KR840002235B1 - Process for preparing carboxylic acid derivatives - Google Patents

Abstract

2-Amino benzoic acid derivative(I) and its salts are prepared from cpmpd.(II) by means of conversion of diazonium salt with sulfuric acid or copper, where R5 = F, Cl, Br, cyano, or hydroxy gp.; R6,R7 = N-alkyl-cyclohexyl amino gp., N-alkylphenyl amino, Nalkyl-benzyl amino, C6-C12 cyclic alkylene amino, C1-C4 alkyl, C1-C3 alkoxy, piperydino, morpholine, thiomorpholino, piperazino, aza-bicycloalkyl, C6-C9 1,4-dioxa-8-aza-spiro-alkane, pyrolidino, or tetrahydro- pyridino gp.; and W = carboxy, aminocarbonyl, cyano, or C2-C4 alkoxy carbonyl.

Description

Method for preparing 2-amino-benzoic acid derivative

The present invention relates to a process for the preparation of a novel 2-amino-benzoic acid derivative of the general formula (I) and an organic or inorganic acid thereof, and, if W is a carboxy group, a salt with a base, wherein the agent of the novel 2-amino-benzoic acid derivative and // Or use as a manufacturing intermediate.

The new compounds of formula (I) show pharmacological properties, ie affect intermediate metabolism. Therefore, general formula (I) compound has a fat lowering activity.

Wherein R ₅ represents fluorine, chlorine or bromine, cyano or hydroxy group,

R ₆ and R ₇ together with the nitrogen to which they are attached N-alkyl-cyclohexylamino group having 2 to 4 alkyl alkyl, N-alkyl-phenylamino or N-alkyl-benzylamino group having 1 to 3 carbon atoms of alkyl, Piperidino substituted with unbranched alkyleneimino group having 6 to 12 carbon atoms, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 4 carbon atoms or phenyl group A group, an alkyl group having 1 to 3 carbon atoms, a piperidino group substituted with two, three or four, a morpholino or thiomorphlino group optionally substituted with one or two alkyl groups having 1 to 3 carbon atoms, 1 to 3 carbon atoms An alkyl group of 2 to 4 carbon atoms, alkoxycarbonyl group of 2 to 4 carbon atoms, phenyl, halogenphenyl, pyridyl, benzyl or furoyl group substituted with a piperazino group, saturated or partially unsaturated of 7 to 10 carbon atoms Keep it up -A bicycloalkyl group, a C6-C9 1, 4-dioxa-8-aza-spiro-alkane group, a pyrrolidino or a tetrahydro-pyridino group,

W is carboxy, aminocarbonyl, cyano or alkoxycarbonyl having 2 to 4 carbon atoms, respectively.

Thus, among the references to defining R ₅ to R ₇ , W includes:

R ₅ is fluorine, chlorine or fluorine, cyano, hydroxy group,

R ₆ and R ₇ together with the nitrogen to which they are attached N-methyl-phenylamino, N-ethyl-phenylamino, N-isopropyl-phenylamino, N-methyl-benzylamino, N-ethyl-benzyl-amino, N -Propyl-benzylamino, N-ethyl-cyclohexylamino, N-propyl-cyclohexylamino, N-isopropyl-cyclohexylamino, N-butyl-cyclohexylamino, pyrrolidino, hepsa methyleneimino, heptamethylene Imino, octamethyleneimino, nonamethyleneimino, decamethyleneimino, undecamethyleneimino, dodecamethyleneimino, methyl-pyrrididino, ethyl-piperidino, propyl-piperidino, isopropyl Piperidino, butyl-piperidino, isobutyl-piperidino, tert-butyl-piperidino, methoxy-piperidino, ethoxy-piperidino, propoxy-piperidino, isopro Foxy-piperidino, methoxycarbonyl-piperidino, ethoxycarbonyl-piperidino, propoxycarbonyl-pipe Lidino, Isopropoxycarbonyl-piperidino, dimethyl-piperidino, trimethyl-piperidino, tetramethyl-piperidino, diethyl-piperidino, dipropyl-piperidino, tetraethyl-pipe Ferridino, methyl-ethyl-piperidino, ethyl-propyl-piperidino, morpholino, methyl-morpholino, ethyl-morpholino, propyl-morpholino, dimethyl-morpholino, diethyl- Morpholino, thiomorpholino, methyl-thiomorpholino, propyl-thiomorpholino, dimethyl-thiomorpholino, N-methyl-piperazino, N-ethyl-piperazino, N-propyl- Piperazino, N-methoxycarbonyl-piperazino, N-ethoxycarbonyl-piperazino, N-iso-propoxycarbonyl-piperazino, N-phenyl-piperazino, N-fluor Rho-phenyl-piperazino, N-chlorophenyl-piperazino, N-bromophenyl-piperazino, N-pyridyl-piperazino, N-benzyl-piperazino, N-furoyl-pi Perrazino, Octa Idro-isoindol-2-yl, tetrahydro-isoquinolin-2-yl, octahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl, tetrahydro-3-benzazin-3- Yl, tecahydro-3-benzazin-3-yl, 3-aza-bicyclo-nonan-3-yl, 1,4, dioxa-8-aza-spiro [4,5] decan-8-yl , 1,4-dioxa-8-aza-spiro [4,6] undecane-8-yl or tetrahydro-pyridino group,

W is carboxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or cyano group.

