JPH0242069A - Benzamides - 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 FIELD OF INDUSTRIAL APPLICATION The present invention relates to new and active benzamides having an II′I activating effect. The conventional technology JP-A No. 53-90274 describes the N-[
It is disclosed that (411'(l alkyl-2(or 3)-morpholinyl)methyl)-substituted penzamide derivatives have reserpine antagonistic effects, tA pain effects, etc., and are used as antidepressants, antipruritic agents, etc. On the other hand, 4-7mi/-5-ri0O-N-EC2-diethylami/)ethyl]-2-methoxybenzamide [generic name metoclopramide; for example, Mercklnde++,
10th edition, 0019 (1983)] was published in 1960.
Since its development as an antiemetic or gastrointestinal function enhancer in the mid-1990s, various substituted benzamide derivatives have been synthesized and their pharmacological properties have been studied. Purpose of the Invention The present inventors have continued their research to find substituted bezamide derivatives that have excellent gastrointestinal function-enhancing effects. The inventors discovered that a substituted benzamide derivative bonded through a group is beyond the scope of the above, and as a result of further research, they completed the present invention. Structure and Effects of the Invention According to the present invention, -formation (I) (hereinafter referred to as blank) [wherein R is a lower alkoxycarbonyl group, a cycloalkyl group, a lower alkyl group having a substituent (the substituent is a di-lower alkylamino group, cycloalkyl group, cycloalkenyl group, furyl group;
Lower alkenyl group, lower alkynyl group. (V means a lower Alkyrev group) or -T-(W) p-Re (Re, T, W and p
is as defined below), and 1 is a hydrogen atom, a halogen atom, or a hydroxy group. a lower alkoxy group, a lower alkoxy group interrupted by an oxygen atom, a lower alkoxy group having a substituent (the substituent is a carboxyl group, an amino group or a phthalimide group);
Lower alkylthio group. means a lower alkyl group, Ra means a group represented by a lower alkyl group, cycloalkyl group, phenyl (lower) alkyl group) or an acylamino group, R2 is a hydrogen atom, a halogen atom, a lower alkoxy group Or it means a nitro group, or R+ and R2 can be combined to form a ureire group, or R3 is a hydrogen atom, a halogen atom, a lower alkoxy group, an amino group, a lower alkylamino group, a di-lower alkyl group. means an amino group, a lower alkali/ylamino group, or a nitro group; R4 is a hydrogen atom, a halogen atom, a lower alkoxy group, a nitro group, an amino group, a di-lower alkylamino group, a lower alkanoylamino group, a sulfamoyl group, or a di-lower It means an alkylsulfamoyl group, or R3 and R4 may be taken together to form a group represented by -NH-N=N- (, Re hydrogen i; i atom, halogen atom or lower It means an alkoxy group, or any two adjacent groups of R+, Rz, Rs, Ra and R6 may be taken together to form a lower alkylenedioxy group, and Ra is a phenyl group or a substituted phenyl group. (The substituent is 1 to 3 atoms or groups from halogen R3, lower alkyl group, lower alkoxy group, carboxyl group, and amino group) or diphenylmethyl group, and X represents a lower alkylene group. T means a single bond or a lower alkylene group, W means an oxygen atom or an imino group, and p means O or 1. However, (i) less than R11 of R1, R3, R4 and R8 (Both two mean a group or group other than a hydrogen atom,
(When HAT is a single bond, p means O, (iii)
R+ is a hydroxy group or a lower alkoxy group, and R
il is an amino group, a di-lower alkylamino group, or a lower alkanoylamino group, R4 is a halogen atom,
When R2 and R6 are hydrogen atoms, R is -T'-(W'
) p-Re' (P means the same as above, R
8' means a phenyl group or a halogenophenyl group, T
' means a lower Alkyrev group, W' means an acid M atom). ] Compounds represented by these and physiologically acceptable acid addition salts thereof are provided. Physiologically acceptable acid addition salts of the compound represented by formula (1) refer to physiologically acceptable acid addition salts of the compound of formula (I) which have a group capable of forming an acid addition salt in the structure. means salt. A specific example is hydrochloride. Inorganic acid salts such as bromide, hydroiodide, phosphate, and sulfate, maleic/acid 10 fumarate, lactate, malate, citrate. Examples include organic acid salts such as tartrates, benzoates, meta/sulfo 7M salts, and the like. Since the compounds of formula (I) contain at least one asymmetric carbon atom, several stereoisomers may exist. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention. Terms used in this specification will be explained below. "Lower" means 1 to 6 carbon atoms unless otherwise specified. lower alkyl group, lower alkyl moiety,
The lower alkylev group or lower alkylene moiety may be linear or branched. "Lower alkoxycarbonyl group J
Specific examples include methoxycarbonyl, ethoxycarbonyl, aboxycarbonyl, and the like. "Cycloalkyl IAJ" means one having 3 to 6 carbon atoms. A specific example of "lower alkyl group" is methyl. Examples include ethyl, propyl, isopropyl, butyl, isopdyl, pentyl, hexyl and the like. The term "lower alkyl group having a substituent" means one in which one of the above-mentioned substituents is present at any position. Specific examples of the "di-lower alkylamino group" include dimethylamino, diethylamino, methylethylamino, methylpropylamino, and the like. "Cycloalkenyl group" has one double bond,
It means one having 5 to 6 carbon atoms. [Lower alkenyl group] means a group having one double bond at a position other than the 1-2 position and having 3 to 6 carbon atoms, such as allyl,
2-butenyl, 3-methyl-2-butenyl, 3- or 4-pentenyl, 2-. 3-. Examples include 4- or 6-hexenyl. "Lower alkynyl group" means 1
- refers to a substance having 3 to 6 carbon atoms and having one triple bond at a position other than the 2-position, such as 2-propynyl, 3-
Examples include butynyl, 5-hexynyl, and the like. "Specific examples of the phenyl (lower) alkenyl group j include cinnamyl, etc."The "halogen atom" refers to fluorine, chlorine,
Means bromine and iodine. Specific examples of the "lower alkoxy group" include methoxy, ethoxy, propoxy, impropoxy, butquin, imbutoxy, and the like. "
The term "lower alkoxy group interrupted by an oxygen atom" means a lower alkoxy group in which any position of the lower alkyl moiety is interrupted by 1 to 2 oxygen atoms, such as 2-methoxyethoxy, (2-methoxyethoxy), ethoxy) methoxy, 2.
