KR20030059961A - A process for preparation of (±)-2-(4-clorobenzoylamino)-3-[2(1h)-quinolinon-4-yl]propionic acid - Google Patents

Abstract

PURPOSE: Provided is (±)-2-(4-chlorobenzoylamino)-3-(2(1H)-quinolinone-4-mono)propionic acid which is prepared through simplified processing steps at high yield and high purity. CONSTITUTION: 4-halomethyl-2(1H)-quinolinone(formula III) reacts with dialkyl 4-chlorobenzoylamino malonate(formula IV) in the presence of an inorganic base in an alcoholic solvent to prepare alkyl 2-(4-chlorobenzoylamino)-2-(alkoxycarbonyl)-3-(2(1H)-quinolinone-4-mono)propionate(formula II) as an intermediate. It selectively suffers decarboxylation and hydrolysis using an acids mixture wherein acetic acid is mixed with other acids in a volume ratio of 1:0.3-10.2, thereby preparing the (±)-2-(4-chlorobenzoylamino)-3-(2(1H)-quinolinone-4-mono)propionic acid(formula I). In the formulas, R is C1-6 alkyl group, and X1 is halogen.

Description

A preparation method of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid {A PROCESS FOR PREPARATION OF (±) -2- (4 -CLOROBENZOYLAMINO) -3- [2 (1H) -QUINOLINON-4-YL] PROPIONIC ACID}

The present invention relates to a novel process for preparing (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid.

(±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid is a compound of formula I, commonly referred to as levamipi, as gastric ulcer, intestinal ulcer It is widely known as an anti-ulcer agent showing an excellent therapeutic effect on peptic ulcers, such as.

Formula I

U.S. Patent No. 4,578,381 and Korean Laid-Open Patent Publication No. 84-5427 prepare compounds of formula VIII and compounds of formula VII as intermediates and use them in a variety of ways to provide (±) -2- (4- Chlorobenzoylamino) -3- [2 (1H) -quinolinone

-4-yl] a process for preparing propionic acid is described, which method is described in Chem. Pharm. Bull., 33 (9), p3775-3786, 1985 and Chem. Pharm. Bull., 34 (11) p4,821-4,824, 1986.

Formula VII

Formula VIII

Wherein R is lower alkyl, preferably ethyl.

In more detail, this method is prepared by reacting a compound of formula III with a compound of formula IX to form a compound of formula VIII, which is decarboxylated and hydrolyzed using an organic acid to yield the compound of formula VII as a final intermediate. And then reacted with a compound of formula (V) to finally form (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic To make an acid.

Formula IX

[Wherein, R 'is a lower alkanoyl group, formyl, acetyl, propionyl, isobutyl, pentanoyl, t-butylcarbonyl, nusananoyl and the like, most preferably an acetyl group (-COCH ₃ )

The prior art described in the above-mentioned known literature is described in more detail as follows.

4-Bromomethyl-2 (1H) -quinolinone corresponding to formula III was used as starting material and diethylacetamino malonate of formula IX in the presence of sodium ethoxide or [metal sodium + ethanol] Ethyl 2-acetylamino-2-ethoxycarbonyl-3- [2 (1H) -quinolinone-4- corresponding to Formula VIII by reaction with (EtO ₂ C-CH (-NHAc) -CO ₂ Et) General] Propionate is prepared. The intermediate obtained according to formula (VIII), which is a compound obtained herein, is heated in the presence of a single acid such as hydrochloric acid to hydrolyze together with the decarboxylation reaction and the removal of the protecting group (-Ac) to yield 2-amino-3- [ 2 (1H) -quinolinone

-4-yl] Synthesized and prepared inorganic salts such as propionic acid or hydrochloride thereof, and then acylated with para-chlorobenzoyl chloride (Cl-Ph-COCl) of formula V in the presence of a base such as potassium carbonate or sodium hydroxide. The reaction produces a final compound of formula I, the final compound of formula (I). This is represented by the chemical reaction formula.

This known method of preparing levamifeed protects the amine group (-NH ₂ ) in formula (IX), and then reacts with the compound of formula (III), followed by hydrolysis using an acid (organic or inorganic acid) to remove the protecting group of the amine. By preparing a compound of formula (VII) and acylating with a compound of formula (V) to prepare a final target compound, a three-step reaction process from the starting material of the general formula (III) to the final target compound, the synthesis process is longer and overall yield There was a problem of this degradation.

