KR820000367B1 - Process for preparing benzoic acid derivatives - Google Patents

Abstract

Benzoates[I; T = H, Cl, Br; W = carboxy; X = III (R1 = C2-8 alkyl, aralkyl, phenyl, C5-8 cycloalkyl; R2 =H, Cl, Br), IV(R3 = C5-8 alkyl, aralkyl, phenyl, C5-8 cycloalkyl); Y = C1-3 hydrocarbon; Z = H, halogen, alkyl, alkoxy, alkenyloxy useful as flood suger concentration lowering agent, were prepd. by reaction of II and XCOOH followed by removing formyl group. Thus, 2-butoxynicotinic acid was treated with ClCO2Me and 4-H2NCH2CH2C6H4CO2Et.HCl to give I[X = III(R1 = H; R2 = Bu); Y = Me; T,Z = H; W = CO2H, which was hydrolyzed to II(R2 = Et).

Description

Method for producing benzoic acid derivatives

The present invention relates to benzoic acid of the following general formula (I).

In the above formula

T 'is hydrogen or halogen, preferably chlorine or bromine,

W 'is a carboxyl group, ester or salt thereof,

X 'is

(In the above formula

R ₁ is aralkyl, phenyl or cycloalkyl of 5 to 8 carbon atoms which may be substituted by alkylalkyl, alkyl or halogen of 2 to 8 carbon atoms; R ₂ is hydrogen or halogen, preferably chlorine or bromine; R ₃ is optionally substituted alkyl, alkyl or substituted aralkyl, phenyl or cycloalkyl having 5 to 8 carbon atoms, which may be substituted by

Y 'is a single chemical bond or a hydrocarbon chain of 1 to 3 carbon atoms;

Z 'is hydrogen, halogen, alkyl, alkoxy, alkoxy, alkoxy or alkenyloxy.

Alkoxy, alkeneoxy, alkoxy Alkoxy in the above definition, alkyl residues in alkoxy and alkylamino, or alkenyl and alkyl are straight-chain or branched hydrocarbon groups with low carbon number.

Most preferred are compounds having up to 6 carbon atoms of alkyl, alkoxy, alkoxy, alkoxy or alkeneoxy groups.

Of the halogens according to the above definition, chlorine and bromine are most preferred, and the corresponding iodine compounds are not recommended. Y 'is preferably a hydrocarbon bridge having two carbons, and this portion may be substituted by an alkyl group.

The -CH ₂ -CH ₂ or -CH (CH ₃ ) -CH ₂ group is particularly recommended. Other linear or branched hydrocarbon bridges having 3 or more carbon atoms are undesirable.

The preparation method of the compound according to the present invention is as follows.

The amino compound of formula (II) or a formyl compound thereof is then reacted with a reactive derivative of formula X'COOH, optionally separating the formyl group, and the resulting compound is optionally converted to their free acid or ester or salt.

The starting compound, the amino compound, is known and can be prepared without difficulty according to a known process for producing a similar compound.

It is preferable to react these amino compounds with reaction derivatives of X'COOH, such as halides, anhydrides mixed anhydrides, azides or esters in the presence of a base.

The compound of the present invention has a blood sugar-lowering effect, and the compound is itself or as a salt or ester thereof, and the rabbit is administered to Hedor-Zensen by administering 10 to 400 mg / kg, preferably 100 mg / kg, or an automatic assay. By measuring the blood glucose level for a long time can prove the hypoglycemic effect.

The compounds of the present invention can be used in the preparation of oral administration products having hypoglycemic effects for the treatment of diabetes mellitus or can be used as such or administered in the form of their salts or esters or for forming salts such as alkalizing agents. That is, it may be administered in the presence of alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates. Suitable medicinal products include conventional carriers or auxiliaries such as talc, starch, lactose, tragacanth or magnesium stearate in addition to the compounds of the present invention in tablet form. Pharmaceuticals, such as tablets or additives (or no additives), comprising the compounds of the present invention as active ingredients, take suitable dosage forms. The dosage per unit is 0.1 to 2 g, preferably 0.5 to 1 g.

Doses above or below this range may be administered and, if desired, may be dispensed or combined prior to administration.

The benzoic acid derivatives of the present invention can be used as is for the treatment of diabetes mellitus or other anti-diabetic agents such as sulfonylureas having hypoglycemic action, as well as biguanides having other chemical structures, especially phenylethyl-biguanide or It can be used in combination with dimethyl biguanide.

The following examples illustrate various processes for the synthesis of the compounds of the invention and do not limit the invention.