Examples include 2-dimethoxyethoxy. "Lower alkoxy group having a substituent" means a group having the above-mentioned substituent at any position; however, when the substituent is a 7-mino group, these 71V are carbon atoms other than the 1-position. is combined with Specific examples include carboxymethoxy, 3-amitube 1
and 3-phthalimidopropoxy. Specific examples of "lower alkylthio groups" include methylthio, edylthio, and propylthio. Examples include isopropylthio, budildio, impudilthio, and the like. "Acyl group" means phenyl substituted unsaturation I
l/I group carboxylic acid residue or halogen atom. Examples of benzoic acid residues which may be substituted with a lower alkyl group, a lower alkoxy group or a nitrobenzoyl group include ethannamoyl, benzoyl, chlorobenzoyl, methylbenzoyl, methoxybenzoyl, nitrobenzoyl and the like. Specific examples of "lower alkylamino'II5" include methylamino, ethylamino, propylamino, and the like. Specific examples of the "lower alkanoyl group" include acetyl, propionyl, butyryl, isobutyryl, and the like. A specific example of "di-lower alkylsulfyl group" is 3 years old, and a specific example of dimethylsulfamoyl "lower alkylene group" is t! , methylene, ethylene, methylmethylene, 1J methylene. Probile/l dimethylmethylene/, tetramethylene. Kisametilef etc. will be given a gift number to Pentamechele Otsu. Among the compounds of the present invention, preferred compounds (in formula (1), R is a be/zyl group and X is a methylene group, (1) R1, R21 R3, Ra and R6
If any or two adjacent zeros are together, CI-C!
1 alkylenedioxy group is formed, and the remaining 3 groups are ≦ water cord.

[child, (2) RI is a C1-C4 alkoxy group or LtCt~
C4 alkylthio group, R4 is sulfamoyl s
Rtr R3 and RlI are hydrogen atoms, (31
R + fJ' is an amino group or Ct~C3 alkylamino, R3 is a /10 gen atom (especially a chlorine atom) or a nitro group, Rtr Ra and R6 are hydrogen atoms, +4J RI is an amino group or C1~ It is a C3 alkylamino group. Ra is a nitro group. a sulfamoyl group or a di(C1-C2 alkyl) sulfamoyl group,
R2. Whether R3 and R11 are hydrogen, (5)
RI is an amino group or CI++C3 alkylamino group, and R3 is a 7% rogene atom (especially a chlorine atom) or C1~
It is a C3 alkylamino group, R4 force≦nitro group, and R2 and Rs are hydrogen atoms. The compound of the present invention can be produced, for example, by the following method. Method (a) 2 General Formula (Summer ■) (Hereinafter in the margin) (In the formula. Above-mentioned R other than group
It means the same thing as +. ) or its reactive derivative and -formation (I
n) Reacting with a compound represented by R' (wherein, X means the same thing as above, and R' means the same thing as above R except for the group that connects a carboxyl group). According to formula (1)
Compounds in which R is R' and RI is R+' can be obtained. Examples of the reactive MW form of the compound of formula (II) include lower alkyl esters, active esters, acid anhydrides, acid halides (particularly acid chlorides), and the like. Specific examples of active esters include p nide [I phenyl ester, 2,4.5-trichlorophenyl ester, pentachlorophenyl ester, cyan methyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, N-hydroxy- 5-norbornene-2,3-dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoli7 ester, 2-hydroxyphenyl ester. 2-hydroxy-4,5-dichlorophenyl ester,
Examples include 2-hydroxypyridine ester and 2-pyridylthiol ester. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides with chloroalkyl esters such as ethyl chlorocarbonate and inbutyl chlorocarbonate; Mixed acid anhydrides with aralkyl esters such as benzyl chlorocarbonate, mixed acid anhydrides with aryl esters of chlorocarbonate such as phenyl chlorocarbonate, mixed acid anhydrides with alkali heptacids such as isovaleric acid and pivalic acid. Examples include things. When using the compound of formula (■), dicyclohequinylpodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-ethoxycarbonyl-2 The reaction can be carried out in the presence of a condensing agent such as -ethoxy-1,2-dihydroquinoline. When synchhexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybe/citriazole, 3-hydroxy -4-oxo-3,4-dihydro-1,2,3-benzotriazine,
N-hydroxy-5-norbornene/-23-dicarboximide or the like may be added and reacted. A compound of formula (II) or its reactive MW form and formula (III)
) with the compound is carried out in a solvent or without a solvent. The solvent to be used should be selected appropriately according to the type of compound, etc., but for example,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol,
Examples include water, and these solvents may be used alone or in a mixture of two or more. This reaction is optionally carried out in the presence of a base, and specific examples of the base include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, or triethylamine. Organic bases such as tributylamine, diisopropylethylamine, and N-methylmorpholine can be used, but an excess amount of the compound of formula (III) can also serve as the base. The reaction temperature varies depending on the amount of raw material compound used, but is usually between -30°C and about 20°C.
