about 60°C, and it is convenient to maintain the reaction mixture at reflux temperature. Alternatively, a mixture of a compound of Formula Vla and a compound of Formula V■ may be reacted by eutectic melting at a temperature of about 110 to about 180°C.

A compound of formula VIa can be prepared by reacting a compound of formula VI with a C1-4 alkanol in the presence of a mineral or organic acid. A suitable example of a mineral acid is gaseous hydrogen chloride, and an example of an organic acid is p-toluenesulfonic acid. The reaction is preferably carried out at a temperature of about -5 to about 40°C. If desired, it is also possible to make the compound of formula VIa without adding acid to the reaction mixture, but in that case the reaction of the compound of formula Vla with the compound of formula VI should proceed in the presence of a strong acid. .

The above reaction is conducted at a pressure of about 0.5 to about 2 atmospheres (preferably about 1 atmosphere pressure).

Compounds of formula VII in which R1 is hydrogen, or pharmaceutically acceptable salts thereof, can be used as aldose reductase activity inhibitors to treat various chronic complications derived from diabetes, such as diabetic cataracts, retinopathy, and neuropathy. It is useful for These compounds can be administered to patients by various known means of application, such as orally, parenterally, and topically, depending on therapeutic needs. Generally, the dose is about 0.5 to about 25 cm per kg of patient body weight per day, preferably about 1.0 to about 10 cm, either orally or parenterally, but the dose may be increased or decreased depending on the patient's symptoms. would be necessary.

The following examples are non-limiting examples for explaining the present invention, and the melting point values are not corrected.

(Left below) -33-Example 1 A Zinc powder (37.0 g> Refluxed benzene (250 ml)
) to the slurry in ethyl bromoacetate (8,35,,)
and phthalic anhydride (7.4 g) in benzene (250 ml)
Add a portion of the solution (15 ml). When the exothermic reaction associated with the addition is complete, the remainder of the benzene solution is added and reflux is continued for 8 hours. The reaction mixture was cooled to room temperature and diluted with aqueous sulfuric acid (
100 ml, 10%) and collect the organic layer. This was washed sequentially with water (2 x 50 ml), aqueous mono-lium bicarbonate solution (25 ml, 10% by weight), and water (25 ml). The washed organic layer is evaporated to dryness. The obtained Feather 1 product is purified by Chroma 1 to Darafy (yield 12.84
,, ). HN M R (CDCl3.6ONlIZ
) δ: 1.25 (t, J=811z, 311),
3.15 (s, 211), 4.2 (Q,...
b811z, 211), 6.25 (b, 廿), 7
．． 6 (III, 4+1)B Zinc copper bond 'h (31
,0+r) in refluxing THF (50 ml), a solution of ethyl bromoacetate (13,1 g) and phthalic anhydride (29,6 g) in THF (150 ml) was gradually added to -37'l - Add. The reaction mixture is refluxed for 2 hours and filtered cold. Solution P is added to aqueous hydrochloric acid WI (200 ml, 10% by volume) and extracted with ethyl acetate (3×5 ml). The ethyl acetate layer is washed with water (2x50ml) and evaporated to give a clear colorless oil (yield 18.2g). 'HNMR is the same as A.

Example 2 From phthalic anhydride (14.81 g), dobutyl bromoacetate (29.25 g), zinc-copper binder (15.0 g) and THF (100 ml), 24.0 g of the title compound was obtained by method B. "C" and purified by chromatography.

'HNMR (CDCI, 250MHz) δ
Two 1.90 (s, 9 old, 4.0 (s, 2t
l) , 6.7-7.2 (111,4H) Example 3 (2) -3-Product 1-oxycarbonylmethylidenephthalide 1,3-dihydro-1-hydroxy-3-oxo-1-
Benzofuran ethyl acetate (2.36 g) was dissolved in 5 m concentrated sulfuric acid.
Dissolve in 100ml and leave at room temperature for 5 minutes. This was slowly poured into 50 ml of ice water, and the white precipitate formed was collected, washed with water (3 x 25 + nl), and then air-dried (yield: 2.08 rr), J, Orq, Chel, 31
．． See 4077 (1966).

