WO1986003742A1 - Process for preparing benzoic acid derivatives - Google Patents

Abstract

Benzoic acid derivatives represented by formula (I), wherein R1 represents lower alkyl, R2' represents -COOH or formula (II), wherein n represents an integer of 2 to 4, R2 and R3 may be the same or different and each represents hydrogen or alkyl or R2 and R3 are combined together to form a hetero-cyclic ring together with the adjacent nitrogen atom, and x represents halogen or formula (III), wherein X, n, R2, and R3 are as defined above, which have excellent antiasthmatic and antiinflammatory effects and are utilized as antiasthmatic or antiinflammatory agents, are advantageously prepared by oxidizing the corresponding aldehyde derivatives, or by condensing the corresponding starting materials.

Description

 - Specification

 Method for producing benzoic acid derivative

Technical field

 INDUSTRIAL APPLICABILITY The present invention exhibits an antagonistic effect on a chemical mediator [Slow Reacting S ubstance of Anaphy xis (SRS-A)] that causes contraction of bronchial smooth muscle and the like, and is useful as a therapeutic agent for asthma and the like. It relates to the manufacturing method of the.

Background art

 As compounds that antagonize the chemical mediator SRS-A, which has a contractile action on bronchial smooth muscle, British Patent Application Publication Nos. 1, 384, 530 and 280, Patent Application Publication No. 28, The compounds described in Japanese Patent Application Publication No. 80,371 are disclosed in Japanese Patent Application Laid-Open No. 80-3771. However, the compounds specifically described as examples of the British Patent Application Publication No. 1,384,530 and the Japanese Patent Application Publication No. 28,063 are not disclosed. The SRS-A antagonism was not sufficient, and improvement of the effect was desired. Further, with respect to the compounds described in European Patent Application Publication No. 80,371, it has been more desired to improve the oral absorption and enhance the sustained action.

Disclosure of the invention

 The present inventors have conducted intensive studies with the aim of obtaining a compound having a sufficient SRS-A antagonism, and found that certain benzoic acid derivatives are suitable for the purpose. The present inventors have found a production method that is advantageous for the present invention, and have further studied, and as a result, completed the present invention.

The present invention provides: )

[Wherein, R ¹ represents lower alkyl, and X represents halogen.] A compound represented by the general formula:

[Wherein, R ¹ and X are as defined above. Production method of benzoic acid derivative represented by

(2) General formula

(Vso

こ式中、 R¹は前記と同意義を有する。 Yは縮合反応の際に脱離する基を それぞれ示す。 ]で表わされる化合物と一般式

In this formula, R ¹ has the same meaning as described above. Y represents a group which is eliminated during the condensation reaction. And a general formula

[Wherein, n is an integer of 2 to 4, and R ² and R ³ are the same or different and form a 5- or 6-membered heterocyclic ring with hydrogen or lower alkyl or an adjacent nitrogen atom. Show. X has the same meaning as described above. ] A general formula characterized by subjecting a compound represented by the formula to a condensation reaction. H 2) 2 "Cn3

 R-, factory 0-(CH

CH ₃ Co,

Wherein n, RR ² , R ³ and X have the same meaning as described above. A method for producing a benzoic acid derivative represented by

Equation (3)

で表わされる化合物と一般式

And a compound represented by the general formula

Υ- (CH ₂ ) ₃

Wherein n, R ² , R ³ , X and Y have the same meaning as described above. A general formula characterized by subjecting a compound represented by

_{, - - I0- (CH 2)} 3 D 2, one,

 (ΠΙ)

CH ' ₃ C0.

[In the formula, n, R ² , R ³ and X have the same meaning as described above. A method for producing a benzoic acid derivative represented by

(4) General formula

[Wherein, Y has the same meaning as described above. And a general formula

Wherein n, R ² , R ³ and X have the same meaning as described above. A method for producing a benzoic acid derivative (IE), which comprises subjecting a compound represented by the formula: to a condensation reaction. ·

In the above formula, the lower alkyl represented by R ¹ is preferably one having 1 to 3 carbon atoms, and specific examples thereof include methyl, ethyl, η-propyl, and isopropyl. Of these, methyl and ethyl are particularly preferred.

In the above formula, examples of the alkyl having 1 to 3 carbon atoms in R ² and R ³ include: methyl, ethyl, η-propyl, isopropyl and the like. Examples of the 5- or 6-membered heterocyclic group include those containing one oxygen atom and those containing one or two nitrogen atoms. Specific examples thereof include morpholino, piperazino, piperidino, And pyrrolidino.