Accordingly, the present inventors solved the problems of the conventional method for preparing levamapid described above, and (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quine at high yield by a simpler process. Nolinone-4-yl] A intensive study of the propionic acid has been made to complete the present invention.

(I) 4-halomethyl-2 (1H) -quinolinol of formula (III) and dialkyl 4-chlorobenzoylamino malonate of formula (IV) are prepared using an inorganic base and an alcoholic solvent. Reaction under conditions to prepare alkyl 2- (4-chlorobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate of formula II as an intermediate And (ii) the obtained alkyl 2- (4-chlorobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate, followed by acetic acid. (±) -2- of Formula I, comprising optionally decarboxylation and hydrolysis with acids mixed with acids in a volume ratio of from 0.3 to 10.2 A method for preparing (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid is provided.

Formula I

Formula II

Formula III

Formula IV

[ _Wherein R is C _1-6 alkyl and X ₁ is halogen.

R is preferably ethyl and X ₁ is preferably chlorine or bromine.

In step (i), the inorganic base used when reacting the compound of formula III with the compound of formula IV is preferably selected from the group consisting of sodium hydride, sodium hydroxide and potassium hydroxide, more preferably sodium hydride.

In step (i), the alcoholic solvent used when reacting the compound of formula III with the compound of formula IV is preferably selected from the group consisting of methanol, ethanol and isopropyl alcohol, more preferably anhydrous ethanol.

Step (i) of reacting a compound of formula III with a compound of formula IV to produce a compound of formula II is preferably carried out by reacting for 1-10 hours by reflux reaction.

In the preparation method according to the present invention, the starting compound is a 4-chlorobenzoyl halide of formula (V) and a dialkyl aminomalonate of formula (VI) or a hydrochloride thereof and an organic solvent and an organic base. It is obtained by making it react on conditions.

Formula V

Formula VI

[Wherein R is as defined above and X ₂ is halogen.

Compounds of formula (V) are generally well known as compounds commonly used in conventional methods for preparing levamifeed. In the present method, the compound of formula (V), which is used as the acylating reactant in the last reaction step of the known levamifeed production method, is first reacted with the compound of formula (VI) to prepare the compound of formula (IV) By reacting with a compound of formula III, which is a substance, it is not necessary to separately protect and deprotect the amine group in formula VI as in a known production method, thereby shortening the entire manufacturing process and increasing yield.

The organic solvent used in the reaction of the compound of the formula V and the compound of the formula VI is preferably selected from the group consisting of dichloromethane, en, ene-dimethylformamide, chloroform, acetonitrile and acetone, more preferably dichloromethane Or n, ene-dimethylformamide.

The organic base used in the reaction of the compound of formula V and the compound of formula VI is preferably selected from the group consisting of triethylamine, diethylamine, trimethylamine and dimethylamine, more preferably triethylamine.

Step (ii) is carried out by selectively decarboxylation of only one of the two esters of the structure of formula (II) using a specific mixed acid comprising acetic acid and the remaining one is hydrolysed.

is) to give (±) -2- (4-chlorobenzoylamino) -3- [2 (1H)

) -Quinolinone-4-yl] propionic acid is prepared.

The mixed acid used in the production process according to the present invention is a mixture of acetic acid and other acids in a volume ratio of 1: 0.3 to 10.2 to effect selective decarbonate and hydrolysis reactions.

On the other hand, the acid used in the above-described known leamimid feed production method is a single acid such as hydrochloric acid, a halogenated hydrochloric acid such as bromic acid, or an inorganic acid such as sulfuric acid, phosphoric acid, and when using these monoacids, an alkali metal hydroxide or the like The hydrolysis reaction does not efficiently perform a selective hydrolysis reaction.

The other acid mixed with acetic acid is preferably selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid or bromic acid.

In the preparation method according to the invention, by using this specific mixed acid, (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic Acids can be produced in high purity and high yields, and also by shortening the chemical synthesis process, the manufacturing process becomes simpler and mass production is easier, thereby increasing economic added value through cost reduction.

Step (ii) is preferably reacted at 90 to 120 ° C. for 0.5 to 5.0 hours, more preferably at 100 to 108 ° C. for 1.0 to 3.0 hours.

