KR20020038469A - A process for the preparation of quinolinone derivatives - Google Patents

Abstract

PURPOSE: A process for preparing quinolinone derivative having therapeutic affects on ulcer is provided, thereby the quinolinone derivative can be cheaply prepared in higher yield without by-products. CONSTITUTION: The process for preparing quinolinone derivative comprises the steps of: reacting benzoyl aminocyanoacetic acid alkylester of formula(2) with 4-halomethyl-1H-quinoline- 2-one of formula(3) to prepare 2-(benzoylamino)- 2-cyano-3-(2-oxo1,2- dihydroquinoline-4-yl) propionic acid ester of formula(4); and hydrolyzing and selectively decarbonating 2-(benzoylamino)-3- (2-oxo-1,2-dihydroquinoline-4-yl) propionic acid derivative of formula(1), in which R is phenyl, 4-chlorophenyl or 4-methoxyphenyl; R1 is cyano and methyl or ethylester; and X is chlorine or bromine.

Description

A process for the preparation of quinolinone derivatives}

The present invention relates to a method for producing a quinolinone derivative represented by the following structural formula (1) , wherein the benzoyl aminocyanoacetic acid alkyl ester represented by the following structural formula (2) and 4-halomethyl represented by the structural formula (3) 2- (benzoylamino) -2-cyano-3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid represented by Structural Formula (4) by reacting -1H-quinolin-2-one The ester was prepared, and then the compound (4) was hydrolyzed and optionally decarbonized to yield 2- (benzoylamino) -3- (2-oxo-1,2-dihydroquinoline- represented by formula (1) . The present invention relates to a method for preparing 4-yl) propionic acid derivative.

In the above formula, R means phenyl, 4-chloro phenyl or 4-methoxy phenyl, R ₁ means cyano and methyl or ethyl ester, X means chlorine or bromine.

The compound of formula (1) of the present invention is a very useful substance for treating peptic ulcer.

Conventional techniques for preparing 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid, which are one of the target substances of the present invention, include Scheme 1 and The same method is known (GB 2,123,825, Republic of Korea Patent Publication (B1) No. 90-0006401).

<Scheme 1>

In the conventional patent method for synthesizing a quinolinone derivative, 4-bromomethyl-1H-quinolin-2-one (3) and diethyl acetamidomalonate (5) are refluxed using sodium metal in anhydrous ethanol solvent. To obtain the compound of formula (6) . Next, using the excess of 20% hydrochloric acid in the obtained compound (6) and reacting for a long time to obtain the amino derivative of formula (7) , and reacted with 4-chlorobenzoyl chloride using potassium carbonate as a base in acetone / water mixed solvent The desired compound (1) was synthesized in about 67% yield.

In the case of the existing patent method, there is a disadvantage that the price of diethyl acetamidomonate (5) used to obtain compound (6) is expensive. In addition, in order to synthesize compound (7) which is a quinolinone amino acid derivative, not only 20% strong acid is used in excess (using 30 vol. Of hydrochloric acid per 1 g of reactant), but also reacted for a long time (about 9 hours). The yield is generally low when acylating the amino acid derivatives obtained above to obtain the final compound (1) . In addition to the synthetic methods mentioned above, sodium hydroxide (34-55%), DCC (21%), triethylamine (55% ), But there are also synthetic methods such as mixed anhydride (45%) reaction and other reactions (10%), but these methods also yield very poor yields. In addition, the by-products of the reaction are not easily recrystallized, there is a disadvantage that it is difficult to purify the raw material to meet the pharmaceutical specifications.