Example 1

4- (2-butoxy-nicotinamido-ethyl) -benzoic acid

6.5 g of 2-butoxy- nicotinic acid (from acetic acid ethyl ester, melting | fusing point 54-56 degreeC) are melt | dissolved in 150 ml of tetrahydrofuran. After adding 14.5 ml of triethylamine, the bath was cooled to 0 ° C. and 3.2 ml of chloroformic acid methyl ester was added dropwise. The shaking was continued at 0 ° C. for 1 hour, followed by addition of 7.6 g of 4- (2-aminoethyl) -benzoic acid ethyl ester-hydrochloride, and the shaking was continued at 0 ° C. for 1 hour, followed by shaking at room temperature for 4 hours. . The bath is evaporated and the residue is mixed with acetic acid ethyl ester. After washing with water, sodium hydrogencarbonate solution, dilute hydrochloric acid and water, the acetic acid ethyl ester solution is dried and evaporated under reduced pressure. The obtained 4- (2- <2-butoxy-nicotinamido> -methyl) -benzoic acid ethyl ester was refluxed in 25 m of 2N sodium hydroxide solution and 50 ml of ethanol for 3 hours. After distilling off the solvent, the product is acidified with dilute acetic acid, filtered off with suction and recrystallized from acetic acid ester. Obtained 4- (2- <2-butoxy- nicotinamido> -ethyl) -benzoic acid has melting | fusing point of 147-149 degreeC.

In a similar manner the following is obtained. 2- (2- <2-cyclohexyloxy-nicotinamido> -ethyl) -benzoic acid melting point 212-213 degreeC from 2-cyclohexyloxy- nicotinic acid (recrystallization melting point 57-58 degreeC from ethanol) (methanol / di Recrystallized from oxane),

2- (2- <2-butoxy-5-chloro- nicotinamido> -ethyl) -benzoic acid from 2-butoxy-5-chloro- nicotinic acid (acetic acid (recrystallization melting point 99-101 degreeC from ethyl ester) Melting point 164-166 캜 (recrystallized from methanol / acetinic acid ethyl ester),

4- (2- <2-phenoxy-nicotinamido> -ethyl) -benzoic acid melting point 162-163 degreeC (recrystallization from methanol from 2-phenoxy- nicotinic acid (recrystallization melting | fusing point 181 to 182 degreeC from ethyl acetate ethyl ester)) ),

From 2-ethoxy-nicotinic acid (recrystallization melting point 89-91 degreeC from ethanol), 4- (2- <2-ethoxy- nicotinamido> -ethyl) -benzoic acid melting point 138-140 degreeC (recrystallization from ethanol),

4- (2- <2-ethoxy-5-chloro-nicotinamido> -ethyl) -benzoic acid melting point 150-151 degreeC from 2-ethoxy-5- chloro- nicotinic acid (recrystallization melting point 115-117 degreeC from ethanol) (Recrystallized from methanol),

4- (2- <2-propoxy-nicotinamido> -ethyl) -benzoic acid melting point 157-158 degreeC (recrystallization from methanol) from 2-propoxy- nicotinic acid (recrystallization melting point 48-50 degreeC from ethanol),

2- (2- <5-chloro-2-propoxy-nicotinamido> -ethyl) from 2-chloro-2-propoxy-nicotinic acid (recrystallization melting point 102-103 degreeC from ethanol)-benzoic acid melting point 173-174 degreeC (Recrystallized from acetic acid ethyl ester),

4- (2- <2-pentyloxy-nicotinamido> -ethyl) -benzoic acid melting point 154-156 degreeC (recrystallized from ethanol) from 2-pentyloxy- nicotinic acid (melting point 37-39 degreeC),

5-chloro-2-pentyloxy acid from (ethanol / H ₂ O-melting recrystallization from 98 to 100 ℃) 4- (2- <5- chloro-2-pentyloxy-nicotinamide FIG amino> ethyl) -benzoic acid Melting point 125 To 127 ° C. (recrystallized from ethanol),

4- (2- <2-octyloxy-nicotinamido> -ethyl) -benzoic acid melting point 104-106 degreeC (recrystallized from ethanol) from 2-octyloxy- nicotinic acid (melting point 53-54 degreeC),

From 5-chloro-2-octyloxy nicotinic acid (recrystallization melting point 98-100 degreeC from ethanol) 4- (2- <5-chloro-2-octyloxy-nicotinamido> -ethyl) -benzoic acid melting point 115-117 degreeC (Recrystallized from ethanol),

5- (2- <5-chloro-2-cyclohexyloxy-nicotinamido> -ethyl) from 5-chloro-2-cyclohexyloxy nicotinic acid (recrystallization melting point 65-67 degreeC from acetinic acid ethyl ester) -Benzoic acid melting point 165-167 캜 (recrystallized from ethanol),