The present invention also provides a process for preparing (i) a 4-halomethyl-2 (1H) -quinolinol of formula III and a dialkyl 4-chlorobenzoylamino malonate of formula IV with an inorganic base and an alcoholic solvent. Reaction under conditions to prepare alkyl 2- (4-chlorobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate of formula II as an intermediate And (ii) alkyl 2- (4-chlorobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate obtained by acetic acid A chemical formula prepared by selectively decarboxylation and hydrolysis with an acids mixture mixed with other acids in a volume ratio of 1: 0.3 to 10.2.

(±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid of I.

The present invention is explained in more detail by the following examples, but the present invention is not limited in any way by these.

Example

Example 1 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid of Formula I 1

Ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₂ CH ₃ ) To 3.0 g of mixed acid of 7.5 ml of acetic acid and 5 ml of sulfuric acid are added, warmed and stirred at 100 to 105 ° C for 2 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 1.8 g of 2 (1H) -quinolinone-4-yl] propionic acid was obtained (yield: 78.0%, purity: 99.7%).

IR (KBr) cm ^-1 : 3270, 3050, 2989, 2967, 1727, 1645, 1600, 1538, 1423, 759

¹ H NMR (DMSO-d ₆ ) ppm: 3.20-3.51 (dd, 2H), 4.72-4.77 (m, 1H), 6.45 (s, 1H),

7.21-7.85 (m, 8H, aromatic), 8.90-8.92 (d, 1H),

11.65 (s, 1H), 13.05 (s, 1H)

M.P. : 288 ~ 290 ℃

Example 2 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid 2

Ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₂ CH ₃ ) A mixed acid of 7.5 ml of acetic acid and 76.8 ml of hydrochloric acid is added to 3.0 g, and the mixture is stirred at 100 to 105 ° C for 2 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 2 (1H) -quinolinone-4-yl] propionic acid 1.5 g was obtained. (Yield: 65.2%, Purity: 99.6%)

Example 3 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid 3

Ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₂ CH ₃ ) To 3.0 g, 7.5 ml of acetic acid and 3.3 ml of phosphoric acid are added, followed by stirring at 102 to 105 ° C for 2.5 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried (±) -2- (4-chlorobenzoylamino) -3- [ 1.7 g of 2 (1H) -quinolinone-4-yl] propionic acid was obtained (yield: 74.0%, purity: 99.7%).

Example 4 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid 4

Ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₂ CH ₃ ) To 3.0 g, 7.5 ml of acetic acid and 20.0 ml of bromic acid are added, followed by stirring at 100 to 102 ° C. for 1.5 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 2 (1H) -quinolinone-4-yl] propionic acid 1.4 g was obtained. (Yield: 61.0%, Purity: 99.5%)

Example 5 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid 5

2.8 g of methyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₃ ) 7.0 ml of acetic acid and 4.7 ml of sulfuric acid were added to the mixture, and the mixture was stirred at 102 to 103 ° C for 3 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 1.8 g of 2 (1H) -quinolinone-4-yl] propionic acid was obtained. (Yield: 77.1%, Purity: 99.7%)

Example 6: Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid

2.8 g of methyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₃ ) To the mixture was added 7.0 ml of acetic acid and 71.6 ml of hydrochloric acid, followed by stirring at 102 캜 for 2 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 2 (1H) -quinolinone-4-yl] propionic acid 1.5 g was obtained. (Yield: 64.0%, Purity: 99.6%)

Example 7 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid

Methyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₃ ) 2.8 g To the mixture was added 7.0 ml of acetic acid and 3.1 ml of phosphoric acid, followed by stirring at 103 ° C. for 2.5 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 1.7 g of 2 (1H) -quinolinone-4-yl] propionic acid was obtained (yield: 73.1%, purity: 99.7%).

Example 8 Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid

Methyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₃ ) 2.8 g 7.0 ml of acetic acid and 18.7 ml of bromic acid are added to the mixture, and the mixture is stirred at 100 to 103 ° C for 3 hours. It was then cooled and 20 ml of water was added to form crystals. The resulting crystals were filtered and then recrystallized with dimethyl sulfoxide and water and dried to give (±) -2- (4-chlorobenzoylamino) -3- [ 2 (1H) -quinolinone-4-yl] propionic acid 1.4 g was obtained. (Yield: 60.8%, Purity: 99.5%)

Example 9 ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH Preparation of ₂ CH ₃ )