Example 4 Ethyl 4-oxo-311-phthalazin-1-ylacetate 1,3-dihydro-1-droxy-3-oxo-1-
Benzofuran ethyl acetate (4,72 g> ethanol (
Hydrazine (1.28 g) is added to the 20 ml solution. The generated white precipitate was collected and diluted with an aqueous hydrochloric acid solution (2
0ml, 10% by volume) and then water. Air dry the solid to obtain the title substance. U, S, Pat, 4,25
See 1°528.

Example 5 1-Butyl 1,3-dihydro-1-droxy-3-oxo-4-oxo-311-phthalazin-1-yl acetate
To a solution of Dobdel 1-benzofuran acetate (7.92 g) in ethanol (200 ml) was added hydrazine hydra-1-
(5.0 ml, 85% by weight) and refluxed for 1 hour.

Collect the precipitated white solid and wash with water <2 x 25 m1)
and air dry. Yield 5.30g, melting point 164-16
6℃.

-36 Example 6 3-Cyazmedel-4-oxo-311-phthalazine-
Methyl 1-ylacetate A4-oxo-3]1-phthalazin-1-yl i! il
:D M F (25ml) of methyl acid (5.45g)
) Potassium dob 1-oxide (2.95 g) is added to the solution at -h. Add acetonyl chloride to the resulting dark green solution.
Slowly add rill (1,89,). The reaction mixture was
Stir for 0 minutes and pour into ice water (100 ml). Enough 10% by volume hydrochloric acid to bring the pl+ of the reaction mixture to 4.0 is added and the precipitated gray solid is collected and air dried. Yield 5.7
4g, melting point 118-119°C.

B To acetic acid chloride, dil-lyl to acetic acid bromide, nitrile (
3.0g) and repeat operation A. The title compound was obtained in a yield of 4.93 g, the melting point being the same as that in Procedure A.

C Procedure A is carried out on twice the scale, substituting cyanomethyl benzenesulfonate (10.90 g) for aceI.dil-lyl chloride. The title compound was obtained in a yield of 10.89 g.

37 Example 7 3-Cyazmedel-4-oxo-3■-phthalazine-1
-ethyl acetate A4-oxo-311-phthalazin-1-yl ethyl acetate (11,31 g) and dry potassium t-butoxide (5
,9g) of DMF (50ml)? Add acetonyl chloride (3.78 g) to Solution B. 30% solution
Stir for a minute and pour into ice water (300 ml). adding enough 10% hydrochloric acid to bring the p++ of the reaction mixture to about 4.0;
Collect the precipitated solid and air dry. Yield 11.81 g
, melting point 113-114°C.

B Ethyl 4-oxo-311-phthalazin-1-ylacetate (10,0
To a solution of g) in DMP (100 ml) is added ace1henyihelyl chloride (3,0 ml) and the mixture is stirred overnight. 111 of the reaction mixture was poured into ice water (500 ml).
Add enough 10% hydrochloric acid to bring the value to about 4.0. Air dry the precipitated solid. Yield 9.7g, melting point 113-114
℃0C4-oxo-311-phthalazin-1-yl ethyl acetate (5.0 g), potassium carbonate (4.5 g), acetone (100 ml) and acetonitrile chloride (2.0 m
The mixture of 1) is refluxed overnight. Treat the reaction mixture as in Procedure B. Yield: 4.1g.

D Ice-cold 3-bromomethyl-4-oxo-311-
Potassium cyanide (0,4
A solution of 9 g) and potassium iodide (2 ml) in water (3.5 ml) was added dropwise. Stir the reaction mixture for 2 hours, 200 ml
Pour into ice water. The precipitated solid is purified by silica gel chromatography, eluting with methylene chloride-ethyl acetate (95:5 volume/base ratio). Yield of the listed compound is 1.54
Obtained in g.

Example 8 3-cyanoethyl-4-oxo-311-phthalazine-
Ethyl 1-ylacetate 4-oxo-311-phthalazin-1-ylacetate (10,91 g) and dry potassium 1-butoxide (
5.90 g) of DMF (50 ml > solution, 3
-Add chloropropionitrile (4,92,).

Stir the solution for 30 minutes and pour into ice water (300 ml).