0°C, preferably about -1θ°C to about 150°C. By the way, when there are groups involved in the reaction in the structure of the compound of formula (IT) or the compound of formula (If), it is desirable to protect these groups according to a conventional method and remove them after the reaction. . Method (b) - A compound represented by general formula (Iα) (wherein R1, R2, R3, R4, Rs and X have the same meanings as above) and general formula (IV) Z -R' (IV) (In the formula, R# means the same as R above except when T is a single bond and Re is a phenyl group or a substituted phenyl group, and Z means a reactive ester residue of alcohol. ) and reacting with a compound represented by formula (I)
Compounds in which R is R# can be obtained. Examples of the reactive ester residue of alcohol represented by Z in formula (IV) include chlorine and bromine. Halogen atoms such as iodine, lower alkylsulfonyloxy groups such as methanesulfonyloxy, f/sulfonyloxy, arylsulfonyl such as benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobe/ze/sulfonyloxy Examples include oxy group. The reaction between the compound of formula (■α) and the compound of formula (IV) is
It is usually carried out in a suitable solvent, and specific examples of solvents include:
Aromatic hydrocarbons such as benzene, toluene, xylene, ketones such as acetone, methyl ethyl keto/
Examples include ethers such as tetrahydrofuran, alcohols such as ethanol and isopropyl alcohol, acetonitrile, and dimethylformamide. These solvents may be used alone or in combination of two or more. This reaction is preferably carried out in the presence of a base, and as specific examples of the base, the specific examples of the base described in the section (a) can be cited as they are. Furthermore, when using a compound in which Z is chlorine or bromine in formula (■), the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. The reaction temperature varies depending on the seeds of the raw material compound used, but is generally 50°C to about 200°C. In addition, when there are groups involved in the reaction in the structure of the compound of formula (■α) or the compound of formula (IV), these groups should be protected according to conventional methods and removed after the reaction. desirable. Method (C) A compound represented by the general formula (Iβ) (wherein, R+ R!* R3* R4+ Rs and X have the same meanings as above) and a compound represented by the general formula (V) Z'-Re ( V) (
In the formula, %R9 is an alkyl group, cycloalkyl group, alkenyl group, alkynyl2! , il! means an alkyl group interrupted by an II atom or an alkyl group forming a substituent,
Z' means a reactive ester residue of alcohol. ) By reacting with a compound represented by formula (1)
A compound in which RI is OR9 can be obtained. As the reactive ester residue of alcohol represented by Z' in formula (V), the specific examples described in the section (b) can be cited as they are. This reaction is usually carried out in a suitable solvent in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, quaternary ammonium hydroxide such as tetrabutylammonium hydroxide, penzyltriethylammonium hydroquine, sodium methoxide, and sodium ethoxide. Examples include alkali metal alkoxides such as sodium hydride, alkali metal hydrides such as potassium hydride, etc. The solvent to be used should be appropriately selected according to class 8i of the raw material compound and base, etc. For example, methylene chloride, acetate/
, acetonitrile, methanol, ethanol, isopropyl alcohol, diglyme. Examples include dimethylformamide and dimethylacetamide. When using a compound in which 2' is chlorine or bromine in formula (V), the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. This reaction also applies to strong 111! compounds such as sodium hydroxide and potassium hydroxide! It can also be carried out using solvent systems commonly used in phase transfer catalytic reactions, such as methylene chloride-water, in the presence of a group and a phase transfer catalyst. Examples of phase transfer catalysts include tetrabutylammonium bromide, cedyltrimethylammonium bromide,
The degree of reaction of benzyltriethylammonium chloride and tetrabutylammonium bisulfate varies depending on the type of raw material compound used, etc., but is usually 5°C to about 150°C.
It is ℃. In addition, when there is a group that stimulates the reaction in the structure of the compound of formula (■β) or the compound of formula (V),
It is desirable to protect these groups in accordance with conventional methods and remove them after the reaction. Method (d) is represented by the general formula (Vl) (wherein, R2, R3, Ra and R5 mean the same as mentioned above, and Rho means a residue obtained by removing the carbonyl moiety from the acyl group). By reacting a compound represented by -formation (m) with a compound represented by -formation (m), a compound in which R is R' and RI is an acylamino group in formula (I) can be obtained. Examples of this reaction include benzene, toluene, and tetrahydrochloride. It can be dissolved in solvents such as dioxatriol. Method (e) General formula (■γ) Chlorophor! (wherein R, R2, R3, Ra, Rs and X have the same meanings as above, and Z# means a halogen atom) Compound and general formula (■) (In the formula, R7 and R8 have the same meanings as above.)
This reaction can be carried out to obtain a compound of the formula by reacting with a compound represented by
℃ to about 150℃. Manufacturing methods (a), (b), (c). If the product obtained by (d) and (C) loses the nido group during its evacuation,
When doing so, it can be converted to the corresponding amine derivative by reduction according to a conventional method. (1) When adding an amino group or a lower alkylamino group during the preparation,
By reacting with a suitable acylating agent according to a conventional method, it can be converted to the corresponding acyl a 71 body. In addition, in formula (I), the compound in which RI is an amino group or an amino group substituted with it and R2 is nitro JJ can be prepared by reducing the phosge 7. By reacting with a reagent such as N,N'-carbonylciimiguzole,
It can be converted into the corresponding 2,3-dihydrobenzimidazol-2-one derivative. The compounds produced by each of the above-mentioned production methods are purified by simple Nl+ methods such as chromatography, recrystallization, reprecipitation, and the like. (Formula (1) having a group capable of forming an acid addition salt during one production)
The compound can be obtained in the form of a free base or an acid addition salt depending on the selection of the raw material compound 1 reaction/processing conditions, etc. The acid addition salt can be obtained using a conventional method, for example, an alkali carbonate. It can be converted to the free base by treatment with a base such as alkali hydroxide. On the other hand, free bases can be converted into acid addition salts by treatment with various acids according to conventional methods. The compound of formula (I) and its physiologically acceptable acid addition salts can be used as an antiemetic or gastrointestinal stimulant.
For the treatment and prevention of acute and chronic gastritis, gastric ulcers, gastric nervous system, gastric ptosis, etc., and for the treatment and prevention of anorexia, nausea, vomiting, abdominal distension, etc., and for the treatment and prevention of esophageal and biliary system disorders 1 and constipation. It can be used for treatment and prevention. It can also be used for the treatment and prevention of nausea and vomiting during administration of anticancer drugs such as nsplaten. The route of administration is oral administration. Jl - Oral administration or intrarectal administration The dosage may vary depending on the type of compound, administration method, patient's symptoms, age, etc., but is usually 0.001 to 20 fg/kg7.
day, preferably 0.004 to 5 w*/kg/day. The compound of formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. As the pharmaceutical carrier, a substance commonly used in the pharmaceutical field and which does not react with the compound of formula (I) or its salt is used. Specifically, for example, lactose, glucose, mannitol, dextrin,
Cyclodextrin, starch7. White sugar, magnesium aluminate mekusilicate. Aluminum silicate, crystalline cellulose, sodium carboxyl methylcellulose, hydroxypyl starch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose. Gelatin Gum Arabic, pullulan, hydroquinepropylcellulose, low-substituted hydroquinepropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolid/, polyvinyl alcohol, light silicic anhydride, magnesium stearate. Talc, tragacanth, bentonite, vegum. Carboxyvinyl polymer, titanium oxide/, nurvita/fatty acid ester, sodium lauryl sulfate. Glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol,
Examples include plant Mh, wax, probile/glycol, and water. Dosage forms include tablets, capsules, granules, powders, syrups, and suspensions. Examples include injections and small portions. These formulations are prepared according to conventional methods. In the case of a liquid preparation, it may be dissolved or suspended in water or other suitable medium before use. Furthermore, tablets and granules may be coated by a well-known method. These preparations contain the compound of formula (I>) or a physiologically acceptable acid addition salt thereof in an amount of 0.5% or more, preferably 1 to 70%.