However, the preferred compound of formula (I) is that R ₅ is chlorine, bromine, hydroxy, cyano group,

R ₆ and R ₇ together with the nitrogen to which they are attached are N-alkyl-cyclohexylamino group having 2 to 4 carbon atoms, unbranched alkyleneimino group having 6 to 12 carbon atoms, and having 1 to 4 carbon atoms. Piperidino group substituted with 4-position by alkyl group, phenyl, methoxy or ethoxy-carbonyl group, 3- and 5-position substituted piperidino group by methyl or ethyl group, 3- by methyl group And 4-position substituted with a 5-positioned tetrasubstituted piperidino group, methyl, benzyl, phenyl, chlorophenyl, pyridyl- (2)-, ethoxycarbonyl or furoyl- (2) -group Piperizino group, morpholino or thiomorpholino group optionally substituted with one or two methyl groups, pyrrolidino, tetrahydro-pyridino, N-methyl-phenylamino, N-methyl-benzylamino, 1,4 -Dioxa-8-aza-spiro [4,5] decan-8-yl, 1,4-dioxa-8-aza-spiro [4,6] undecane-8-yl, 3-aza-bissai Rho-nonan-3-yl, 1,2,4,5, -tetrahydro-3-benz azepin-3-yl, decahydro-3-benzazin-3-yl, 1,2,3,4 , -Tetrahydro-isoquinolin-2-yl, 1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl or octahydro It is preferable that the compound is an isoindol-2-yl group and W is a carboxy, aminocarbonyl, methoxycarbonyl or cyano group, and a salt thereof, especially when R ₅ is present at the 5-position of the benzene ring.

Particularly preferred compounds of formula (I) are

R ₅ is chlorine or bromine in the 5-position

R ₆ and R ₇ together with the nitrogen to which they are attached are non-branched alkyleneimino groups having 6 to 8 carbon atoms, 1,4-dioxa-8-aza-spiro [4,5] decane-8-yl , 1,4-dioxa-8-aza-spiro [4,6] undecane-8-yl, decahydro-3H-3-benzazin-3-yl or 4-methoxy-piperidino group ,

W is a physiologically toxic acid addition salt with a compound that is a carboxy group and its organic or inorganic acid, or a salt with a base when W is a carboxy group.

According to the present invention a novel compound is obtained by the following method. The compound of formula (II) is reacted with nitrite and the diazonium salt obtained is optionally heated in the presence of copper or the corresponding copper (I) salt.

The compound of formula (II) is converted into a diazonium salt at a low temperature of -10 to 5 ° C. with nitrite or nitrite ester such as sodium nitrite in a suitable solvent such as water / hydrochloric acid, methanol / hydrochloric acid or dioxane / hydrochloric acid.

The corresponding diazonium salts obtained are the same as fluoroborate, hydrosulfate in sulfuric acid, copper or copper (I) / hydrochloric acid as chlorides, copper bromide (I) / bromic acid or trisodium-cyanide (I) It is heated to 15 to 90 ℃ in pH 7 in the presence of a copper (I) salt to convert to the corresponding compound.

The compound of formula (I) wherein W is a cyano, alkoxycarbonyl or aminocarbonyl group obtained according to the invention can be converted by hydrolysis to the corresponding compound of formula (I) wherein W is a carboxy group.

Hydrolysis is preferably carried out at high temperatures such as boiling points of the reactants in the presence of acids such as hydrochloric acid or sulfuric acid or bases such as sodium hydroxide and potassium hydroxide in water miscible solvents such as methanol, ethanol, dioxane, water / ethanol or water / tetrahydrofuran.

The compounds obtained of formula (I) can also be converted to their physiologically toxic salts by inorganic or organic acids or bases if W represents a carboxy group. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and suitable bases include sodium hydroxide, potassium hydroxide or cyclohexylamine.

Compounds of formula (II) used as starting materials are known in the literature and are each obtained according to known methods. For example, the compound of general formula (II) is reacted with 2-chloro- or 2-bromo-nitro carboxylic acid or a derivative thereof with the corresponding amine, and the nitro group of the obtained 2-amino compound is catalytically activated hydrogen, generator hydrogen Obtained by reduction with a metal or metal salt.

As mentioned above, the novel compounds of general formula (I) exhibit pharmacologically effective properties, in particular affecting intermediate metabolism. General formula (I) compound especially shows a fat lowering activity. Compounds of formula (I) are useful intermediates in the preparation of novel compounds with hypoglycemic activity.

Fat lowering activity was tested for the following compounds.

A = 5-Chloro-2- (1,4-dioxa-8-aza-spiro [4,5-] deca-8-yl) -benzoic acid

B = 2- (Decahydro-3-benzazine) -5-chloro-benzoic acid

C = 2- (Decahydro-3-benzoazine) -5-bromo-benzoic acid

D = 5-Chloro-2- (4-methoxy-piperidino) -benzoic acid

1.fat lowering activity

Literature: p. this. Shure et al. Atherosclerosis Drug Discovery (1976), editor: poetry. this. day ; Plenium, New Ork, page 215

Young males with an average body weight of 100 g are hyperlipidemic with four days of feeding consisting of 10% coconut fat, 1.5% clesterine, 0.5% cholic acid, 0.2% clean chloride and 15% sucrose. The test compound is continuously administered for 2 days by gastrointestinal tubing in methylcellulose suspension. Animals are then starved overnight and blood is collected 5 to 24 hours after the last dose of test compound and serum is separated. Enzymatically determine the amount of cholesterol (Möllinger Mannheim test combination 187.313) and triglycerides (Möllinger Mannheim test combination 126.039) in serum. After precipitation with Ca ⁺⁺ and heparin, β-tipoproteins are measured by the turbidity method using an automatic analyzer. Percent reduction is calculated by comparison with the control group.