5 g of diethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH ₂ CH ₃ ), 0.8 g of 60% sodium hydride and 200 ml of anhydrous ethanol were added together, stirred at room temperature for 1.5 hours, and 4-bromomethyl 3.8 g of -2 (1H) -quinolinone (Formula III, X ₁ = Br) was added thereto, followed by stirring under reflux for 3 hours. After the reaction was completed, the solvent was concentrated to remove the solvent, and then 200 ml of water was added to the concentrate, followed by stirring. The resulting crystals were filtered off, recrystallized from water and dried to give ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] pro 6.6 g of cypionate was obtained. (Yield: 86.1%, Purity: 97.8%)

IR (KBr) cm ^-1 : 3401, 2960, 2925, 1737, 1660, 1650, 1479, 1203, 1093, 752

¹ H NMR (DMSO-d ₆ ). ppm: 1.14-1.17 (m, 6H), 3.81 (s, 2H), 4.13-4.20 (m, 4H),

6.18 (s, 1H), 6.99 to 7.69 (m, 8H), 8.46 (s, 1H), 11.72 (s,

1H)

M.P. : 202-207 deg.

Example 10 ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH Preparation of ₂ CH ₃ )

5 g of diethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH ₂ CH ₃ ), 0.8 g of 60% sodium hydride and 200 ml of anhydrous ethanol were added together and stirred at room temperature for 1 hour, followed by 4-chloromethyl-2 ( 1H) -quinolinone <Formula III, X ₁ = Cl> 3.1 g was added and stirred under reflux for 3 hours. After the reaction was completed, the solvent was concentrated to remove the solvent, and then 200 ml of water was added to the concentrate, followed by stirring. The resulting crystals were filtered off, recrystallized from water and dried to give ethyl 2- (4-chlorobenzoylamino) -2- (ethoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] pro 6.4 g of cypionate was obtained (yield: 83.3%, purity: 97.8%).

Example 11: Methyl 2- (4-chlorobenzoylamino) -2- (methoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₃ ) Manufacture of

5 g of dimethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH ₃ ), 0.9 g of 60% sodium hydride and 200 ml of anhydrous ethanol were added together and stirred at room temperature for 1 hour, followed by 4-bromomethyl-2 (1H). -4.2 g of quinolinone (Formula III, X ₁ = Br) was added thereto, followed by stirring under reflux for 3 hours. After the reaction was completed, the solvent was concentrated to remove the solvent, and then 200 ml of water was added to the concentrate, followed by stirring. The resulting crystals were filtered, then recrystallized from water and dried to give methyl 2- (4-chlorobenzoylamino) -2- (methoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] pro 6.9 g of cypionate was obtained (yield: 87.4%, purity: 97.8%).

IR (KBr) cm ^-1 : 3401, 2960, 2925, 1737, 1660, 1650, 1479, 1203, 1093, 752

¹ H NMR (DMSO-d ₆ ). ppm: 3.52 (s, 6H), 3.81 (s, 2H), 6.18 (s, 1H), 6.99-7.69 (m,

8H), 8.46 (s, 1H), 11.72 (s, 1H)

M.P. : 189 ~ 196 ℃

Example 12 Methyl 2- (4-chlorobenzoylamino) -2- (methoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate (Formula II, R = CH ₃ ) Manufacture of

5 g of dimethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH ₃ ), 0.9 g of 60% sodium hydride, and 200 ml of anhydrous ethanol were added together, stirred at room temperature for 1 hour, and 4-chloromethyl-2 (1H)- 3.4 g of quinolinone (Formula III, X ₁ = Cl) was added thereto, followed by stirring under reflux for 3 hours. After the reaction was completed, the solvent was concentrated to remove the solvent, and then 200 ml of water was added to the concentrate, followed by stirring. The resulting crystals were filtered, then recrystallized from water and dried to give methyl 2- (4-chlorobenzoylamino) -2- (methoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] pro 6.7 g of cypionate was obtained (yield: 84.4%, purity: 97.8%).

Example 13 Preparation of Diethyl 4-Chlorobenzoylamino Malonate (Formula IV, R = CH ₂ CH ₃ )

To 10 g of diethyl amino malonate hydrochloride (Formula VI, R = CH ₂ CH ₃ ), 200 ml of dichloromethane and 13.2 ml of triethylamine were added together and stirred at room temperature for 30 minutes, followed by 4-chlorobenzoyl chloride (Formula V). , X ₂ = Cl) slowly add dropwise 7.2 ml. After the reaction was completed, 100 ml of water was added to separate the layers, and the organic layer was taken. The organic layer was treated with anhydrous sodium sulfate (drying agent), dehydrated, concentrated, and the resulting compound was recrystallized from dichloromethane and hexane and dried to give 13.5 g of 4-chlorobenzoylamino malonate. (Yield: 91.0%, Purity: 98.2 %)