Enough 10% hydrochloric acid is added to bring the pH of the reaction mixture to about 4.0, and the precipitated solid is collected and recrystallized from methanol. Yield 7.64g, melting point 125-126°C.

Example 9 Ethyl 4-oxo-311-phthalazin-1-yl acetate (23,42 g >, ethanol (200 ml) and aqueous formaldehyde solution (37% concentration, 100 ml)
) is refluxed for 40 hours. 100ml of this solution
Concentrate to 1 and pour into ice water (750 ml). Collect the precipitated solid and air dry. Yield 17.1 g, melting point 113-1.
14℃.

Example 10 A mixture of 4-Saiko 311-phthalazin-1-yl methyl acetate (2,18 g)-methanol (50 ml) and an aqueous formaldehyde solution (37% strength, 10 ml) was
Reflux for 40 hours. The reaction mixture was cooled to room temperature and diluted with water (
50ml). The resulting solid is collected and recrystallized from methanol. Yield 0.5g, melting point 154-155°C.

Example 11 3-bromomethyl-4-oxo-311-phthalazine-
Ethyl 1-ylacetate 3-hydroxymethyl-4-oxo-311-phthalazin-1-ylacetate (13.1 g), phosphorus tribromide (1
3.5 g) and anhydrous ether (250 ml),
- Stir at room temperature at night. Next, this was mixed with water (200ml
). The organic layer was collected and washed again with water (3 x 100 m1
) and dried over anhydrous sodium sulfate. The dried organic extract was dried and the resulting crude solid was chromatographed on silica gel with methylene chloride-ethyl acetate (95;
5 volume ratio).

A yield of 9.8 g of the title compound having a melting point of 96° C. was obtained.

Example 12 3-promomedyl-4-oxo-311-phthalazine-
Methyl 1-ylacetate 3-hydroxymethyl-4-oxo-311-phthalazin-1-ylacetate (0.49 g), phosphorus tribromide (
0.54 g) and methylene chloride (10 ml),
Stir at room temperature for 2 hours. Next, this was mixed with ice water (5 ml
) and collect the separated methylene chloride layer, dry and evaporate to give a pale yellow solid. Yield 0.43g, melting point 98-1
04℃.

Example 13 3-chloromethyl-4-oxo-311-phthalazine-
Ethyl 3-droxymethyl-4-oxo-311-phthalazin-1-ylacetate (1,31 g) containing ethyl pyridine 1-ylacetate (0,8 ml) and methanesulfonyl chloride (0,8 ml).
A solution of 69 g) in methylene chloride (10 ml) is stirred overnight at room temperature. The methylene chloride is then distilled off and the residue is purified by chromatography on silica gel, eluting with chloroform-ethyl acetate (9.1 volume ratio). The title compound was obtained in a yield of 0.51 g, melting point 99-100°C.

The title compound can also be obtained by following the method of Example 11 and replacing phosphorus tribromide with phosphorus trichloride.

Example 14 3-(5-trifluoromethylbenzothiazole-2-
ylmethyl)-4-oxo-3-phthalazin-1-yl acetate A3-cyanomethyl-4-oxophthalazin-1-ylacetate (2,71 g), 2-amino-4-1 helifluoromethylthiophenol hydrochloride ( A mixture of 2.40 g) and ethanol (20 ml) is refluxed for 8 hours.

Upon cooling, the resulting precipitate is filtered and the weighed solid is air-dried to yield the title compound. Yield 4.3g, melting point 136°C.

A mixture of B3-cyanomethyl-4-oxophthalazin-1-yl ethyl acetate (0,27 g) and 2-amino-4-trifluoromethylthiophenol hydrochloride (0,23 g) is heated to 180° C. for 10 minutes to melt it. . The fluid liquid is cooled and then suspended in water. The mixture is filtered to give the title compound in 75% yield.

Example 15 Mixture of ethyl 3-cyanomethyl-4-oxophthalazin-1-yl acetate (1,29 g), 2-amino-4,6-cyfluorothiophenol hydrochloride (0,98 g) and ethanol (20 ml) is refluxed for 6 hours. Upon cooling, the title compound precipitates out as a pale yellow solid. Yield 1.
62g, melting point 115-117°C.