The following table shows the result.

Serum reduction 5 hours after the last dose of the substance, other values measured 24 hours after the last dose of the substance

2. Acute Toxicity

Acute toxicity is measured after oral administration (1% methyl cellulose suspension) using a single dose of male cancer and male rats weighing 20 to 26 g.

Observation time: 7 days minimum

The following table shows the result.

Because of the pharmacological characteristics, the compounds of formula (I) prepared according to the invention are useful for the treatment of atherosclerosis and hyperlipidemia, in particular type IIA, IIB and IV. For pharmaceutical administration, it may optionally be used in combination with other active ingredients to prepare conventional formulations such as tablets, tablets, capsules, suppositories, suspensions or solutions. The single dose of an adult is from 200 mg, preferably 5 to 50 mg, and the daily dose is 10 to 500 mg, preferably 15 to 150 mg.

The following examples illustrate the invention.

Preparation of Starting Material

Example A

2- (Decahydro-isoquinolin-2-yl) -5-nitro-benzoic acid

19 g (0.136 mole) of decahydro-isoquinoline, 27.3 g (0.136 mole) of 2-chloro-5-nitro-benzoic acid, 38.6 g of potassium carbonate are refluxed for 18 hours with stirring in 500 ml of ethanol. After distilling off the ethanol, the residue was dissolved in 800 ml of water and adjusted to pH 4 by adding 2N hydrochloric acid to obtain the reaction product in crystalline form.

Yield: 38 g (92% of theory)

Melting Point: 132-134 ° C (Isopropane)

Calculation: C63.14 H6.62 N9.20

Found: 63.02 6.48 9.38

Example B

2- (1,4-Dioxa-8-aza-spiro [4,5] decan-8-yl) -5-nitro-benzoic acid

A mixture of 20.1 g (0.1 mole) 2-chloro-5-nitro-benzoic acid, 42.9 g (0.3 mole) 1,4-dioxa-8-aza-spiro [4,5] decane was refluxed in 200 ml of ethanol Heat at temperature for 8 hours. After distilling off the solvent, the evaporated residue was dissolved in water and adjusted to pH 5.2 by adding 2N hydrochloric acid, to precipitate the product. The reaction product is then extracted with chloroform, dried over sodium sulphate and the solvent is distilled off to crystallize the compound.

Yield: 12 g (39% of theory)

Melting Point: 155 ° C (ethanol)

Calculated Value: C54.54 H5.24 N9.09

Found: 54.20 5.13 8.97

Similar to Examples A and B, the following compounds are prepared.