It can be included at a rate of %. These formulations may also contain other ingredients of therapeutic value. In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. The compounds were identified using elemental analysis values, mass spectra, IR spectra, NMR spectra, etc. Further, in the following reference examples and examples, the following abbreviations may be used to simplify the notation α. Me: Methyl group: Ethyl group: Propyl group: Phenyl group: Acetyl group: Ethanol: A7to/Nia7tonitrile: Chloroform: Dioxane: Methylene chloride: Diethyl ether: Hexane: Cyclohexane: Isopropyl alcohol: Methanol: Diisopropyl Ether: Toluene Reference Example I Preparation of 2-aminomethyl-4-benzylmorpholine: (J) Syn, Commun, 10.59~
4, synthesized according to the method α described in 73 (1980).
-Benzyl-2-chloromethylmorpholine 80.4g
, a mixture consisting of 78.0 g of potassium phthalimide and 700 g of dimethylformamide was heated with stirring to
Heat to reflux for an hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from inpropyl alcohol to obtain 107 g of N-[(4-be/zi-2-morpholinyl)methylcottalimide. Melting point 136-1
39°C (2) Add ethanol + 801 and 20.0 g of 85% hydrazine hydrate to 67.2 g of the above phthalimide compound,
Heat for 30 minutes while stirring. Filter off the precipitated crystals,
Add chloroform and water to solution d and shake. The organic layer was washed with saturated saline water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 33.5 g of the desired product as an oil. A portion of this free base is dissolved in a small amount of ethanol, an ethanol solution of fumaric acid is added thereto, concentrated, and then cooled to precipitate the target product, 3/2 fumarate 1/2 hydrate, as crystals. Melting point: 166-108°C Reference Example 2 Production of 2-amizmedel-4-phenylmorpholine: Using 2-chloromethyl-4-phenylmorpholine in place of 4-benzyl-2-chloromethylmorpholine in Reference Example 1 (1), Reference (PH(II)) The target product is obtained by reacting and treating in the same manner as (2). Reference Example 3 Preparation of 2-amino/methyl-4-be/zylmorpholine i0: (+1 4-benzyl-2-chloro Methylmorpholine 1
A mixture of 5.0 g of sodium azide, 8.6 g of sodium azide, and 150 g of dimethylformamide was stirred at 130°C for 2 hours. Water was added to the reaction mixture and extracted with diethyl ether. The organic layer was diluted with water and then with saturated brine. After washing, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily 2
15 g of -azidomethyl-4-benzyl morpholif are obtained. ■ A 70% toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride, which had been cooled to -5°C in advance, was added to a toluene 401 solution containing 15 g of the above azide compound.
Drop into 01 little by little. After the addition was completed, the mixture was stirred at room temperature for 1.5 hours. After adding a 10% aqueous sodium hydroxide solution little by little to the reaction solution to decompose the remaining reducing agent, the organic layer was separated, washed with water and then with saturated saline, and washed with anhydrous magnesium sulfate in Q2. dry The solvent is distilled off under reduced pressure to obtain 11 g of the target product of Urabo. Reference Example 4 Production of 2-acetylaminomethyl-4-be/dylmorpholine: 1132 g of N-[(4-benzyl-2-morpholinyl)methyl]phthalimide + 43 of 85% hydrazine hydrate
．． A mixture of 3ff and 100 ml of ethanol is heated with stirring for 20 minutes. The precipitated crystals are removed by d.2, and chloroform and water are added to the filtrate and shaken. The organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. Insoluble matters were removed by filtration, and 98.3 g of acetic anhydride was added to the filtrate, followed by stirring at room temperature for 2 hours. After adding an aqueous sodium hydroxide solution to the reaction solution and shaking, the organic layer is washed with water and then with saturated brine. The organic layer dried over anhydrous magnesium sulfate was concentrated under reduced pressure, and the residue was recrystallized from toluene to obtain the desired product 10.
Obtain 1 g. Melting point: 110-111°C Reference Example 5 Production of 2-acetylaminomethylmorpholine: 2-acetylamitumedel-4-benzylmorpholine 120F,
Eta/-le 1000■! A mixture consisting of 301 and acetic acid is heated and hydrogenated at normal pressure using 5 g of 10% palladium on carbon as a catalyst. After absorbing the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure to obtain the desired product 7+11. Reference Example 6 Production of 2-acedelaminomethyl-4-(4-methylbenzyl)morpholino: 4.0 g of 2-acetylaminomethylmorpholine. A mixture consisting of 3.5 g of 4-methylbenzyl chloride, 17.5 g of anhydrous potassium carbonate, 0.4 g of potassium iodide and methyl edyl ketone 4001 was heated under reflux for 17 hours. σ・! and concentrate the filtrate under reduced pressure. Chloroform and water are added to the residue and shaken, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from toluene-hexane to obtain 5.1 g of the desired product. Melting point: 97-98°C Reference Examples 7-23 The corresponding alkylating agent was used in place of 4-methylbenzyl chloride in Reference Example 6, and the reaction and treatment were carried out in the same manner as in Reference Example 6 to obtain the compounds shown in Table 1. Table 1 Table 1 (Continued) Reference Example 24 Production of 2-amitumedel-4 (methylbenzyl) morpholine: Add lθ% salt ff150m+ to 3.0 g of 2-acedelaminomethyl-4-(4-methylbenzyl)sorforin. , and heat to reflux for 4 hours. The reaction solution is made alkaline by adding an aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer is washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain the desired product as an oil. Reference Example 25 Production of 2-aminomethyl-4-substituted morpholine: Reference Example 4.7.0 in place of 2-acetylamitumedel-4-(4-methylbenzyl)morpholino in Reference Example 24
．． The products of 14.1[+ and 19 to 22 are reacted and treated in the same manner as in Reference Example 24 to obtain the corresponding 2-aminomethyl compound. Reference Example 26 Production of 2-aminomethyl-4-(4-methoxybenzyl)morpholine: To 3.3 g of 2-acetylaminomethyl-4-(4-methoxybenzyl)morpholine was added 001 aqueous thorium solution to hydrate Iθ%, Heat to reflux for 20 hours. The reaction solution was extracted with chloroform, and the organic layer was washed with water, then with saturated saline, and then dried over anhydrous magnesium sulfate. The tB medium is distilled off under reduced pressure to obtain an oily target product. Reference Example 27 Production of 2-aminomethyl-4-substituted morpholine: Instead of 2-acetylaminomethyl-4-(4-methoxybenzyl)morpholine in Reference Example 26, Reference Example 8.1
Using the products of 0 to 13.15.17.18 and 23,
The reaction and treatment are carried out in the same manner as in Reference Example 2B to obtain the corresponding 2-aminomethyl compound. Reference Example 28 Production of 2-aminomethyl-4-ethoxycarbonylmorpholine: (1) To 30.0 g of N-[:(4-be/di-2-morpholinyl)methyl]phthalimide was added 200 μl of toluene, and the mixture was heated at 60°C. Warm to. Ethyl chlorocarbonate 19.4g
After adding dropwise, the mixture was heated under reflux for 1 hour. The reaction solution was washed with water, then with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl alcohol-diethyl ether to give N-[(4-
27.8 g of ethoxycarbonyl-2-morpholinyl)methyl]phthalimide are obtained. Melting point: 3 to 115°C (2) 10.0 g of the above ethoxycarbonyl compound and 85
A mixture consisting of 2.9 g of % hydrazine hydrate and 10 ml of ethanol is heated under reflux for 10 minutes. Filter off the precipitated crystals,
Add chloroform and water to the filtrate and shake. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.8 g of the desired product as an oil. Reference Example 29 Production of 2-benzylamino-5-nitrobenzoic acid: A solution of 5 g of 2-chloro-5-nitrobenzoic acid and 15 g of benzylamine in 40 ml of ethanol was heated under reflux for 10 hours, and then the solvent was distilled off under reduced pressure. do. The residue is suspended in 100 ml of water and made weakly acidic (pH about 4) with acetic acid. Stir at room temperature for 1 hour and filter the precipitated crystals to obtain the desired product 4.8.