 These heterocyclic groups may have a substituent, and examples of the substituent include lower alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, l-propyl, isopyl pill) and the like. Can be

Examples of the halogen represented by X include bromine, chlorine, fluorine, and iodine. It is.

R ^{2 In the} present invention: — CHO, — CO OH, one CO 0 (CH ₂ ) n <^ ,,

R ³ One CO OR ⁺ described later is preferably in the para position, and X is preferably in the ortho position. In the above formula, the group leaving during the condensation reaction represented by Y includes, for example, a halogen atom (eg, chlorine, bromine, iodine), ρ-toluenesulfonyloxy, methanesulfonyloxy, etc. Is mentioned.

 Examples of the reagent used in the reaction for obtaining the compound (I) by subjecting the compound () to an oxidation reaction include potassium permanganate, chromate, hydrogen peroxide, silver (I) oxide, silver (II) oxide, oxygen and the like. No. In the reaction, about 1 to 4 equivalents of the oxidizing agent is used for 1 equivalent of the compound (1V), and a common organic solvent can be used as a solvent for the reaction. Particularly, acetic acid, acetate, benzene, acetonitrile and the like, or a mixed solvent thereof and the like can be mentioned. Sometimes it can also be carried out by a two-layer reaction with water. The reaction temperature is preferably room temperature, but a temperature up to the boiling point of the solvent is appropriately selected. The reaction time varies depending on the oxidizing agent, but is about 0.5 to 5 hours.

In the condensation reaction of the compounds (V) and (VI), the compounds (VI) and (VI), and the compounds (IX) and (VI), one equivalent of the compound (V), (W) or (K) is used. On the other hand, about 0.5 to 2 equivalents of each of the corresponding compound (VI) or ("VI) is usually used. In the reaction, it is preferable to carry out the reaction in the presence of a base. Examples include carbon dioxide lime, sodium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, etc. In order to carry out the reaction under a more moderate condition with good yield, the amount of the catalyst is equimolar. It is preferable to add a small amount of potassium iodide or sodium iodide, and the solvent used in the reaction may be dimethylformamide, hexamethylphosphoric triamide, acetate, methylethylketone, tetrachloride. For drofuran, dioxane, etc. Can be. The reaction temperature is about 50 to 150 ° C, and the reaction temperature time is about 1 to 6 hours.

 The target compound obtained by the above method can be separated and purified from the reaction mixture by a means known per se, for example, recrystallization or chromatography.

 In each reaction step of the present invention, a starting compound in the form of a salt of each compound may be used. The target object may be searched for in the form of salt. As the salt in the raw material compound and target substance of the present invention, a pharmacologically acceptable salt is preferable, and examples thereof include metal salts such as sodium salts and potassium salts, and hydrochlorides, sulfates, and salts. Inorganic and organic acid salts such as oxalate, fumarate, maleate and oxalate.

 The raw material compound of the present invention (RO is a raw material compound (V) described later)

HO ^? _CHO (X) (wherein X has the same meaning as described above), and the same reaction conditions as those used for producing compounds (H) and (ΠΙ). It can be manufactured by reacting below.

The substance compound (V) can be obtained by converting the known raw material compound (IX) into a compound represented by the general formula FTCO—Z (2), wherein R ¹ has the same meaning as described above, and Z is removed during the acylation reaction. The leaving groups are shown. The reaction can be carried out by reacting with an acylating agent represented by the formula Examples of the group leaving during the acylation reaction represented by Z include acyloxy groups such as acetooxy and propionyloxy groups and halogen atoms such as chlorine and bromine.

The reaction for producing the compound (V) by reacting the compound (IX) with the acylating agent (H) is carried out by reacting about 2 to 30 equivalents of the acylating agent (XI) with respect to 1 equivalent of the compound (IX). Let it. The reaction is preferably performed in the presence of a base such as pyridine, 4-dimethylaminopyridine, and triethylamine. As the solvent used, For example, there may be mentioned form-form, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane and the like. In general, ': is often used in excess of pyridine or the like without using a solvent. The reaction time is about 1 to 48 hours. The reaction temperature is usually from ice-cooled to around the boiling point of the reagent and solvent used.

 The starting compound (VI) can be produced by the following production steps.