2- (2-Methyl-piperidino) -5-nitro-benzoic acid

Yield: 99% of theory, Melting point: 164 ° C

2- (3-Methyl-piperidino) -5-nitro-benzoic acid

Yield: 85% of theory, Melting point: 161 ° C

2- (4-Methyl-piperidino) -5-nitro-benzoic acid

Yield: 85% of theory, Melting point: 155 ° C

2- (3-Ethyl-6-methyl-piperidino) -5-nitro-benzoic acid

Yield: 76% of theory, Melting point: <20 ° C

2- (3,5-Dimethyl-piperidino) -5-nitro-benzoic acid

Yield: 65% of theory, Melting point: 172 ° C

2- (4-Methoxy-piperidino) -5-nitro-benzoic acid

Yield: 68% of theory, Melting point: 140 ° C

5-Nitro-2- (4-phenyl-piperidino) -benzoic acid

Yield: 88% of theory, Melting point: 196 ° C

2- (4-Ethoxycarbonyl-piperidino) -5-nitro-benzoic acid

Yield: 82% of theory, Melting point: 160 ° C

5-Nitro-2-thiomodolino-benzoic acid

Yield: 80% of theory, Melting point: 235 ° C

5-Nitro-2- (1,2,4,5-tetrahydro-3-benzazino) -benzoic acid

Yield: 68% of theory, Melting point: 222 ° C

5-Nitro-2- (1,2,3,4-tetrahydro-isoquinolino) -benzoic acid

Yield: 70% of theory, Melting point: 195 ° C

5-Nitro-2- (4-phenyl-piperazino) -benzoic acid

Yield: 88% of theory, Melting point: 196 ° C

5-Nitro-2- (4-pyridyl- (2) -piperazino) -benzoic acid

Yield: 66% of theory, Melting point: 192 ° C

2- (Trans--3,5-dimethylpiperidino) -5-nitro-benzoic acid

Yield: 63% of theory, Melting point: 132 ° C

2- (3,3,5,5-Tetramethyl-piperidino) -5-nitro-benzoic acid

Yield: 98% of theory, Melting point: 138 ° C

2- (3,5-Dimethyl-morpholino) -5-nitro-benzoic acid

Yield: 75% of theory, Melting point: 164 ° C

2- (3,5-Dimethyl-thiomorpholino) -5-nitro-benzoic acid

Yield: 70% of theory, Melting point: 118 ° C

2- (3-Aza-bicyclo [3,2,2] nonan-3-yl) -5-nitro-benzoic acid

Yield: 72% of theory, Melting point: 221 ° C

5-Nitro-2-nonamethyleneimino-benzoic acid

Yield: 80% of theory, Melting point: 127 ° C

5-Nitro-2-decamethyleneimino-benzoic acid

Yield: 92% of theory, Melting point: 128 ° C

5-Nitro-2-undecamethyleneimino-benzoic acid

Yield: 91% of theory, Melting point: 120 ° C

5-Nitro-2-dodecamethyleneimino-benzoic acid

Yield: 95% of theory, Melting point: 115 ° C

2- (N-Methyl-N-phenylamino) -5-nitro-benzoic acid

Yield: 10% of theory, Melting point: 115 ° C

2- (N-ethyl-cyclohexylamino) -5-nitro-benzoic acid

Yield: 78% of theory, Melting point: 74 ° C

2- (N-butyl-N-cyclohexylamino) -5-nitro-benzoic acid

Yield: 84% of theory, Melting point: 56 ° C

2- (N-cyclohexyl-N-isobutylamino) -5-nitro-benzoic acid

Yield: 63% of theory, Melting Point: <20 ° C

2- (Decahydro-3-benzeazin-3-yl) -5-nitro-benzoic acid

Yield: 98% of theory, Melting point: <20 ° C

2- (Otahydro-isoindol-2-yl) -5-nitro-benzoic acid

Yield: 80% of theory, Melting point: 128 ° C

2- (4-Isopropyl-piperidino) -5-nitro-benzoic acid

Yield: 79% of theory, Melting point: 142 ° C

2- (4-tert-Butyl-piperidino) -5-nitro-benzoic acid

Yield: 57% of theory, Melting point: 136 ° C

2- (1,4-Dioxa-8-aza-spiro [4,6] undecane-8-yl) -5-nitro-benzoic acid

Yield: 75% of theory, Melting point: 135 ° C

2,4-Dipiperidino-5-nitro-benzoic acid

Yield: 31% of theory, Melting point: 152 ° C

4-Chloro-2-piperidino-5-nitro-benzoic acid

Yield: 18% of theory, Melting point: 133 ° C

5-Nitro-2- (1,2,3,6-tetrahydro-pyridino) -benzoic acid

Yield: 58% of theory, Melting point: 215 ° C

2- (N-Methyl-N-benzylamino) -5-nitro-benzoic acid

Yield: 93% of theory, Melting point: 123 to 126 ° C

2- [4- (4-Chlorophenyl) -piperazino] -5-nitro-benzoic acid-hydrochloride

Yield: 71.5% of theory, Melting point: 225 to 227 ° C (decomposition)

2- (4-Caethoxy-piperazino) -5-nitro-benzoic acid

Yield: 23.1% of theory, Melting point: 155 to 156 ° C

2- [4- (2-Furoyl) -piperazino] -5-nitro-benzoic acid

Yield: 64.8% of theory, Melting point: 200-205 ° C

2- (4-Benzyl-piperazino) -5-nitro-benzoic acid-hydrochloride

Yield: 86.6% of theory, Melting point: 142-145 ° C

Example C

2-hexamethyleneimino-5-nitro-benzoate nitrile

A mixture of 18.4 g (0.11 mol) of 2-chloro-5-nitro-benzoic acid nitrile and 22.4 g (0.21 mol) of hexamethyleneimine is refluxed in 250 ml of ethanol for 4 hours. After cooling, 500 ml of water was added to precipitate the product into the oil phase. The precipitate is dissolved in chloroform, dried over sodium sulfate and the chloroform is distilled off and the evaporation residue is recrystallized from ethanol.

Yield: 19.7 g (73% of theory)

Melting Point: 70 ℃

Calculated Value: C63.65 H6.16 N17.13

Found: 63.80 6.07 17.05

Example D

5-Amino-2- (decahydro-isoquinolin-2-yl) -benzoic acid

36 g (0.118 mole) of 2- (decahydro-isoquinolin-2-yl) -5-nitrobenzoic acid is dissolved in 250 ml of dimethylformamide and 5 bar of hydrogen in the presence of 10% palladium charcoal as catalyst Hydrogenate at room temperature under pressure. After the absorption of hydrogen is complete, the catalyst is filtered off, the solvent is distilled off in vacuo and the residue is recrystallized from ethanol.

Yield: 31.2 g (96% of theory)

Melting Point: 252 ℃

Calculated Value: C70.04 H8.08 N10.20

Found: 70.09 7.85 10.12

Example E

5-Amino-2- (1,4-dioxa-8-aza-spiro [4,5] decan-8-yl) -benzoic acid

12 g (0.039 mol) of 2- (1,4-dioxa-8-aza-spiro [4,5] decane-8-yl) -5-nitro-benzoic acid as a catalyst in 100 ml of dimethyl formamide as a 10% palladium Hydrogenate at 5 bar hydrogen pressure in the presence of charcoal.

After the absorption of hydrogen is complete, the catalyst is filtered off, the solvent is distilled off and recrystallized from ethanol.