Accordingly, the present invention is to provide a novel method that can solve the above-mentioned drawbacks and obtain a high yield of the target product, in the case of the present invention, instead of the diethyl acetamidomonate used in the existing patent, the raw material is cheap The benzoyl aminocyanoacetic acid alkylester of formula (2) was synthesized from the noacetic acid alkylester (8) with high yield. The advantage of the compound as formula (2) is that it can be synthesized much cheaper than the diethyl acetamidomonate used in the existing reaction, from which the compound of formula (4) can be obtained with high yield. In addition, in the case of the existing patent method, the amino derivative is made and then subjected to acylation reaction again to obtain the final material (1) through two steps, but when using the compound of the structural formula (2) synthesized by the present inventors in one step After the synthesis is completed, the cyano group of the obtained compound of formula (4) is hydrolyzed in a salt or an acid, and then selectively decarbonized to obtain the final compound (1) very effectively. In addition, when the reaction is acylated as in the conventional patent method, the yield is about 10 to 67%, but in the case of the present reaction, there is a big advantage that the target product can be easily obtained quantitatively (more than 80%) without any by-products generated.

The present invention relates to a method for producing a quinolinone derivative represented by the following structural formula (1), wherein the benzoyl aminocyanoacetic acid alkyl ester represented by the following structural formula (2) and 4-halomethyl represented by the structural formula (3) 2- (benzoylamino) -2-cyano-3- (2-oxo-1,2-dihydroquinolin-4--yl) represented by Structural Formula (4) by reacting -1H-quinolin-2-one Propionate ester is prepared, and then hydrolyzed and optionally decarboxylated to compound (4) to give 2- (benzoylamino) -3- (2-oxo-1,2-dihydroquinoline- represented by formula (1). The present invention relates to a method for preparing 4-yl) propionic acid derivative.

The target compound (1) of the present invention is synthesized by the same method as in Scheme 2 below.

<Scheme 2>

In the above structural formula, R means phenyl, 4-chloro phenyl or 4-methoxy phenyl, R ₁ means cyano and methyl or ethyl ester, X means chlorine or bromine.

Summarizing the process for preparing the quinolinone derivative of the present invention by process,

A) Second step: Synthesis process of compound (2) from cyanoacetic acid alkyl ester (8) ,

B) first step: synthesis process of precursor (4) of quinolinone amino derivative, and

C) Second step: hydrolysis and selective decarbonation reaction process.

Each step reaction of the present invention will be described in detail as follows.

Secondary step: Synthesis of the compound of formula (2) from cyanoacetic acid alkyl ester (8).

<Scheme 3>

In Scheme 3, R and R ₁ are as defined in Scheme 2.

constitutional formula(2)Compound synthesis was carried out by using cyanoacetic acid alkyl esters in a mixed solvent of glacial acetic acid and water.(8)Add. A small amount of sodium nitrite is added thereto to first prepare a 2-hydroxyaminocyano derivative (intermediate). This was converted into an amine by adding a reducing agent in the presence of glacial acetic acid, and then added with a benzoyl derivative.(2)Make a compound.

Suitable solvents used in this case may be water, glacial acetic acid, ether, dichloromethane, dichloroethane or tetrahydrofuran.

Suitable benzoyl derivatives may be used, such as benzoyl, 4-chloro benzoyl or 4-methoxy benzoyl.

Suitable reducing agents may be used, such as sodium borohydride, lithium aluminum hydride, ranei nickel or zinc. The amount of reducing agent used is 1 to 5 equivalents, preferably 2 to 3 equivalents, in the case of benzoyl derivatives. The reaction temperature is preferably 0 to 60 ° C, preferably 40 to 50 ° C.

Step 1: Synthesis of Precursor (4) of Quinolinone Amino Derivative

<Scheme 4>

In Scheme 4, R and R ₁ are as defined in Scheme 2.

2- (benzoylamino) -2-cyano-3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid ester(4)Compound is a structural formula(2)The compound and sodium metal are dissolved in anhydrous alcohol, and then the compound of formula (3) is added thereto and refluxed to obtain a product.

In this case, alcohols such as methanol and ethanol may be used as a suitable solvent.

As a suitable basic substance, sodium amide, sodium hydride, potassium hydride, sodium metal, etc. can be used. At this time, the reaction temperature is suitable to 150 ℃ at room temperature, preferably 80 to 110 ℃. The reaction time is suitable for 2 to 10 hours, preferably 4 to 5 hours.