ΗΟ

 () (xm

_{Y- (CH 2) 3 - 0} · ,.

 -^ COOH 01)

Formula (XI): In the formula, X has the same meaning as described above, and R ⁺ represents lower alkyl such as methyl and ethyl. In a compound represented by the general formula: Y (CH ₂ ) ₃ Y (Xni): wherein Y has the same meaning as described above, and two Ys represent the same or different cases. By reacting the compound, a compound of the general formula (XPO can be produced. The reaction conditions used in this case are compound (VI) and compound (VI) or compound (IX) and compound (W) to compound (II). Then, the reaction conditions are used to produce the compound (X is led to a compound of the general formula (XV) by a hydrolysis reaction. The reaction is carried out using an excess amount of sodium hydroxide, hydroxylating water, etc. As the solvent, a mixed solution with water such as methanol, ethanol, etc. is used The reaction temperature is from room temperature to the boiling point of the solvent. A reaction time of about 0.5 to 5 hours is usually used. General formula HO- (CH ₂ ) nN <^ 3 (XVI) wherein R ² , R ³ and n have the same meaning as described above. Or a compound represented by the general formula T- (CH ₂ ) n—N <^ ₃ (XW) wherein R ² ,

R ³ and n have the same meaning as described above, and T represents a group which is eliminated upon esterification. And the compound represented by the general formula (VI) can be produced.

 Examples of the reactive derivative of the compound (XV) include an acid halide. Examples of the halogen in the acid halide include chlorine, bromine and iodine.

 Examples of the group leaving during the esterification reaction represented by T in compound (XW) include, for example, halogen (eg, chlorine, bromine, iodine, etc.), di-toluenesulfonyloxy, methansulfonyloxy, hydroxyl group And the like. When the reactive derivative of compound (XV) is an acid halide, the acid halide can be obtained by reacting compound (XV) or a salt thereof with a halogenating agent.

Examples of the halogenating agent in the reaction of reacting the compound (XV) or a salt thereof with a halogenating agent include, for example, thionyl chloride, phosphoryl chloride, thionyl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous oxychloride, and phosphorous chloride. Examples include phosphorus bromide. The compound (XV) and the σ-genizing agent are reacted at a reaction temperature of about 80 to 120, for example, in a solvent such as chloroform, dichloromethane, tetrax-roethane, tetrahydrofuran, and dioxane. And react for about 0.5 to 12 hours. -When reacting the acid halide of the above compound (XV) with the compound (XΥΙ): about 1 to 3 equivalents of the compound (XVI) are acted on 1 equivalent of the acid halide. Let it. Examples of the solvent used include acetone, chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, and dioxane. The reaction is preferably carried out in the presence of a base. Examples of the base include triethylamine, pyridine, 4-dimethylaminopyridine, dimethylaniline and the like. The reaction temperature is about 15 to 80 hours, and the reaction time is about 1 to 10 hours.

 In the step of reacting compound (XV) or a salt thereof with compound (XVH), an esterification reaction using a compound in which T of compound (XW) is a halogen or a p-toluenesulfonyloxy-methanesulfonyloxy group In the above, as a salt of the compound (XV), titanium, potassium, silver, tributylammonium salt or the like is used, and about 1 to 0 equivalent of the compound (XVI) is used for 1 equivalent of the compound (XV). . The reaction is preferably performed in the presence of a base. Examples of the base include triethylamine, pyridine, dimethylaniline, 4-dimethylaminopyridine and the like. In the reaction, for example, a solvent such as dimethylformamide, hexamethylphosphoric acid triamide, acetone, methylethylketone, tetrahydrofuran, or dioxane is used. The reaction temperature is about 100 to 150 ° C, and the reaction time is about 1 to 6 hours.

 The starting compound (Ί) can be produced by the following production steps.

Η0, ヽ R OO, K R'COO,

-^ rCOOH ~~ 1 — T-C00H ~~: — C00 (CH ₂ ) n <_ no, no--no

 (XVI) (XIX) (XX) ^ Ό

-General formula (>,) [wherein, X has the same meaning as described above. Compound represented by] The product is acylated to obtain a compound represented by the general formula (XIX): wherein X and R ¹ have the same meaning as described above. ]. The reaction reagent used for the acylation is an acid anhydride, and the reaction conditions and reaction time are the conditions used for producing the compound (V). Next, the compound of the general formula (XX) can be prepared by converting the compound (XIX) into an acid halide and then reacting the compound (XVI). The conditions for converting compound (XIX) into an acid halide and the conditions for the step of reacting compound (XVI) are the same as those used for producing compound () from compound (XV). Compound (XX) is reacted in water such as ammonia water, carbonated sodium carbonate, sodium carbonate, etc., methanol, ethanol or a mixture thereof under ice-cooling to about 50 to 0.1 to 5 hours. This leads to compound (VI).