Yield: 9 g (83% of theory)

Melting Point: 209 ℃

Calculation: C60.42 H6.56 N10.07

Found: 60.18 6.58 10.12

The following compounds are prepared by analogy of Examples D and E.

5-Amino-2-pyrrolidino-benzoic acid

Yield: 79% of theory, Melting point: 208 ° C

5-Amino-2- (2-methyl-piperidino) -benzoic acid

Yield: 84% of theory, Melting point: 240 ° C

5-Amino-2- (3-methyl-piperidino) -benzoic acid

Yield: 75% of theory, Melting point: 192 ° C

5-Amino-2- (4-methyl-piperidino) -benzoic acid

Yield: 88% of theory, Melting point: 215 ° C

5-Amino-2- (3-ethyl-6-methyl-piperidino) -benzoic acid

Yield: 59% of theory, Melting point: 219 ° C

5-Amino-2- (cis-3,5-dimethyl-piperidino) -benzoic acid

Yield: 87% of theory, Melting point: 234 ° C

5-Amino-2- (4-methoxy-piperidino) -benzoic acid

Yield: 80% of theory, Melting point: 228 ° C

5-Amino-2-heptamethyleneimino-benzoic acid

Yield: 64% of theory, Melting point: 214 ° C

5-Amino-2- (4-phenyl-piperidino) -benzoic acid

Yield: 76% of theory, Melting point: 275 ℃

5-Amino-2- (4-ethoxycarbonyl-piperidino) -benzoic acid

Yield: 85% of theory, Melting point: 203 ° C

5-Amino-2-thiomorpholino-benzoic acid

Yield: 76% of theory, Melting point: 193 ° C

5-Amino-2- (1,2,4,5-tetrahydro-3-benzazino) -benzoic acid

Yield: 86% of theory, Melting point: 258 ° C

5-Amino-2- (1,2,3,4-tetrahydro-isoquinolino) -benzoic acid

Yield: 66% of theory, Melting point: 220 ° C

5-Amino-2- (4-phenyl-piperazino) -benzoic acid

Yield: 83% of theory, Melting point: 255 ° C

5-Amino-2- (4-pyridyl- (2) -piperazino) -benzoic acid

Yield: 80% of theory, Melting point: 248 ℃

5-Amino-2- (trans-3,5-dimethyl-piperidino) -benzoic acid

Yield: 89% of theory, Melting point: 156 ° C

5-Amino-2- (3, 3,5,5-tetramethyl-piperidino) -benzoic acid

Yield: 98% of theory, Melting point: <20 ° C

5-Amino-2- (3,5dimethyl-morpholino) -benzoic acid

Yield: 83% of theory, Melting point: 255 ° C

5-Amino-2- (3,5-dimethyl-thiomorpholino) -benzoic acid

Yield: 50% of theory, Melting point: 233 ° C

5-Amino-2- (3-aza-bicyclo [3,2,2] nonan-3-yl) -benzoic acid

Yield: 86% of theory, Melting point: 288 ℃

5-Amino-2-octamethyleneimino-benzoic acid

Yield: 88% of theory, Melting point: 191 ° C

5-Amino-2-nonamethyleneimino-benzoic acid

Yield: 80% of theory, Melting point: 212 ° C

5-Amino-2-decamethyleneamino-benzoic acid

Yield: 52% of theory, Melting point: 202 ° C

5-Amino-2-undecamethyleneimino-benzoic acid

Yield: 93% of theory, Melting point: 242 ° C

5-Amino-2-dodecamethyleneimino-benzoic acid

Yield: 59% of theory, Melting point: 224 ° C

5-Amino-5- (N-methyl-N-phenylamino) -benzoic acid

Yield: 47% of theory, Melting point: 184 ° C

5-Amino-2- (N-ethyl-N-cyclohexylamino) -benzoic acid

Yield: 66% of theory, Melting point: 160 ° C

5-Amino-2- (N-butyl-N-cyclohexylamino) -benzoic acid

Yield: 48% of theory Melting Point: 140 ° C

5-Amino-2- (N-cyclohexyl-N-isobutylamino) -benzoic acid

Yield: 62% of theory, Melting Point: <20 ° C

5-Amino-2- (decahydro-3-benazazin-3-yl) -benzoic acid

Yield: 54% of theory, Melting point: 204 ° C

5-Amino-2- (octahydro-phosphoindol-2-yl) -benzoic acid

Yield: 43% of theory, Melting point: 228 ° C

5-Amino-2- (4-isopropyl-piperidino) -benzoic acid

Yield: 50% of theory, Melting point: 231 ° C

5-Amino-2- (4-tert-butyl piperidino) -benzoic acid

Yield: 81% of theory, Melting point: 276 ° C

5-Amino-2- (1,4-dioxa-8-aza-spiro [4,6] undecane-8-yl) -benzoic acid

Yield: 49% of theory, Melting point: 235 ° C

5-Amino-2- (1,2,3,6-tetrahydro-pyridino) -benzoic acid

Yield: 51% of theory, Melting point: 232 ° C

5-Amino-2- (4-methyl-piperazino) -benzoic acid hydrochloride

Yield: 90% of theory, Melting Point: <20 ° C

5-Amino-2- (N-methyl-N-benzylamino) -benzoic acid

Yield: 95% of theory, Melting Point: <20 ° C

5-Amino-2- [4- (4-chloro-phenyl) -piperazino] -benzoic acid hydrochloride

Yield: 80.5% of theory, Melting point: 305 ° C (decomposition)