Example 16 A ethyl 3-<5-1-lifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3-phthalazin-1-ylacetate (5.0 g), methanol (60 g)
ml), T HF (30 ml) and 10% aqueous potassium hydroxide solution (20 ml) are stirred at room temperature for 10 minutes.

Concentrate the solution to 20 ml and dilute with water (50 ml).

The resulting solution is acidified with sufficient 10% hydrochloric acid to pH approximately 4.0. Collect the precipitated gray solid and air dry. Yield 4
．． 8g, melting point 197-198°C.

A mixture of ethyl B3-cyanomethyl-4-oxophthalazin-1-ylacetate (2,71 g), 2-amino-4-trifluoromethylthiophenol hydrochloride (2,40 g) and ethanol (20 ml) is refluxed overnight.

The reaction mixture was cooled to 40°C and added with THP (10ml
> and 5% aqueous potassium hydroxide solution (10 ml).

The mixture is stirred at room temperature for 1 hour and the solvent is evaporated.

The residue is diluted with water (50 ml) and the resulting solution is extracted with needles (20 ml). Collect the basic aqueous layer and acidify with sufficient 10% hydrochloric acid to pl+about 4.0. Collect the precipitated solid and air dry. Yield 3.68g, melting point 197
-198℃.

Example 17 Ethyl 3-(5,7-cyfluoropenzothiazol-2-ylmethyl)-4-oxo-3-phthalazin-1-yl acetate (1,OK) was hydrolyzed using the method of Example 16A. The title compound is obtained. Melting point 178°C0 Example 18 3-cyanoethyl-4-oxo-311-phthalazine-
Ethyl 1-ylacetate (2,71g), 2-amino-4
-trifluoromethylthiophenol hydrochloride (2,29
A mixture of g) and ethanol (20 ml) is refluxed overnight.

The crude product obtained by distilling off the ethanol is purified by silica gel chromatography, eluting with hexane-THF (4.1 volume ratio). The obtained white solid (0,3
g> is used directly in the next step.

This compound was dissolved in ethanol (20 ml) containing a 5% aqueous potassium hydroxide solution (2 ml), and stirred at room temperature for 2 hours. The ethanol is distilled off and the residue is diluted with water (>10ml). This is extracted with ether (2 x 10+ml) and
The aqueous extract is acidified to pH 2.0. The precipitated solid is collected and recrystallized from ethanol. Yield 0.12g
, melting point 184-185°C.

Example 19 Ethyl 3-cyanomethyl-4-oxophthalazin-1-yl acetate (27.1 g) in dry THF (200 ml)
and pure ethanol (5.9 ml), pass through dry hydrogen chloride scum for 5 minutes. - Separate the precipitate that forms after standing at room temperature overnight to obtain the desired product. Yield: 913.05 g, melting point: 20g-210℃0 Example 20 Ethyl acetate 3-(ethyl acetimiate 1-14-oxo-31-phthalazin-1-yl ethyl acetate hydrochloride (0.35g) and 2-amino-5-trifluoromethylthiophenol hydrochloride A mixture of salt (0.23 g) was added to toluene (20 ml).
) for 16 hours. The precipitate formed upon cooling is recrystallized from ethanol to obtain the product. Melting point: 136°C.

Example 21 Following the procedure of Example 7D and substituting potassium periocyanide for potassium cyanide, the title compound is obtained.

[Brief explanation of the drawing]

The figure shows the synthetic route for each compound of the present invention.

Claims (10)