 The target compound (I). (方法), (ΠΙ) of the method of the present invention is directed against the slow reacting substance of anaphylaxis (SRS-A) which is a chemical ftAchemical mediator that causes the contraction of bronchial smooth muscle. Has significant antagonism-

SRS-A: Produced by various stimuli such as immune responses, and is considered to be an immediate mediator of allergic diseases such as bronchospasm in allergic asthma. SRS-A includes leukotriene C (LTC) and leukotriene D (LTD), etc. The contractile action on the ileum is stronger in LTD than in LTC [S.E Dahlen et al. Ature, 288, 484 (1800); RALewis et al. Biochemical and Biophysical Research Communicat ions, 96, 2 7 1 (1 980). The antagonism of drugs against SRS-A can be examined using the guinea pig ileum [R. A. Appleton et al. Journal of Medicinal Chemistry, 20, 371 (1977)]. A is LT Since it is a mixture of C and LTD, and its production ratio is not constant, it is desirable to examine the antagonism using synthetic products. Therefore, when the anti-SRS- A activity of certain ones of the present invention have found that the target compound of the present invention a method using a LTD ₄ which form engagement was绸base in the manner described below, the synthesis leuco preparative Rie emissions D ₊ For guinea pigs based on intravenous administration of (LTD ₊ ), some of the target compounds of the method of the present invention are superior to the control compound by oral administration 1 hour before the administration of LTD ₊ to the airway constriction reaction of It showed a remarkable suppression effect.

(1) Experimental method

Using Hartley dwarf males and females weighing about 400 g as groups of 6 to 10 animals, the airway constriction response based on LTD ₊ was determined by the Konzett-RGssler method (Konzett, H. and Rossler, R: Measured according to aunyn-Schmieder bergs Archiviur Experimen-telle Pathologie and Pharmakologie 1995, 71-74 (1940). The guinea pig was fixed in a dorsal position under anesthesia with Lirethane (l. 5 g / g, i.p. (intraperitoneal administration)), and the incised trachea was passed through a forcepneumatic neurorespirator. Respirator's model 6800. Herbarium. Apparatus. Connected to f. (US): f Also, tracheal cannula 0; bronchospasm transducer 7 0 20- Shinore ♦ Connected to 'ヽ ヽ σ カ ル カ ル カ ル''' リ リ サ ー チ サ ー チ 'サ ー チ サ ー チ サ ー チ''サ ー チ''サ ー チ サ ー チRectigraph-8 S (San-Ei-Sensing) The amount of air that overflows σ- (overflow) is set via a transducer, with the air supply volume 4 to 7 ml, the air supply frequency 70 times / min, and the load pressure on the lungs 10 cm H _20. Instrument Co., Japan). After treatment with gallamine trietiodide (1 mg / Kg.iv (intravenous administration)), intravenous administration of LTD ₊ (10 ^ gZKg) dissolved in physiological saline was performed to elicit an airway dilatation reaction. i. Recorded for 5 minutes. The test drug was suspended in 5% gum arabic solution or dissolved in water, and orally administered in a volume of 0.2 ml per 100 g of guinea pig body weight ₄ hours before the administration of LTD4. LTD ₊ is pre-loaded into the jugular vein The dose was administered via a worn force neura. For LTD, lmg / methanol (1 ml) stored at 170 ° C was selected using physiological saline. (2) Experimental results

 · 1 《• 2 I D 5o (p.o.)

 Compound (β mol / g)

 A 4 7

 B 4 9

 C 4 1

 D 4 9

 E δ 2

Control compound ' ^: 1 4 6

^Χ1 A: Compound of Example 1 B: Compound of Example 5 (3)

 C: Compound of Example 3 D: Compound of Example 5 (4)

 E: Compound of Examples 4 and 6

⁵⁸² ID ₅ . (50% suppression剁用amount) Ding 0 ₊ was calculated from the relationship between the inhibition constant dose for administration 3 0 seconds amount of air over one full σ- from put that airway maximum response following (percentage)

 3 Control compound: a compound represented by the following formula described in European Patent Application Publication No. 80, 371

化合物 A ,化合物 Cまたは化合物 Eのマウスにおける急性毒性試験の 成績は以下の通りである。

The results of the acute toxicity test in mice of Compound A, Compound C or Compound E are as follows.