IR (KBr) cm ^-1 : 3340, 3313, 2944, 2740, 2532, 1733, 1660, 1641, 1513, 1444,

1398, 1373, 1349, 1280, 1261, 1236, 1172

¹ H NMR (CDCl ₃ ) ppm: 1.302 to 1.337 (t, 6H), 4.262 to 4.351 (m, 4H), 5.306 to 5.323 (d,

1H), 7.092-7.109 (d, 1H), 7.418-7.802 (dd, 4H, aromatic)

M.P. : 182 ~ 190 ℃

Example 14Diethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH₂CH₃Manufacturing

To 10 g of diethyl amino malonate hydrochloride <Formula VI, R = CH ₂ CH ₃ > 200 ml of dichloromethane and 13.2 ml of triethylamine were added together and stirred at room temperature for 30 minutes, followed by 4-chlorobenzoyl bromide <Formula V, X ₂ = Br> 13.2 g is added dropwise for about 1 hour. After the reaction was completed, 100 ml of water was added to separate the layers, and the organic layer was taken. The organic layer was treated with anhydrous sodium sulfate (drying agent), dehydrated, concentrated, and the resulting compound was recrystallized from dichloromethane and hexane and dried to give 13.2 g of diethyl 4-chlorobenzoylamino malonate. (Yield: 89.0%, purity) : 98.1%)

Example 15:dimethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH₃Manufacturing

To 10 g of dimethyl amino malonate hydrochloride (Formula VI, R = CH ₃ ), 200 ml of dichloromethane and 15.1 ml of triethylamine were added together and stirred at room temperature for 30 minutes, followed by 4-chlorobenzoyl chloride (Formula V, X ₂ = Cl) 8.3 ml is added dropwise for about 1 hour. After the reaction was completed, 100 ml of water was added to separate the layers, and the organic layer was taken. The organic layer was treated with anhydrous sodium sulfate (drying agent), dehydrated, concentrated, and the resulting compound was recrystallized from dichloromethane and hexane and dried to give 13.5 g of dimethyl 4-chlorobenzoylamino malonate. (Yield: 87.0%, Purity: 98.2%)

IR (KBr) cm ^-1 : 3340, 3313, 2944, 2740, 2532, 1733, 1660, 1641, 1513, 1444,

1398, 1373, 1349, 1280, 1261, 1236, 1172

¹ H NMR (CDCl ₃ ) ppm: 3.68 to 3.68 (s, 6H), 5.30 to 5.32 (d, 1H), 7.09 to 7.71 (d, 1H),

7.418-7.802 (dd, 4H, aromatic)

M.P. : 171 ~ 178 ℃

Example 16:dimethyl 4-chlorobenzoylamino malonate (Formula IV, R = CH₃Manufacturing

To 10 g of dimethyl amino malonate hydrochloride (Formula VI, R = CH ₃ ), 200 ml of dichloromethane and 15.1 ml of triethylamine were added together and stirred at room temperature for 30 minutes, followed by 4-chlorobenzoyl bromide (Formula V, X ₂ = Br) 14.4 g is added dropwise for about 1 hour. After the reaction was completed, 100 ml of water was added to separate the layers, and the organic layer was taken. The organic layer was treated with anhydrous sodium sulfate (drying agent), dehydrated, concentrated, and the resulting compound was recrystallized from dichloromethane and hexane and dried to give 13.4 g of dimethyl 4-chlorobenzoylamino malonate. (Yield: 86.0%, Purity: 98.2%)

Comparative Example 1: Preparation of (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid (Formula I)

To 3.0 g of 2-amino-3- [2 (1H) -quinolinone-4-yl] propionic acid and hydrochloride and 1.4 g of sodium hydroxide, 80 ml of acetone and 80 ml of water are added and stirred at 0 to 5 ° C. 1.9 ml of 4-chlorobenzoyl chloride (formula V, X ₂ = Cl) were slowly added dropwise to the reaction solution, followed by stirring at 0-5 ° C. for 1 hour. At the end of the reaction, the solution is concentrated to remove acetone, 1N-sodium hydroxide solution is added to adjust the pH to 12-13, and then filtered to remove the defects and the filtrate is taken. 1N hydrochloric acid was added to the filtrate to adjust the pH to 4. The resulting crystals were filtered and recrystallized with dimethyl sulfoxide and water to give (±) -2- (4-chlorobenzoylamide) -3- [2 (1H)- Quinolinone-4-yl] 2.0 g of propionic acid was obtained. (Yield: 49.0%, Purity: 99.6%)

Therefore, the production method of (±) -2- (4-chlorobenzoylamide) -3- [2 (1H) -quinolinone-4-yl] propionic acid according to the present invention is higher than that of the conventional production method. It can be seen that the yield yields (±) -2- (4-chlorobenzoylamide) -3- [2 (1H) -quinolinone-4-yl] propionic acid.