get g. @Point 23B to 248°C (recrystallized from ethanol) Reference Example 30 Production of 2-hexylamino-5-nitrobenzoic acid: React in the same manner as in Reference Example 29 using hexylamine instead of benzylamine in Reference Example 29.・Process and obtain the desired object. Melting point 101~! 63°C (recrystallized from diimpropyl ether-hexane) Reference Example 31 Production of 2-acetylamino-4-dimethylamino-5-nitrobenzoic acid: 2-acetylamino-4-chloro-5-nitrobenzoic f
i11.3g, 40% dimethylamine aqueous solution 4011
A mixture of 100 parts and 1 part ethanol was heated under reflux for 5 hours, and then concentrated under reduced pressure. Add 100 parts of water to the residue, make it weakly acidic (pH about 4) with acetic acid, and collect the precipitated crystals by filtration to obtain 8.6 g of the desired product. Melting point: 230-255°C (recrystallized from ethanol) Reference Example 32 Production of 2-amino-4-9methylamino-5-nitrobenzoic acid: 8.5 g of 2-acetylamino-4-dimethylamino-5-nitrobenzoic acid, A mixture consisting of 201 cm of +C1 hydrochloric acid and 80 cm of water was stirred for 30 minutes at 1°C. After cooling, 5 g of sodium hydroxide was added to the reaction solution, and then a 10% aqueous sodium hydroxide solution was added until a homogeneous solution was obtained. Make it weakly acidic (pH about 4) with acetic acid and take 4 precipitated crystals to obtain the desired product number, 8 g. Melting point: 240-250°C (recrystallized from methanol) Reference Example 33 2-Amino-4-methylamino-5 -Production of nitrobenzoic acid: 2-acetylamino-4-chloro o-5-nitrobenzoic W
A mixture of IilOg and 40% monomethylamine aqueous solution 60- is stirred at 80°C for 10 hours. The reaction solution was heated under reduced pressure for 15 minutes.
After condensation, 40% monomethylamine aqueous solution 1001 was added to the residue, and the mixture was further stirred at 80° C. for 20 hours. After cooling, water 501
1 was added, the mixture was made weakly acidic (pH approximately 4) with acetic acid, and 4 precipitated crystals were taken to obtain 7.6 g of the desired product. EA point 200-272℃ (recrystallized from acetonitrile)
Reference Example 34 Production of 2-acetylamino/-4-chloro-5-dimethylaminosulfonylbenzoic acid: (+) Gradually add 8.5 g of 2-acetylamino-4-riaa benzoic f @ 25 g of chlorsulfone at room temperature. and then slowly increase the temperature to 150°C, 4.5
Heat for an hour. After cooling, slowly pour the reaction solution into water.
Three aliquots of the precipitated crystals were washed with water and then dried to obtain 4.5 g of 2-acetylamino-4-chloro[10-sulfonylbenzoic acid]. C) A 30% dimethylamine aqueous solution 301 is added to a solution of 4.5 g of tetrahydrofuran 50w+lfJ containing 5-ri-rjO sulfonyl compound while cooling with water, and the mixture is stirred at the same temperature for 1 hour. Add 100 x 1 of water to the reaction solution, make it acidic with concentrated hydrochloric acid,
The precipitated crystals are collected by filtration, thoroughly washed with water, and then dried to obtain 3.9 g of the desired product. Reference Example 35 Production of 2-amino-4-di0o-5-dimethylaminosulfonylbenzoic acid: Iθ% salt of 3.9 g of 2-acetylamino-4-chloro-5-dimethylaminosulfonylbenzoic acidffi+001
The suspension is heated to reflux for 4 hours. After removing water under reduced pressure,
The pH is adjusted to 5 with a 20% aqueous potassium carbonate solution, and the precipitated crystals are idI&, washed with water, and then dried to obtain 2.8 g of the desired product. Reference Example 36 Production of 2-amino/-5-poumo-3-nitrobenzoic acid: To a solution of 5.0 g of 3-nitroanthranilic acid in 20 ml of dimethylformamide, 5.0 g of N-promosucci/imide was added.
Add 5g and leave at room temperature overnight. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration, thoroughly washed with water, and then dried to obtain 6.5 g of the desired product. Melting point 206-213°C Reference Example 37 Tzudimethylami/-6-nitro-2-phenyl-4H
Production of -3,1-benzoxazin-4-one: 2-ami/-4-dimethylamino-5-nitrobenzoin #
3. After adding 5.1 g of be7zoyl chloride to a solution of Og in pyridine 301 at room temperature, it was heated to 21+ at 80-100'C.
! ! Stir for a while. Pour the reaction solution into ice water, make it weakly acidic (pH about 0) with acetic acid, collect the precipitated crystals, and recrystallize from acetonitrile to obtain 3.7 g of the desired product. Melting point 178-179°C Reference Examples 38-46 Reaction and reaction were carried out in the same manner as in Reference Example 37 using the corresponding raw material compounds.