(1) Experimental method Five male Jcl: ICR mice (5-week old) weighing about 3 Og per group were used. Compound A, C or E was suspended in a 5% gum arabic solution and orally administered at 0.2 ml / Og body weight.

(2) Experimental results

 The compound C or E 200 Omg / Kg and the compound A 50 Omg / Kg were orally administered to mice, respectively, and the toxicity was examined. No significant symptoms attributable to the drug were observed at this dose. Necropsy 7 days after administration showed no abnormal findings.

 From the above, it is considered that the toxicity of the target compounds (() to (DI) of the method of the present invention is low.

 Therefore, Compounds (I) to (! II) can be used for diseases caused by SRS-A, such as asthma, hay fever, chronic bronchitis, allergic diseases of the eye, allergic diseases of the gastrointestinal tract and circulatory disorders, It can be used as a treatment for allergic dermatitis and other inflammations. For example, Compounds (I)-(II) or a salt thereof can be administered to a mammal (eg, mouse, rat, guinea pig, human, etc.) at a daily dose of about 1-2 Omg / Kg as an asthma therapeutic or anti-inflammatory. ) Is administered orally or parenterally.

For oral administration, compounds (I) to (! C) or a salt thereof can be converted into a pharmacologically acceptable carrier, excipient, diluent (eg, lactose, starch, cell sigma derivative). Parenteral administration, for example, as tablets, capsules, granules, troches, solutions, syrups, etc., together with stearylate, magnesium stearate, sucrose, gelatin, gum arabic, etc. (I)-(!) [[] Or a salt thereof is a pharmacologically acceptable carrier, vehicle, diluent (eg, white cellulose, hydrophilic plaster, oily plaster, glyceride, polyethylene glycol, etc.) In addition, they can be formulated and administered as ointments, suppositories, aerosols, inhalants, injections, etc. in the usual manner. The method of the present invention is a method capable of industrially and advantageously producing the compounds (I) to (!) Which have remarkably excellent effects.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples.

Reference example 1

 2,4-Dihydroxy-1--3-propylacetophenone (2.7 g), 1,3-dibutene-propane (2.8 ml) and potassium carbonate (1.9 g) were added to acetone (5 Oml ), And ripened to reflux for 3 hours. After the insolubles were filtered, the filtrate was concentrated and the resulting syrup was purified by flash chromatography on silica gel (closed sigma form: hexane = 1: 1) to give a colorless and transparent syllabus. There was obtained 2.9 g of 4-acetyl-3-hydroxy-2-propylphenoxy) σ-pyrbromide.

_{N RCC DC 1 3) <5} :. 0.92 (3H, t J = 7Hz), 1.30 - 1.70 (2H, m), 2.33

(2H, m), 2.54 (3H, s), 2.63 (2H, t, J = 6Hz), 3.60 (2H, t, 6Hz), 4.18 (2H, t, J = 6Hz), 6.43 (lH, d, J = 9Hz), 7.-δδ (1Η, d, 9Hz)

Reference example 2

3- (4-Acetyl-3-Hid σxy 2-P σPilphenoxy) P σ Pyruv σ mid (2.8 g), triethylamine (6.2 mi) and dimethylamino pyridine (10 mg) After dissolving in methylene chloride, acetic anhydride (4.2 ml) was added dropwise under ice cooling. After reacting for 3 hours, methanol (5 ml) was added and left for 10 minutes. The syrup obtained by distilling off the solvent was dissolved in chloroform, washed with water, dried and concentrated. The resulting syrup was purified by flash chromatography on silica gel (silica gel form) to give a colorless and transparent syrup, 3- (3-acetoxy-4-acetyl-2-propylphenoxy) propyl sigma mid (2.7 g) was obtained. _{NMR (CD Cl 3) 5:} 0.93 (3H, t, J = 7Hz), 1.30 - 1.70 (2H, m), 2.36 (3H, s), 2.50 (3H, s), 2.20~ 2. · 70 (4Η , m), 3.59 (2H, t, J = 6Hz),

 4.29 (2H, t, J = 6Hz), 6.79 (1H, d, J = 9Hz), 7.71 (1H, d, J = 9Hz) Reference example 3