Comparative Example 2: Preparation of 2 -amino-3- [2 (1H) -quinolinone-4-yl] propionic acid hydrochloride (Formula VII)

To 3.0 g of ethyl 2-acetylamino-2- (ethylcarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate, 84 ml of 20% aqueous hydrochloric acid solution was added and stirred under reflux. When the reaction was completed, the resultant was concentrated and recrystallized with ethanol to obtain 1.8 g of 2-amino-3- [2 (1H) -quinolinone-4-yl] propionic acid hydrochloride. 86.1%, Purity: 99.1%)

IR (KBr) cm ^-1 : 3374, 3137, 2991, 2960, 2858, 1652, 1548, 1511, 750

¹ H NMR (DMSO-d ₆ ) ppm: 3.35-3.40 (d, 2H), 4.42-4.44 (m, 1H), 6.49 (s, 1H), 7.21

~ 7.84 (m, 4H, aromatic), 8.63 (s, 1H), 11.76 (s, 1H)

M.P. : 220 ~ 225 ℃

Thus, according to the (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid according to the present invention, alkyl 2- (4 -Halobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate is prepared as an intermediate and formulated using certain mixed acids Only one of the two ester structures present in the compound of II is subjected to decarboxylation reaction and selective hydrolysis to yield (±) -2- (4-chlorobenzoylamino)- By preparing 3- [2 (1H) -quinolinone-4-yl] propionic acid, the desired compound can be prepared with high yield and high purity in a shorter production process in comparison with the known methods.

Claims (13)

(i) a 4-halomethyl-2 (1H) -quinolinol of formula III and a dialkyl 4-chlorobenzoylamino malonate of formula IV with an inorganic base and an alcoholic solvent c solvent) to react the alkyl 2- (4-chlorobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate of formula II as an intermediate Preparing as, and (ii) an acid obtained by obtaining alkyl 2- (4-chlorobenzoylamino) -2- (alkoxycarbonyl) -3- [2 (1H) -quinolinone-4-yl] propionate, and acetic acid; ) And 1: decarboxylati with an acids mixture mixed at a volume ratio of 0.3 to 10.2 on) and hydrolysis, comprising (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid How to prepare. Formula I Formula II Formula III Formula IV [ _Wherein R is C _1-6 alkyl and X ₁ is halogen. The method of claim 1, wherein R is ethyl and X ₁ is bromine. The compound of formula (IV) is obtained by reacting 4-chlorobenzoyl halide of formula (V) with dialkyl aminomalonate of formula (VI) or a hydrochloride thereof under organic solvent and organic base conditions. Way. Formula V Formula VI [Wherein R is as defined in claim 1 and X ₂ is halogen. The organic solvent of claim 3, wherein the organic solvent is dichloromethane, N, N-dimethylformamide, chloroform, acetonitrile. tonitrile) and acetone, and the organic base is triethylamine, diethylamine, trimethylamine amine) and dimethylamine. The process of claim 4 wherein the organic solvent is dichloromethane and the organic base is triethylamine. 5. The process of claim 4 wherein the organic solvent is en, ene-dimethylformamide and the organic base is diethylamine. The process of claim 1 wherein the inorganic base is selected from the group consisting of sodium hydride, sodium hydroxide and potassium hydroxide and the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropyl alcohol. 8. The method of claim 7, wherein the inorganic base is sodium hydride and the alcoholic solvent is anhydrous ethanol. The method of claim 1 wherein the other acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid or bromic acid. The process of claim 1, wherein step (i) is carried out by reacting for 1-10 hours in a reflux reaction. The process according to claim 1, wherein step (ii) is carried out by reacting at 90-120 ° C. for 0.5-5.0 hours. The process according to claim 11, wherein step (ii) is carried out by reacting at 100-108 ° C for 1.0-3.0 hours. (±) -2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl] propionic acid prepared according to the method of claim 1.