Processing yields the compounds shown in Table 2. (The following is a blank space) Table 2 4-Amino-5-chloro-2-methquine-N-(2-morpholinylmethyl 4-amino-5-chloro-N- produced according to the method α described in Example 2 below) (4-ethoxycarbonyl-
2-morpholinyl)methyl]-2-methoxype/zamide 0.1 g, potassium hydroxide lO. A mixture of 1 g and 801 g of inpropyl alcohol is heated under reflux for 3 hours with stirring. The tB medium is distilled off under reduced pressure, and chloroform and water are added to the residue, which is then shaken. After washing the organic layer with saturated brine and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
1.4 g of the target product was obtained. Melting point 101-162
°C Reference Example 48 Production of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-hydroxybenzamide: (+)2-aminomethyl-4-benzylmorpholif [1
．． 4-amino-5-chloro-2-methoxybenzoic acid in a solution of 0 g of methylene chloride 601! IIO. O g 1 then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride e. o g and stirred at room temperature for 3 hours. The reaction solution is washed successively with water, aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified from a7ton-toluene to give 4-amino-N-[(4-benzyl-2
8.6 g of -morpholinyl)methyl]-5-chloro-2-methoxybenzamide are obtained. Melting point 148-150℃■
To a suspension of 0.52 g of 60% sodium hydride in dimethylformamide 201, add elas/thiol 0,81 under water cooling.
Add 51g of dimethylformamide solution and reduce to 0 at room temperature.
．． Stir for 5 hours. 4-Amino-N-[(
Add 3.4 g of 4-be/gi-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide, and
Stir for 1 hour at °C. After 6 hours, the solvent is distilled off under reduced pressure. Water is added to the residue, washed with chloroform, and then neutralized with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water, and then recrystallized from isopropyl alcohol to obtain 2.3 g of the desired monohydrate. Melting point 153-155°C Reference Example 49 4-Amino-5-chlorocj-2-methoxy-N-[[:
4-[3-(4-nitrophenoxy)propyl]-2
-Production of morpholinyl]methyl]benzamide: Instead of 2-aminomethyl-4-benzylmorpholine in Reference Example 4g (1), 2-amitumedel-4-
[3-(4-nitrophenoxy)propyl 1 Using morpholine, react and treat in the same manner as in Reference Example 48(1),
Obtain the target product 1 15 EtOll. Melting point 149-153°C (recrystallized from ethanol) Example I N-[(/l-benzyl-2-morpholinyl)medyl]
-6-Bromo-2,3-dimethoxybenzamide production: To 301 parts of chloroform, 1.5 g of 6-bromo-2,3-dimethoxybenzoic acid, 1.5 g of thionyl chloride. Add Og and 1 drop of dimethylformamide, and heat to reflux for 1 hour while stirring. After chloroform was distilled off under reduced pressure, 201 g of toluene was added and the mixture was further concentrated under reduced pressure. The residue was dissolved in chloroform 201, and triethylamine 81 was added thereto, and then 2-aminomethyl-4-benzylmorpholif 1ITB solution was added dropwise at room temperature. After stirring the reaction solution at room temperature overnight, water, aqueous sodium hydroxide solution, t! Wash with Japanese saline solution and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.1 g of the target product as an oil. Mass Spect/L# m/z: 448 (M”
) Example 2 Preparation of 4-7mino-5-chloro-N-[(4-ethoxycarbonyl-2-morpholinyl)methyl]-2-methoxybenzamide: Chlorination of 5.8 g of 2-7minomethyl-4-ethoxycarbonylmorpholine 4 amino-5 in 100ml methylene solution
-Chloro-2-methoxybenzoic acid 5.021 then 1-
Add 5.2 g of ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and stir at room temperature for 4 hours. The reaction solution is washed successively with water, an aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the residue is dissolved in chloroform, and column chromatography is performed using 80 g of silica gel. The chloroform eluate was discarded, 10% of the 10% 0% methanol fume was collected, and the Li1 medium was distilled off to obtain 7.5 g of the target product in the form of an oil. Dissolve this free base in ethanol and add 1.9 g of oxalic acid.
Add an ethanol solution to reduce the volume to about 10ml, and then add diethyl ether. Six precipitated crystals are collected to obtain the target oxalate. Melting point! 40-151°C Examples 3-65 The corresponding raw r4 compounds were reacted and treated in the same manner as in Examples 1 and 2 to obtain the compounds shown in Tables 3-5. Table 3 Table (continued) Table 5 Example 66 Preparation of 4-amino N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-(3-phthalimidopropoxy) be/zamide: 4-amino /-N
-[(4-benzyl-2-morpholinyl)methyl]-5
-2.0 g of chloro-2-hydroxybenzamide IN
Dissolve in 20-1 aqueous sodium hydroxide solution, and add 1.7 g of tetrabutyl ammodium bromide while stirring. Subsequently, 20 ml of methylene chloride and 1.7 g of 3-phthalimidopropyl bromide were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution is concentrated under reduced pressure, ethyl acetate is added to the residue, washed with water and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with 5% methanol-chloroform to obtain 2.2 g of oil-wetted product. This was dissolved in ethanol 201, 0.6 g of fumaric acid was added, and the mixture was stirred for a while. The precipitated crystals are collected by sigma and recrystallized from inpropyl alcohol to obtain 2.1 g of the target heptamarate 1/2 hydrate. Melting point 139-143°C Example 67 Preparation of 4-amino-N-[(4-benzyl-2-mol:1.linyl)methylcola-chloro-2-[(2-methoxyethoxy)methoxy]benzamide: Example In place of 3-phthalimidopropyl bromide in 6G, (2-methoxyethoxy)methyl chloride was used, and the reaction and treatment were carried out in the same manner as in Example 6G to obtain the desired product 2.
7 malate salt is obtained. Melting point 153-156°C (recrystallized from isopropyl alcohol) Example 68 Preparation of 5-[N-(4-benzyl-2-morpholinyl)methyl]carbamoyl-6-medoxy-111-be/citriazole: in Example 2 5-carboxy-6 instead of 4-amino/-5-chloro-2-methynebenzoic acid and 2-aminomethyl-4-ethquincarbonylmorpholine, respectively.
-Medoxy 11- Using 1-benzotriazole, 2-aminomethyl-4-benzyl mole; and phosphorus, the reaction and treatment are carried out in the same manner as in the first paragraph of Example 2 to obtain the desired product. Melting point 145-147°C (recrystallized from ethyl acetate-acetone) Example 69 2-Benzoylamino-N-[(4-benzyl-2-
Preparation of Ni-dimethylamino-6-nitro-2-phenyl-4H
-3,1-benzoxazin-4-one 3.3 g, 2-
A solution of 2.2 g of aminomethyl-4-benzylmorpholif in tetrahydrofuran 601 is heated under reflux for 4 hours. After distilling off the solvent under reduced pressure, the residue is subjected to silica gel column chromatography. Elute with 2% methanol-chloroform, and evaporate the solvent to obtain 4.5 g of the desired product. Melting point: 161-104°C (recrystallized from ethanol) Examples 70-78 Reaction and reaction were carried out in the same manner as in Example 69 using the corresponding raw material compounds.