 3- (3-acetoxy-4-acetyl-2-buta-pyruphenoxy) propyl bromide (2.3 g), 3-promo '4-hydroxyhydroxybenzaldehyde (1, 29 g), potassium iodide (1. 07g) and potassium carbonate (0.89g) were reacted in dimethylformamide (30ml) at 70-80 with stirring for 1.5 hours. After addition of chloroform (100 ml), the insolubles were filtered off, washed with water, dried and concentrated to give a brown syrup. The syrup was purified by silica gel chromatography (silica gel) and treated with isopropyl ether. When recrystallized from hydroalcoholic alcohol, light yellow crystals were obtained as 4- [3- (3-acetoxy-14-acetyl-2-propylpropyloxy) propoxy] —3-butyl crmobenzaldehyde (2.28 g). )was gotten. Mp 120-121. C

Reference example 4

 4-acetoxy 3-bromobenzoic acid (1.5 g) is suspended in thionyl chloride (6 ml), heated to reflux for i hours, concentrated to dryness, the residue is dissolved in toluene, and the toluene is distilled off. Was repeated twice. The obtained oil was dissolved in acetone (10 ml), 3-dimethylaminopropanol (0.8 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The produced crystals were collected by filtration and recrystallized from ethanol monoether to give colorless crystals of 3-dimethylaminopropyl 4-acetoxy-3-bromobenzoate hydrochloride (1.8 g). Melting point 16 3〜1 6 7 ° C

Reference example 5 '

3-dimethylaminopropyl 4-acetoxy-3-bromobenzene To a solution of methanol (380 mg) in methanol (4 ml) was added 2N aqueous ammonia (0.75 mi), and the mixture was reacted at room temperature for 15 minutes. Was crystallized from acetone and recrystallized from methanolic ether to give colorless crystals (20 mg) of 3-dimethylaminopropyl 3-promo 4-hydroxybenzoate 'hydrochloride. Was. Melting point 1 86-190 ° C Reference example 6

 Methyl 3-promo 4-hydroxybenzoate (44 g), acetate (300 ml), lithium carbonate (25 g), 3-bromo-1-alk σ σ σ pan (3 After the mixture of (lg) was ripened and refluxed for 16 hours, the inorganic salts were removed by filtration, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane monoacetic acid ethyl ester 4: 1) to give methyl 3-buta-mo-41- (3-chloro-propoxy) benzoate crystals (50 g). Obtained.

Melting point 6 7-6 8

Reference Example 7

A mixture of methyl 3-bromo-41 (3-alkoxypropoxy) benzoate (2.8 g), methanol (10 mt), and ^2X sodium hydroxide (5 ml) was mixed with δ 0 ^ΰ ~ 60. After stirring for 1 hour, methanol was distilled off, and the mixture was acidified with dilute hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, dissolved in chloroform, and subjected to silica gel column chromatography, and eluted with chroma-form. After the eluate was concentrated, hexane was added, and the resulting crystals were collected by filtration to obtain 3-promo 4- (3-co σ σ σ oxy) benzoic acid (2.5 g). Melting point i 49-150

Reference Example 8

A solution of 3-but σ-mo 4- (3-octanol σ-poxy) benzoic acid (1.2 g), σ-σ-form (5 ml) and thionyl chloride (1 ml) was ripened and refluxed for 1 hour. The solvent was distilled off, and dried over sodium hydroxide. Acetate residue (200 ml), and added thereto (500 mg) and then triethylamine (2 ml), and the mixture was stirred at room temperature for 1 hour. After that, the precipitate was filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with ethyl acetate), and 2-pyrrolidinoethyl 3-buta-mo-41- (3-chloropropoxy) benzoate (1.1 g) was obtained as an oil. I got it.

_{MR (CDC 1 3) <5} : 1.40 -1.90 (4H, m), 2.10 -2.90 (8H, m), 3.77 (2H, t, J = 6Hz), 3.90 -4.50 (4H, m) (6.83 (1H , d, J = 8Hz), 7.85 (1H, dd, J = 2 and 8Hz), 8.lOClH.d, J = 2Hz)

Reference Example 9

 The following compound was produced in the same manner as in Reference Example 8.