4- (2- <2-benzyloxy-nicotinamido> -ethyl) -benzoic acid melting point 184-185 degreeC (recrystallization from methanol) from 2-benzyloxy- nicotinic acid (recrystallization melting point 57-58 degreeC from ethanol),

Example 2

4- (2- (1-benzyl-1-, 2-dihydro-2-oxo-nicotinamido> -ethyl) -benzoic acid

20 ml of acetone are added to 16 ml of a solution of about 1 mole of a 3- (2-aminoethyl) -benzoic acid containing a corresponding amount of sodium acetate, and to which 1-benzyl-1,2-dihydro-2--2- 3.7 g of oxo-nicotinic acid chloride (prepared from 1-benzyl-1,2-dihydro-2-oxo-nicotinic acid and thionyl chloride) are added with shaking cooling. The shaking is continued at room temperature for 1 hour, the acetone is removed under reduced pressure, and diluted hydrochloric acid is added to the residue. The precipitated product was suction filtered, reprecipitated from dilute ammonia water and recrystallized from dilute methanol to give 4- (2- <1-benzyldihydro-1,2--2-oxo-) having a melting point of 150 to 152 ° C and 171 to 173 ° C. Nicotinamido-> ethyl) -benzoic acid is obtained. In a similar way the following is obtained:

4- (2- (1-cyclohexyl-1,2-dihydro-2-oxo-nicotinamido> -ethyl) -benzoic acid from 1-cyclohexyl 1-2, 2-dihydro-2- oxo- nicotinic acid chloride Melting point 176 ° C. (recrystallized from ethanol),

4- (2- <1- (4-methylcyclohexyl) -1,2-dihydro-2-oxo from 1- (4-methylcyclohexyl) -1,2-dihydro-2-oxo-nicotinic acid chloride -Nicotinamido-> ethyl) benzoic acid melting | fusing point 202 degreeC (recrystallized from ethanol),

Example 3

4- (2- (2-ethoxy-nicotinamido> -ethyl) -benzoic acid

Melting point 205-206 degreeC (from acetin ester) 4- (2-chloro- nicotinamido> -ethyl) -benzoic acid (2-chloro- nicotinic acid and 4- (2-aminoethyl)-by a continuous saponification method 1.52 g) (prepared from a mixed anhydride of benzoic acid ethyl ester-hydrochloride) is dissolved in 50 ml of an ethanol solution containing 0.23 g of sodium. The bath is refluxed for 2 hours, concentrated under reduced pressure, dissolved in water and acidified with diluted acetic acid. The product is dissolved in chloroform and extracted (twice) and the chloroform layer is concentrated to dryness over sodium sulfate. 4- (2- <2-ethoxy-nicotinamido> -ethyl) -benzoic acid obtained by recrystallizing the solid residue with ethanol has a melting point of 138 to 140 캜. The melting point mixed with the acid obtained according to Example 1 did not decrease.

Example 4

4- (2- (2-ethoxy-5-chloro-nicotinamido> -ethyl) -benzoic acid

3.14 g of 4- (2- <2-ethoxy-nicotinamido> -ethyl) -benzoic acid are suspended in 200 ml of water and heated for 3 hours in an oil bath having a temperature of 60 to 70 캜. Gaseous chlorine is introduced into the suspension with shaking. After completion of the reaction (by thin layer chromatography), the bath is cooled and the precipitate is suction filtered to recrystallize from methanol. Obtained 4- (2- <2-ethoxy-5-chloro-nicotinamido> -ethyl) -benzoic acid has a melting point of 150 to 151 캜 and shows no degradation at the melting point mixed with the material obtained according to Example 1 .

Claims (1)

A method for preparing the benzoic acid derivative of formula (I), wherein the amino compound of formula (II) or a formyl compound thereof is reacted with a reaction derivative of formula X'COOH, and then the formyl group in the product is removed.

Wherein T 'is hydrogen or halogen, in particular chlorine or bromine, W' is a carboxyl group, ester or salt thereof,

[Wherein R ¹ is aralkyl, phenyl or cycloalkyl of 5 to 8 carbon atoms, which may be substituted by alkyl, alkyl or halogen of 2 to 8 carbon atoms, R ² is hydrogen or halogen, in particular chlorine or bromine, R ³ is aralkyl, phenyl or cycloalkyl of 5 to 8 carbon atoms, which may be substituted by alkyl, alkyl or halogen of 5 to 8 carbon atoms; Y 'is a hydrocarbon chain or a single chemical bond having 1 to 3 carbon atoms, and Z is hydrogen, halogen, alkyl, alkoxyalkoxy alkoxy or alkenyloxy.