Processing yields the compounds shown in Table 6. Table 6 1) m/z in mass spectrum (M”) (same below) Example 79 N-[(4-benzyl-2-morpholinyl)methylgo2-methylamino-5-dimethylami/suk +t,
Preparation of Nylbenzamide: N-[(4-benzyl-2-morpholinyl)methyl]
-To a solution of 1.0 g of -5-dimethylaminosulfonyl-2-fluorobenzamide in 10 parts of ethanol, 1 part of a 30% methylamine ethanol solution was added and heated for 48 hours.
Flow. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 0.6 g of the desired product. Melting point 145-140°C Examples 80-81 Reaction and reaction were carried out in the same manner as in Example 79 using the corresponding raw material compounds.
Processing yields the compounds shown in Table 7. (Leaving space below) Table 7 Production of 5-ami/-2-be/siyalamino-N-[(4-be/zi-2-morpholinyl)methyl]-4-dimethylaminobenzamide: 2-beacylamino-N-[( 4-Benzyl-2-
morpholinyl)methyl]-4-dimethylamine-5-nitrobenzamide and 350 ml of methanol suspension of salt fi15m+, add stannous chloride dihydrate 5
g and stirred at room temperature for l 111 hours. Add 2 parts of water to the reaction solution
Add 0.00 liters of irises, make alkaline with 10% aqueous sodium hydroxide solution, and then extract with chloroform. After drying the chloroform layer, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with 2% methanol-chloroform, and the solvent was distilled off to obtain 1.9 g of the target product in powder form. Mass spectrum m/z: 487 (M”) Example 83 5-Benzoylamino-N-[(4-benzyl-2-
Preparation of N-[(4-benzyl-2-morpholinyl)methyl]-2-dimethylaminobenzamide: N-[(4-benzyl-2-morpholinyl)methyl]
-2-dimethylamino-5-nitrobenzamide 1.1
A mixture of 5% palladium on carbon and 100 ml of methanol is hydrogenated in a room at room temperature and rt pressure using 100 ml of 5% palladium on carbon as a catalyst. After the calculated amount of hydrogen has been absorbed, the catalyst is removed and the filtrate is concentrated under reduced pressure. The residue was dissolved in chloroform 2011, 0.5 g of benzoyl chloride was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is washed with dilute aqueous sodium hydroxide solution, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 2% methanol-chloroform, and the solvent was distilled off to obtain 0.8 g of the desired product in powder form. Mass spectrum m/z: 472 (M”
) Example 84 5-acetylamino-2-benzoylamino-N-[
Preparation of (4-benzyl-2-morpholinyl)methyl-coi-dimethylaminobenzamide: 5-amino-2-benzoylamino-N-[(4-benzyl-2-morpholinyl)methyl]-4-dimethylaminobe/zamide 0
．． 6g and l of acid anhydride! ! After leaving the pyridine 51 solution of 211 at room temperature overnight, add 100 ml of water and make it weakly alkaline (1)) (approximately 8) with acetic acid. The aqueous layer is decanted, the residual oil-wetted material is extracted with chloroform, and the chloroform layer is dried and then condensed under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 2% methanol-chloroform, and the solvent was distilled off to obtain the target product in powder form.
get g. Mass spectrum m/z: 529 (M
) Example 85 Preparation of 4-[N-[(4-benzyl-2-morpholinyl)methyl]carbamoyl]-2,3-dihydrobenzimidazol-2-one: 2-Amino-N-[(4-benzyl 1.7 g of stannous chloride was added to a methanol IOm+ solution of 0.9 g of -2-morpholinyl)methyl]-3-nitropenzamide under water cooling.
After dropping 113 ml of a solution of salt, the mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was made alkaline by adding an aqueous sodium hydroxide solution, extracted with chloroform, and dried over anhydrous magnesium sulfate for 92 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with anhydrous tetrahydrochloride.
1 and N,N'-carbonyldiimidazole 0.
Add 5g and leave at room temperature overnight. The solvent was distilled off under pressure, and the residue was dissolved in chloroform and subjected to column chromatography on silica gel. Elute with 2% chloroform-methanol, and evaporate the solvent to obtain the desired product in powder form. Mass spectrum m/z: 308 (M”) Example 86 4-Amino-N-[[4-(4-carboxybenzyl)
-2-morpholinyl]methyl]-5-chloro-2-methoxybenzamide production: 4-ami/-5-chloro-2
-Methoxy-N-(2-morpholinylmethyl)benzamide 3.8 g. 2.7 g of 4-bromomethylbenzoic acid, Ig of potassium iodide, 18 g of anhydrous potassium carbonate, and methyl ethyl) 7
Heat to reflux with 80 ml of dimethylformamide for 1 hour. Insoluble matter is filtered, dissolved in water, and acidified with concentrated hydrochloric acid to precipitate crystals. This is collected by filtration and recrystallized from ethanol to obtain 2.0 g of hydrochloride monohydrate of the target product. Melting point 240
~242°C Example 87 4-Amino-5-chloro-N- [[- [3-(2.
Production of 3-dihydrobenzimidazol-2-one-1-yl)propyl]-2-morpholinyl]medyl]-2-methoxybenzamide = 4-amino-5-chloro-2
-Methoxy-N-(2-morpholinylmethyl)benzamide 3.8 g. 2.7 g of 1-(3-chloropropyl)-2.3-dihydrobenzimidazol-2-one, 1 g of potassium iodide, 18 g of anhydrous potassium carbonate, and 8 g of methyl ethyl ketone.
01 and dimethylformamide were heated under reflux for 21 hours. Insoluble matters were removed by filtration, and the filtrate was vacuumed.
tJ shrinks. Add chloroform and water to the residue and shake.
The remaining organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel 5.