(1) 2-morpholinoethyl 3-promo 41- (3-chloro σ-propoxy) benzoate (oil)

_{MR (CD C 1 3) <} 5: 2.10-2.90 (8H, m), 3.55-4.00 (6H, m), 4.10- 4.55 (4H, m), 6.87 (1H, d, J = 8Hz), 7.90 ( 1H, dd, J = 2 and 8Hz), 8.15 (lH, d, J = 2Hz)

 (2) 3-dimethylaminop sigma pill 3-promo 41- (3-chloro sigma-poxy) benzoate (oil)

_{XMR (CDC 1 3) (5} : i.60 -2.60 (6H, ni), 2.23 (6H (s), 3.81 (2H, t, J = 6Hz), 4.29 (4H, q, J = 6Hz), 6.86 (iH, d, J = 8Hz), 7.90 (lH, dd, J = 2 and 8Hz), 8.i5 (lH, d, J = 2Hz)

 (3) 4- (N, N-dimethylamino) butyl 3-bu sigma-mode 4- (3-chloropropoxy) benzoate (oil)

 (4) Dimethylaminoethyl 3-promo 4- (3-propoxy) benzoate (oil)

(5) 2- (4-Methyl-1-piperazinyl) ethyl 3-bromo-1-41 (3-chloro σ propoxy) benzoate (oil)

Example〖

 4- [3- (3-acetoxy 4-acetyl- 2-py σ-pyruphenoxy) -p σ-pokin] -13-bromo-1-benzaldehyde (2.39 g) in acetone (5 OmD solution in sulfuric acid) (5 ml), and then ground potassium permanganate (1.58 g) was added little by little with sufficient stirring at room temperature. The residue obtained by concentration under reduced pressure was extracted with sigma-form.The insolubles were filtered off, the filtrate was washed with dilute aqueous hydrogen peroxide solution and then with water, dried and concentrated to obtain a colorless transparent silica gel. When crystallized from aqueous alcohol, colorless crystals were obtained as colorless crystals of 4- [3- (3-acetoxy-14-acetyl-2-p σ-pyruphenoxy) propoxy] -1-bromobenzoic acid ('2. (Tg) The melting point is 15 δ to 15 6

Example 2

 3- (3-acetoxy 4-acetyl-2-propylphenoxy) propyl sigma mid (1.6 g), 3-dimethylamino sigma pill 3-b sigma-mo 4 —hydroxybenzoate 'Hydrochloride (7 g), potassium iodide (0.83 g) and potassium carbonate (0.7 g) were added to dimethylformamide (30-70 in 60-70%). The reaction was carried out while stirring for a period of time.The insoluble material was removed by filtration, and the filtrate was concentrated, and the resulting sila'sop was purified by flash chromatography using silica gel to give 3-dimethylaminopropyl. This gave 3- (3-acetoxy-1-acetyl-2-propylpropylenoxy) p σ-poxy] —3—bromobenzoate (1.8 g), which was dissolved in ether and an equivalent of oxalic acid (2 Addition of δ Omg) yielded oxalate crystals (1.8 g) Melting point 141-142.

Example 3

2,4-dihydroxy 3-propyl acetophenone (1.0 g), 2- Morpholinethyl 3-butyl sigma-mo 4- (3-chloropropoxy) benzoate (35 g), dimethylformamide (0 ml), potassium carbonate (0 g), iodide The mixture of urea (about 10 mg) was stirred at 90 to 1000 for about 21 hours, and then the insoluble matter was removed by filtration. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (hexane monoethyl acetate 1: 1), and the eluate was crystallized with hexane. By recrystallization from ethanol-water, 2-morpholinoethyl 4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -13-bromobenzoate crystals (6 0 Omg). Melting point 98-99 C

Example 4

 2,4-Dihydroxy-3-propylacetophenone (2 16 mg), 3-dimethylaminopropyl 3-promo 41- (3-chloropropoxy) benzoate (210 mg), potassium iodide A mixture of (100 mg), lithium carbonate (228 mg) and dimethylformamide (5 ml) was 60 to 70%. After stirring with C for 14 hours, dimethylformamide was distilled off. Ethyl acetate was added to the residue, and the mixture was applied to a silica gel column (30 g) and eluted with σ σ form-methanol (10: 1). The eluate was concentrated and crystallized from hexane. By working, 3-dimethylaminop sigma pill 4-1 [3-(4-a cetyl-3-hydroxy-1-propylphenoxy) propoxy]-3-bromobenzoate crystals (i 34 mg ). Melting point 7 1 to 7 2 V Example 5

 The following compound was produced in the same manner as in Example 4.