5-Amino-2- (4-carethoxy-piperazino) -benzoic acid

Yield: 87.5% of theory, Melting point: 195-197 ° C

5-Amino-2- [4- (2-furoyl) -piperazino] benzoic acid

Yield: 97% of theory, Melting point: 20 ° C

5-Amino-2- (4-benzyl-piperazino) -benzoic acid hydrochloride

Yield: 80% of theory, Melting point: 200-210 ° C

Preparation of the final product

Example 1

5-Chloro-2- (decahydro-isoquinolin-2-yl) -benzoic acid

10 g (0.0365 moles) of 5-amino-2 (decahydro-isoquinolin-2-yl) -benzoic acid is dissolved in 55 ml of medium concentration hydrochloric acid and 2.7 g (0.039 moles) of sodium nitrate in 10 ml of water The solution which melt | dissolved the rate was added dropwise at 0 degreeC, and diazotization is carried out. After completion of the dropwise addition, the reaction mixture is plated for 15 minutes, and the diazonium salt solution is added dropwise to a suspension of 4 g of copper powder in 40 ml of concentrated hydrochloric acid. After stirring overnight, a dark green uniform solution is obtained, diluted with 100 ml of water and extracted completely with chloroform. After drying over sodium sulphate, the chloroform evaporation residue is purified by chromatography on silica gel column using ethyl acetate / methanol (9.5: 0.5) as eluent.

Yield: 4.8 g (45% of theory)

Melting Point: 138 ℃

Calculation: C65.41, H6.85 N4.76 Cl12.06

Found: 65.51, 7.07 4.89 12.32

Example 2

5-Chloro-2- (1,4-dioxa-8-aza-spiro [4,5] decan-8-yl) -benzoic acid

8.5 g (0.031 mol) of 5-amino-2- (1,4-dioxa-8-aza-spiro [4,5] decan-8-yl) -benzoic acid is dissolved in 28 ml of dihydrochloric acid and 10 ml of water Diazolation at 0 ° C. with 2.4 g (0.034 moles) of sodium nitrite solution in water. While stirring the diazonium salt solution, it is dripped at 3 g of copper powder suspension in 3 ml of concentrated hydrochloric acid. After nitrogen production is complete, the reaction mixture is stirred for 2 hours, diluted with water and extracted with chloroform. After drying over sodium sulphate, the solvent is distilled off and the evaporation residue is warmed with petroleum ether to give 6.1 g (66% of theory) of the compound.

Melting Point: 180 ℃

Calculated Value: C56.47 H5.42 N4.71

Found: 56.11 5.37 4.83

Similar to Examples 1 and 2 to prepare the following compounds.