Subject to 0 g column chromatography. lO% meta/
-Collect the chloroform eluate and remove the solvent under reduced pressure to obtain the desired product. This is treated with an ethanolic solution of oxalic acid to form an oxalate, and recrystallized from methanol to obtain the target 2-oxalate 1/2 MeOl-1. Melting point 191~! 95°C Example 88 4-Amino-N- [[4-[3-(4-aminophenoxy)probyl-co-2-morpholinyl]methyl]
Production of -5-chloro-2-methoxybenzamide: 4-amino-5-chloro-3-methoxy-N- [ [4
- [3- (4-nitrophenoxy)propyl]-2
-morpholinyl]methyl]benzamide・1 15 E
A mixture of 1.7 g of tO)1 and 50 g of ethanol is hydrogenated at room temperature and normal pressure using 0.3 g of platinum oxide as a catalyst. After absorbing the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure to a concentration of about 10. To this residual solution, add a 51% solution of citric acid in ethanol, concentrate again to about 101%, and then add diethyl ether. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain the target product, oxalate 3/2 EtOH 1/2 hydrate (0.8
get g. Melting point 212-218°C Example 89 4-Amino-2-(3-7minoproboxy)-N-[(
Preparation of 4-be/gi-2-morpholinyl)methyl]-5-chlorobenzamide: 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloroI=1-
2-(3-phthalimidopropoxy)benzamide 1
．． Add 0.22 g of 85% hydrazine hydrate to 2 g of 30 x 1 solution of ethanol, and heat under reflux for 2 hours while stirring. The precipitated crystals were filtered off, chloroform was added to the filtrate,
water. After washing with saturated saline, drying with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the obtained oil is crystallized with ethyl acetate to obtain 0.7 g of the monohydrate of the target product. Melting point 177-179°C Example 90 Preparation of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-2-carboxymethoxy-5-chlorobenzamide: Preparation of 3-phthalimidopropyl bromide in Example 6B Instead, bromoacetic acid ethyl ester was used and reacted and treated in the same manner as in the first paragraph of Example 66 to obtain oil-wetted 4
-Amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-ethoxycarbonylmethoxybenzamide is obtained. In a solution of 0.7 g of this product in ethanol 1511, IN
Add 4.51ml of aqueous sodium hydroxide solution and heat under reflux for 1 hour. Ethanol was distilled off, and the remaining solution was neutralized with 10% hydrochloric acid and then concentrated to dryness. The residue was dissolved in water-ethanol (1:
Recrystallize from 1) to obtain 0.3 g of quarter hydrate of the target product. Melting point 252-255℃ Patent applicant Dainippon Pharmaceutical Co., Ltd.

Claims (6)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R is a lower alkoxycarbonyl group, a cycloalkyl group, a lower alkyl group having a substituent (the substituent is a di-lower alkylamino group, a cycloalkyl group) group, cycloalkenyl group, furyl group, thienyl group, or benzisoxazolyl group), lower alkenyl group, lower alkynyl group, phenyl (lower) alkenyl group, lower alkylene group) or -T-(W)_p-R_6 (R_6, T, W and p are as defined below), R_1 is a hydrogen atom, Halogen atom, hydroxy group, lower alkoxy group, lower alkoxy group interrupted by an oxygen atom, lower alkoxy group having a substituent (the substituent is a carboxyl group, amino group or phthalimide group), lower alkylthio group, nitro group , amino group, ▲numerical formula, chemical formula, table, etc.▼ (R_7 means a hydrogen atom or a lower alkyl group, R_8 means a lower alkyl group, a cycloalkyl group,
(means a phenyl (lower) alkyl group) or an acylamino group, and R_2 means a hydrogen atom, a halogen atom, a lower alkoxy group, or a nitro group, or R_1 and R_2 together represent a ureylene group. A group may be formed, and R_3 is a hydrogen atom, a halogen atom, a lower alkoxy group,
means an amino group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, or nitro group, R_4 is a hydrogen atom, a halogen atom, a lower alkoxy group,
It means a nitro group, an amino group, a di-lower alkylamino group, a lower alkanoylamino group, a sulfamoyl group or a di-lower alkylsulfamoyl group, or R_3 and R_4 taken together -NH-N=N
A group represented by - may be formed, and R_5 means a hydrogen atom, a halogen atom, or a lower alkoxy group, or any two adjacent of R_1, R_2, R_3, R_4 and R_5 are combined together. may form a lower alkylenedioxy group, R_6 is a phenyl group, a substituted phenyl group (the substituent is 1 to 3 atoms selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, and an amino group) or a diphenylmethyl group, X means a lower alkylene group, T means a single bond or a lower alkylene group, W means an oxygen atom or an imino group, p is 0 or 1 means. However, (i) R_1, R_2, R_3, R_4 and R_
At least two of 5 represent atoms or groups other than hydrogen atoms, (ii) when T is a single bond, p means 0, (iii) R_1 is a hydroxy group or lower alkoxy group, and R_3 is an amino group, a di-lower alkylamino group, or a lower alkanoylamino group, R_4 is a halogen atom, and R
When _2 and R_5 are hydrogen atoms, R is -T'-(W'
)_p-R_6' (P means the same as above, R_
6' means a phenyl group or a halogenophenyl group, T
' means a lower alkylene group, W' means an oxygen atom). ] A compound represented by these and its physiologically acceptable acid addition salts. (2) R is a benzyl group, R_1, R_2, R_3
, R_4 and R_5 together form a C_1 to C_3 alkylene dioxy group, the remaining three are hydrogen atoms, and X is a methylene group. Claim 1 Compounds and physiologically acceptable acid addition salts thereof. (3) R is a benzyl group, and R_1 is C_1 to C_4
The compound according to claim 1, which is an alkoxy group or a C_1-C_4 alkylthio group, R_4 is a sulfamoyl group, R_2, R_3 and R_5 are hydrogen atoms, and X is a methylene group, and its physiological Acceptable acid addition salts. (4) R is a benzyl group, and R_1 is an amino group or C
The compound according to claim 1, wherein _1 to C_3 is an alkylamino group, R_3 is a chlorine atom or a nitro group, R_2, R_4 and R_5 are a hydrogen atom, and X is a methylene group, and its physiological Acid addition salts acceptable for. (5) R is a benzyl group, and R_1 is an amino group or C
_1-C_3 is an alkylamino group, R_4 is a nitro group, sulfamoyl group or di(C_1-C_2 alkyl)sulfamoyl group, R_2, R_3 and R_5
2. The compound according to claim 1, wherein is a hydrogen atom and X is a methylene group, and physiologically acceptable acid addition salts thereof. (6) R is a benzyl group, R_1 is an amino group or C
_1-C_3 alkylamino group, R_3 is a chlorine atom or C_1-C_3 alkylamino group, R_4
The compound according to claim 1, and its physiologically acceptable acid addition salts, wherein is a nitro group, R_2 and R_5 are hydrogen atoms, and X is a methylene group.