[Claims] (1) The following formula VII ▲There are mathematical formulas, chemical formulas, tables, etc.▼VII [In the formula, R^1 is hydrogen or alkyl of C_1_-_4; R^3 and R^4 are the same or different hydrogen, fluorine,
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4
is alkylthio of C_1_-_4, alkylsulfinyl of C_1_-_4, alkylsulfonyl of C_1_-_4 or a nitro group, or R^3 and R^4 together are alkanedioxy of C_1_-_4; R^5 and R^ 6 is the same or different hydrogen, fluorine, chlorine, bromine, trifluoromethyl,
C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4 alkylthio, C_1_-_4 alkylsulfinyl, C_1_-_4 alkylsulfonyl, nitro or benzo, R^5 and R^6
together are C_1_-_4 alkanedioxy; Z
is hydrogen or a methyl group; U is sulfur, methylene, or a covalent bond] A method for producing a compound of the formula VI ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^ 3, R^4 and Z are as defined above; W' is sulfur, methylene or a covalent bond;
Q is -C(=NH)-OR^2 (However, R^2 is C_1_
−__4 alkyl) or cyano], or an acid addition salt thereof; and a compound of formula VII ▲There are mathematical formulas, chemical formulas, tables, etc.▼VII [wherein R^5 and R^6 are defined above] react with the compound or its acid addition salt (provided that if neither of the compounds of Formula VI and Formula VII is an acid addition salt at the time they are added to the other, the reaction is carried out in the presence of a strong acid) ), if desired, a compound of formula VIII in which R^1 is not hydrogen is hydrolyzed to obtain a compound of the corresponding formula VIII in which R^1 is hydrogen, such as a heterocyclic ring such as benzothiazole. A method for producing oxophthalazinyl acetic acids having a chain. (2) A compound of formula VI in which Q is cyano is expressed as formula IV▲
There are chemical formulas, tables, etc. ▼ IV [In the formula, R^1, R^3 and R^4 are defined in Section 1] Compound and ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [Formula In, X is chlorine, bromine, -OSO_2(C_1_-_
4 alkyl) or -OSO_2 (aryl), where aryl is phenyl, naphthyl, substituted phenyl or substituted naphthyl, and the substituents on substituted phenyl and substituted naphthyl are C_1_-_4 alkyl, halogen or nitro] and A method for producing oxophthalazinyl acetic acids having a heterocyclic side chain such as benzothiazole according to claim 1, which is obtained by reacting the following in the presence of an appropriate base. (3) Compounds of formula VI, where W' is a covalent bond and Z is hydrogen, are converted to compounds of formula V, where Y is chlorine or bromine; R^1, R^3, and R4 are The benzothiazole according to claim 1, which is obtained by reacting V and an alkali metal or alkaline earth metal cyanide. A method for producing oxophthalazinyl acetic acids having a heterocyclic side chain such as. (4) A complex compound such as a benzothiazole according to claim 1, wherein the compound of formula VI is eutectic with a pre-prepared acid addition salt of the compound of formula VII at a temperature of about 110 to about 180°C. A method for producing oxophthalazinyl acetic acids having a ring side chain. (5) The following formula II [wherein R^1 is hydrogen or alkyl of C_1_-_4; R^3 and R^4 are the same or different hydrogen, fluorine,
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4
is alkylthio of C_1_-_4, alkylsulfinyl of C_1_-_4, alkylsulfonyl of C_1_-, or nitro group, or R^3 and R^4 together are alkanedioxy of C_1_-_4] ▲Mathematical formula, chemical formula, table, etc. There is a method for producing a compound of formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. A process for producing a compound of formula II, characterized in that it is reacted with a compound of formula II, wherein R^1 is as defined above. (6) Formula VI ▲There are mathematical formulas, chemical formulas, tables, etc.▼VI [In the formula, R^1 is hydrogen or alkyl of C_1_-_4; R^3 and R^4 are the same or different hydrogen, fluorine,
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4
is alkylthio of C_1_-_4, alkylsulfinyl of C_1_-_4, alkylsulfonyl of C_1_-_4 or nitro group, or R^3 and R^4 together are alkanedioxy of C_1_-_4]. Then, a compound of the formula IV ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV [In the formula, R^1, R^3 and R^4 are as defined above] and a compound of the formula XCH_2CN [In the formula, X is chlorine, bromine, -OSO_2(C_1_-_