5-Chloro-2-pyrrolidino-benzoic acid

Yield: 30% of theory, Melting point: 164 ℃

5-Chloro-2- (2-methyl-piperidino) -benzoic acid

Yield: 74% of theory, Melting point: 124 ° C

5-Chloro-2- (3-methyl-piperidino) -benzoic acid

Yield: 47% of theory, Melting point: 165 ° C

5-Chloro-2- (4-methyl-piperidino) -benzoic acid

Yield: 52% of theory, Melting point: 107 ° C

2- (3-Ethyl-6-methyl-piperidino) -5-chloro-benzoic acid

Yield: 73% of theory, Melting Point: <20 ° C

5-Chloro-2- (cis-3,5-dimethyl-piperidino) -benzoic acid

Yield: 46% of theory, Melting point: 167 ° C

5-Chloro-2- (trans-3,5-dimethyl-piperidino) -benzoic acid

Yield: 63% of theory, Melting point: 132 ° C

5-Chloro-2- (4-methoxy-piperidino) -benzoic acid

Yield: 63% of theory, Melting point: 136 ° C

5-Chloro-2-heptamethyleneimino-benzoic acid

Yield: 58% of theory, Melting point: <20 ° C

5-Chloro-2- (4-phenyl-piperidino) -benzoic acid

Yield: 51% of theory, Melting point: 217 ° C

5-Chloro-2- (4-ethoxycarbonyl-piperidino) -benzoic acid

Yield: 97% of theory, Melting Point: <20 ° C

5-Chloro-2-hexamethyleneimino-benzoic acid

Yield: 34% of theory, Melting point: 113 ° C

5-Chloro-2-thiomorpholino-benzoic acid

Yield: 16% of theory, Melting point: 160 ° C

5-Chloro-2- (1,2,4,5-tetrahydro-3-benzazino) -benzoic acid

Yield: 59% of theory, Melting point: 174 ° C

5-Chloro-2- (1,2,3,4-tetrahydro-isoquinolino) -benzoic acid

Yield: 50% of theory, Melting point: 182 ° C

5-Chloro-2- (4-phenyl-piperazino) -benzoic acid

Yield: 42% of theory, Melting point: 154 ° C

5-Chloro-2- (4-pyridyl- (2) -piperazino) -benzoic acid

Yield: 45% of theory, Melting point: 168 ° C

5-Bromo-2- (2-methyl-piperidino) -benzoic acid

Yield: 31% of theory, Melting point: 168 ° C

5-Chloro-2- (3,3,5,5-tetramethyl-piperidino) -benzoic acid

Yield: 62% of theory, Melting Point: <20 ° C

5-Bromo-2- (4-methoxy-piperidino) -benzoic acid

Yield: 48% of theory, Melting point: 138 ° C

5-Chloro-2- (3,5-dimethylmorpholino) -benzoic acid

Yield: 50% of theory, Melting point: 174 ° C

5-Chloro-2- (3,5-dimethyl-thiomorpholino) -benzoic acid

Yield: 18% of theory, Melting point: 134 ° C

5-Bromo-2-heptamethyleneimino-benzoic acid

Yield: 15% of theory, Melting point: 104 ° C

5-Chloro-2- (3-aza-bicyclo [3,2,2] nonan-3-yl) -benzoic acid

Yield: 16% of theory, Melting point: 199 ° C

5-Chloro-2-octamethyleneimino-benzoic acid

Yield: 70% of theory, Melting point: 84 ° C

5-Chloro-2-nonamethyleneimino-benzoic acid

Yield: 30% of theory, Melting point: 78 ° C

5-Chloro-2-decamethyleneimino-benzoic acid

Yield: 65% of theory, Melting point: 70 ° C

5-Chloro-2-undecamethyleneimino-benzoic acid

Yield: 41% of theory, Melting point: 41 ° C

5-Chloro-2-dodecamethyleneimino-benzoic acid

Yield: 36% of theory, Melting point: 40 ° C

5-Chloro-2- (N-phenyl-N-methylamino) -benzoic acid

Yield: 27% of theory, Melting point: 164 ° C

2- (N-ethyl-N-cyclohexylamino) -5-chloro-benzoic acid

Yield: 24% of theory, Melting point: 152 ° C

2- (N-butyl-N-cyclohexylamino) -5-chloro-benzoic acid

Yield: 16% of theory, Melting point: 145 ° C

5-Chloro-2- (N-cyclohexyl-N-isobutylamino) -benzoic acid

Yield: 22% of theory, Melting point: 131 ° C

5-Chloro-2- (decahydro-3-benzeazin-3-yl) -benzoic acid

Yield: 70% of theory, Melting point: 153 ° C

5-Bromo-2- (decahydro-3-benzeazin-3-yl) -benzoic acid

Yield: 54% of theory, Melting point: 154 ° C

5-Chloro-2- (octahydro-isoindol-2-yl) -benzoic acid

Yield: 33% of theory, Melting point: 164 ° C

5-Bromo-2-octamethyleneimino-benzoic acid

Yield: 48% of theory, Melting point: 94 ° C

5-Chloro-2- (4-isopropyl-piperidino) -benzoic acid

Yield: 43% of theory, Melting point: 172 ° C

5-Chloro-2- (4-tert-butyl-piperidino) -benzoic acid

Yield: 35% of theory, Melting point: 161 ° C

5-Chloro-2- (1,4-dioxa-8-aza-spiro [4,6] undecane-8-yl) -benzoic acid

Yield: 42% of theory, Melting point: 163 ° C

5-Chloro-2- (1,2,3,6-tetrahydro-pyridino) -benzoic acid

Yield: 73% of theory, Melting point: 173 ° C

5-Chloro-2- (4-methyl-piperazino) -benzoic acid hydrochloride

Yield: 75% of theory, Melting point: 132 ° C (decomposition)

5-Chloro-2- (N-methyl-N-benzylamino) -benzoic acid

Yield: 18.2% of theory, Melting point: 156 to 157 ° C

5-Chloro-2- [4- (4-chloro-phenyl) -piperazino] benzoic acid

Yield: 30.5% of theory, Melting point: 228 to 230 ° C

5-Chloro-2- [4- (2-furoyl) -piperazino] benzoic acid

Yield: 33.1% of theory, Melting Point: 200-202 ° C

2- (4-Benzyl-piperazino) -5-chloro-benzoic acid hydrochloride

Yield: 42.8% of theory, Melting point: 230 to 232 ° C

Example 3

5-Chloro-2-hexamethyleneimino-benzoic acid nitrile

20 g (0.092 mole) of 5-amino-2-hexamethyleneimino-benzoic acid nitrile is dissolved in 90 ml of dihydrochloric acid and diazotized by dropwise addition of a 6.5 g (0.094 mole) sodium nitrite solution in 30 ml of water at 0 ° C. do. After the addition is completed, the reaction mixture is stirred for 15 minutes. The diazonium salt solution is stirred and dripped at the copper chloride (I) solution in concentrated hydrochloric acid heated at 70 degreeC. After nitrogen formation is complete, the reaction solution is extracted with chloroform. After drying over sodium sulfate and distilling chloroform, the evaporated residue is purified by chromatography on silica gel column (eluant: toluene).

Yield: 5 g (23% of theory)

Condensation Point: <20 ℃

Example 4

5-Chloro-2-hexamethyleneimino-benzoic acid

5 g (0.021 mol) of 5-chloro-2-hexamethyleneimino-benzoic acid nitrile is heated to 170 ° C. in 32 g of potassium hydroxide solution and 20 ml of water for 8 hours. When the cooled melt is dissolved in water and acidified to pH 5, the amide precipitates quantitatively. Hydrolysis with dihydrochloric acid yields 3.6 g (67.4% of theory) of the compound.