 (1) 2-Pi-D-Lidinoethyl 41 :: 3- (4-Acetyl-3-hydroxy-1-propoxy) propoxy] -13-bromobenzoate Melting point 79-80 ° C

(2) 4- (Ν, Ν-dimethylamino) butyl 4- [3- (4-acetyl — 3-Hydroxy-2-propylphenoxy) p σ-poxy] — 3-Bromobenzoate Melting point 69-70. C

 (3) 2-dimethylaminoethyl 4- [3- (4-acetyl-3-hydroxy-2-propylpropyloxy) propoxy] -13-bromobenzoate ♦ Hydrochloride · monohydrate Melting point 3 8 ~ 4 0: (absorbent)

 (4) 2- (4-Methyl-1-piperazinyl) ethyl 4- [3— (4-Acetyl-3-hydroxy-2-propoxy) propoxy] -1-3-bromobenzoate dihydrochloride 〖Hydrate Melting point 14 2 to 144 ° C Example 6

4- (3-chloropropoxy) -1-hydroxy-3-phenylpropylphenone (700 mg), dimethylformamide (10 ml), potassium iodide (450 mg) , 3 Jimechiruami Roh propyl 3- Bro乇one 2-arsenide Dorokishi base Nzoa Ichito hydrochloride (9 0 0 mg), 5 a mixture of carbonate force potassium (5 0 0 mg) at 7 0 to 8 0 ^S C Stirred for hours. After removing the insoluble matter by filtration and concentrating the filtrate, the residue was subjected to chromatography with a silica gel column and eluted with ethyl acetate. The desired fraction was concentrated and recrystallized from n-hexane to give 3-dimethylaminopropyl 4- [3- (4-acetyl-3-hydroxy-2-propylpyruquinoine) propoquine] —3-s-mobenzova One colorless crystal (91 mg) was obtained. Melting point 7 1 ~ 7 2 ° C

Industrial applicability

 Compounds (I) to (! Π) or salts thereof have excellent anti-asthmatic and anti-inflammatory effects, and can be used as therapeutic or anti-inflammatory agents for mammals.

Claims

 The scope of the claims  L. General formula

In the two formulas, R ¹ represents lower alkyl, and X represents halogen. A compound represented by the general formula: R'CO CH

Wherein R ¹ and X have the same meaning as described above. A method for producing a benzoic acid derivative represented by: 2. —General formula

'. People, `` Q- (CH ₂ ) ₃ -Y CH ₃ C0,,: .—— In the formula, R ¹ represents lower alkyl, and Y represents a group which is eliminated during the condensation reaction. And the general formula

In the formula, n is an integer of 24, and R ² and R ³ are the same or different and may be hydrogen. Or lower alkyl or a 5- or 6-membered heterocyclic ring with an adjacent nitrogen atom. X has the same meaning as above. A compound represented by the general formula: I

[Wherein n.Ri.RS.R ³ and X have the same meaning as described above. A method for producing a benzoic acid derivative represented by 3. Expression

Compound represented by NO to CH ₃ C0 and the general formula Y '-(CH ₂ ) ₃ -0— R C00CCH ₂ ) nN <_D;  R [In the formula, n is an integer of 2 to 4, and R ² and R ³ are the same or different and are together with hydrogen or lower alkyl or an adjacent nitrogen atom (to form a 5- or 6-membered heterocyclic ring) Wherein X is a halogen, Y is a group which is eliminated during the condensation reaction, and a compound represented by ₃ ] is subjected to the condensation reaction.

[Wherein 1 1 1 ² , 1 ^{3 and 3} have the same meanings as described above. A method for producing a benzoic acid derivative represented by the formula: 4. General formula

;: In the formula, Y represents a group which is eliminated during the condensation reaction. And the general formula X  H0— C00 (CH ₂ ) n < In the two formulas, n: an integer of 24, and R ² and R ³ are the same or different, and form a 5- or 6-membered heterocyclic ring with hydrogen or lower alkyl or an adjacent nitrogen atom. And X represents a halogen. A compound represented by the general formula:

^H0 , —,: “0- (CH ₂ ) ₃ -0” Τ:-I ':! --C00 (CH ₂ ) nN CH ₃ C (Glue <5 ₃ Wherein n, R ² , R ³ and X have the same meaning as described above. : Represented by A method for producing a benzoic acid derivative.