4 alkyl) or -OSO_2 (aryl), where aryl is phenyl, naphthyl, substituted phenyl or substituted naphthyl, and the substituents on substituted phenyl and substituted naphthyl are C_1_-_4 alkyl, halogen or nitro] A method for producing a compound of formula VI, which comprises reacting the compound with the compound in the presence of a suitable base. (7) Formula VI ▲There are mathematical formulas, chemical formulas, tables, etc.▼VI [In the formula, R^1 is hydrogen or alkyl of C_1_-_4; R^3 and R^4 are the same or different hydrogen, fluorine,
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C_1_-_4 alkylsulfinyl, C_1_
-_4 alkylsulfonyl or nitro group, or R
^3 and R^4 together are C_1_-_4 alkanedioxy] A method for producing a compound of the formula V ▲There are mathematical formulas, chemical formulas, tables, etc. ▼V [In the formula, Y is chlorine or bromine; R^1, R^3 and R^4 are as defined above] and an alkali metal or alkaline earth metal cyanide. manufacturing method. (8) Formula X ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C_1_-_4 alkoxy, C1_-_4 alkylthio, C_1_-_4 alkylsulfinyl, C_1_-4 alkylsulfonyl or nitro group, or R^3 and R^4 together are C_1_-_4 alkanedioxy; V is oxygen, sulfur or NH group; Het has [1] one nitrogen, oxygen or sulfur;
a five-membered heterocycle having two nitrogens (one of which may be substituted with oxygen or sulfur) or three nitrogens (one of which may be substituted with oxygen or sulfur); ,
The ring is substituted with one or two fluorine, chlorine, C_1_-_4 alkyl or phenyl, or fused with benzo, or substituted with one pyridyl, furyl or thienyl; Phenyl or benzo may optionally be one iodo or trifluoromethylthio or one or two fluorine, chlorine, bromine, C1-4 alkyl, C1-4 alkoxy, C_1_-_4 alkylthio, C_1_-_4 alkylsulfinyl, C_1
____4 may be substituted with alkylsulfonyl or trifluoromethyl, and the pyridyl, furyl or thienyl may be substituted with fluorine, chlorine, bromine, C_1_-_4 alkyl or C_1_-_4 alkoxy as the case may be. [2] A six-membered heterocycle having 1 to 3 nitrogen atoms, or 1 or 2 nitrogen atoms and 1 oxygen or sulfur, which may be substituted,
the ring is substituted with one or two C_1_-_4 alkyl or phenyl or fused with benzo,
or substituted with one pyridyl, furyl or thienyl, and the phenyl or benzo is optionally substituted with one iodo or trifluoromethylthio or one or two
fluorine, chlorine, bromine, C_1_-_4 alkyl, C
_1_-_4 alkoxy, C_1_-_4 alkylthio, C_1_-_4 alkylsulfinyl, C_1
____4 may be substituted with alkylsulfonyl or trifluoromethyl, and the pyridyl, furyl or thienyl may be substituted with fluorine, chlorine, C_
[3] An oxazole or thiazole fused with a six-membered aromatic ring containing 1 or 2 nitrogen atoms, or with thiophene or furan, which may be substituted with 1_-_4 alkyl or C_1_-_4 alkoxy. these may optionally be substituted by one fluorine, chlorine, bromine, trifluoromethyl, methylthio or methylsulfinyl, [4] imidazolopyridine, [5] naphthothiazole or [6] naphthoxazole. A method for producing a compound of the formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼V [wherein R^1, R^3 and R^4 are as defined above; Y is chlorine or bromine] and a compound of formula HV-Het (V and Het are as defined above). (9) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II [In the formula, R^1 is hydrogen or alkyl of C_1_-_4; R^3 and R^4 are the same or different hydrogen, fluorine,
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4
or R^3 and R^4 together are C_1_-_4 alkanedioxy]. (10) Formula X I [wherein R^1 is hydrogen or C_1_-_4 alkyl; R^3 and R^4 are the same or different hydrogen, fluorine,
Chlorine, bromine, trifluoromethyl, C_1_-_4 alkyl, C_1_-_4 alkoxy, C_1_-_4
is alkylthio, C_1_-_4 alkylsulfinyl, C_1_-_4 alkylsulfonyl or nitro group, or R^3 and R^4 together are C_1_-_4 alkanedioxy; Z is hydrogen or methyl; can be;
W' is sulfur, methylene or a covalent bond; Y is a hydroxyl group, chlorine, bromine, cyano or -C(=NH)-OR^2(
R^2 is C_1_-_4 alkyl) (however, W
When ' is sulfur, Y cannot be a hydroxyl group, chlorine, or bromine)] ▲There are mathematical formulas, chemical formulas, tables, etc.▼Compounds of X I.