Melting Point: 113 ℃

Similarly to Examples 3 to 4, the following compounds were prepared.

5-Chloro-2-morpholino-benzoic acid nitrile

Yield: 20% of theory, Melting point: 57 ° C

5-chloro-2-morpholino-benzamide

Yield: 98% of theory, Melting point: 280 ° C

5-Chloro-2-morpholino-benzoic acid

Yield: 60% of theory, Melting Point: 157 ℃

Example 5

5-Cyano-2-octamethyleneimino-benzoic acid

26.2 g (0.1 mole) of 5-amino-2-octamethyleneimino-benzoic acid was dissolved in 38 ml of concentrated hydrochloric acid, 280 ml of water was added and 7.6 g (0.11 mole) of sodium nitrite solution in 30 ml of water was added to 0 ° C. Add drop by to diazotize. After stirring for 30 minutes, the solution is adjusted to pH 7 with sodium carbonate. Trisodium-tetracyano-copper (I) complex salt solution is then added dropwise to the diazonium salt solution at 0 ° C. A copper (I) complex salt solution is obtained as follows.

32 g (0.128 mole) copper sulfate 5H ₂ O and 8.7 g sodium chloride in 100 ml of water dissolved in 6.6 g (0.0635 mole) of sodium hydrogen sulfite and 4.4 g of sodium hydroxide in 50 ml of water. The solution is reduced to copper chloride (I). The precipitated copper chloride (I) was suction filtered and suspended in 50 ml of water and dissolved in a solution of 17 g (0.346 mol) of sodium cyanide in 30 ml of water. After nitrogen production was completed, the reaction mixture was heated to 70 ° C. for 1 hour. After cooling the reaction mixture, the mixture was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with chloroform. The chloroform phase is dried over sodium sulfate, the chloroform is distilled off, and the crude product obtained is purified on a silica gel column with ethyl acetate as the eluent.

Yield: 9 g (30% of theory)

Melting Point: 20 ℃

Calculation: C70.56 H7.40 N10.28

Found: 70.38 7.20 10.10

Example 6

2-heptamethyleneimino-5-hydroxy-benzoic acid

26.7 g (0.107 mole) of 5-amino-2-heptamethyleneimino-benzoic acid was dissolved in 190 ml of 3N sulfuric acid, and a solution of 8.3 g (0.12 mole) of sodium nitrite in 30 ml of water was added dropwise at 0 ° C. To diazotize. After stirring for 30 minutes, 2 g of crushed urea are added. The diazonium salt solution was stirred and added dropwise to 320 ml of 50% sulfuric acid heated to 90 ° C. After nitrogen production is complete, the reaction mixture is adjusted to pH 4 with ammonia at room temperature and extracted with chloroform. After drying over sodium sulfate and distilling chloroform, the dried residue obtained is purified on a silica gel column with chloroform as eluent. After recrystallization from isopropanol 8 g (30% of theory) of the compound are obtained.

Melting Point: 190 ℃

Calculation: C67.45 H7.68 N5.61

Found: 66.87 7.71 5.65

In the same manner as in Example 6, the following compounds were prepared.

2-hexamethyleneimino-5-hydroxy-benzoic acid

Yield: 24% of theory, Melting point: 214 ° C

5-Hydroxy-2-octamethyleneimino-benzoic acid

Yield: 24% of theory, Melting point: 208 ° C

5-hydroxy-2- (4-tert-butyl-piperidine) benzoic acid

Yield: 33% of theory, Melting point: 240 ° C

5-Hydroxy-2- (cis--3,5-dimethyl-piperidino) -benzoic acid

Yield: 67.4% of theory, Melting point: 248 to 250 ° C

Claims (1)

The compound of formula (II) is converted to the diazonium salt by nitrite and the diazonium salt obtained is converted to the compound of formula (I) by heating in the presence of sulfuric acid and copper or the corresponding copper- (I) -salts. To prepare novel 2-amino-benzoic acid derivatives of general formula (I) and acid addition salts and base salts thereof

In which R ₅ is fluorine, chlorine or bromine atom, cyano or hydroxy group, R ₆ and R ₇ together with the nitrogen to which they are attached are N-alkyl-cyclohexylamino group alkyl having 2 to 4 carbon atoms, N-alkyl-phenylamino or N-alkyl-benzylamino group having 1 to 3 carbon atoms of alkyl, A piperidino group substituted with a cyclic alkyleneimino group having 6 to 12 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms or a phenyl group, An alkyl group having 1 to 3 carbon atoms, a piperidino group substituted with two, three or four, an morpholino or thiomorpholino group optionally substituted with one or two alkyl groups having 1 to 3 carbon atoms, an alkyl having 1 to 3 carbon atoms Group, piperazino group having 4 positions substituted by alkoxycarbonyl group having 2 to 4 carbon atoms, phenyl, halogenphenyl, pyridyl, benzyl or furoyl group, saturated or partially unsaturated aza- with 7 to 10 carbon atoms anecdote 1,4-dioxa-8-aza claws alkyl group, having 6 to 9-spiro-alkane group, a pyrrolidino or tetrahydro-pyrido a dino group, W is carboxy, aminocarbonyl, cyano or alkoxycarbonyl having 2 to 4 carbon atoms in total.