Second Step: Hydrolysis and Selective Decarbonation Reaction

Scheme 5

R and R ₁ in Scheme 5 are as defined in Scheme 2.

2- (benzoylamino) -3- (2-oxo-1,2-dihydroquinoline-4-yl) propionic acid(One)In the case of the compound, an appropriate amount of a base and an acid are added to the compound (4) to hydrolyze the cyano group, and then decarbonize to obtain the target compound (1).

At this time, a suitable base may be used sodium hydroxide, sodium carbonate, potassium hydroxide or calcium carbonate. Suitable acids may be hydrochloric acid or sulfuric acid. At this time, the reaction temperature is suitably 20 to 150 占 폚, and preferably 70 to 120 占 폚. The reaction time is suitably 1 to 10 hours, preferably 3 to 5 hours.

Examples are described below, but the present invention is not limited to these examples.

Reference Example 1 Preparation of (4-chlorobenzoylamino) cyano acetate ethyl ester

30 mL of glacial acetic acid and 40 mL of water are added to 18 mL of ethyl cyanoacetate, and the reaction solution is cooled to 5 ° C. using an ice bath. Slowly add 32 g of sodium nitrite. Sodium nitrite is added and stirred at room temperature for 4 hours, and then the reaction solution is extracted with 50 mL of ether. Add 100 mL of glacial acetic acid to this solution, and then slowly add 39 g of zinc. Again 20 mL of 4-chlorobenzoyl chloride was added thereto and stirred at room temperature for 2 hours. The inorganic material produced during the reaction was filtered and washed with 50 mL of ether. The extracted ether was washed with water and brine, respectively, and dehydrated with anhydrous forget-me-not. The dehydrated ether solution was distilled under reduced pressure and crystallized to obtain 24 g (60%) of (4-chlorobenzoylamino) cyano acetate ethyl ester.

m.p. 109 ~ 111 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (3H, t), 4.39 (2H, q, J = 7.2), 5.70 (1H, d), 7.4-7.8 (4H, m); IR (KBr, cm ¹ ): 3290, 1740, 1650, 1640 cm ^-1 .

Example 1 Preparation of 2- (4-chlorobenzoylamino) -2-cyano-3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid ethyl ester

To 75 mL of anhydrous ethanol, add 6.7 g of (4-chlorobenzoylamino) cyanoacetic acid ethyl ester and 0.75 g of sodium metal, and dissolve completely. To this was added 6 g of 4-bromomethyl-1H-quinolin-2-one. The reaction solution was refluxed for 3 hours, distilled under reduced pressure, and added with water to 8.3 g (78%) of 2- (4-chlorobenzoylamino) -2-cyano-3- (2-oxo-1,2 -Dihydroquinoline-4-yl) propionic acid ethyl ester was obtained.

m.p. 253-258 ° C

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.93 (3H, t), 3.70 to 3.98 (4H, m), 6.64 (1H, s), 7.19 to 8.0 (8H, m), 9.88 (1H, s), 12.92 (1 H, s); IR (KBr, cm ¹ ): 3350, 1760, 1660, 1650 cm ¹ .

Example 2 Preparation of 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid

3.25 g of 2- (4-chlorobenzoylamino) -2-cyano-3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid ethyl ester and 0.6 g of sodium hydroxide are suspended in 13.5 mL of water. Then refluxed for 2 hours. When the reaction solution was completely dissolved and became a clear solution, 4 mL of 3N hydrochloric acid was added again and refluxed for 30 minutes to give 2.25 g (80%) of 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2- solid product. Dihydroquinoline-4-yl) propionic acid was obtained.

m.p. 288 ~ 290 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.2 to 3.6 (2H, m), 4.7 to 4.8 (1H, m), 6.48 (1H, s), 7.4 to 7.9 (8H, m), 8.95 (1H, d), 11.7 (1 H, s); IR (KBr, cm ⁻¹ ): 3300, 1720, 1640 cm ⁻¹ .

According to the present invention, the production cost is low, the precursor and the target product can be obtained in high yield, and there is no production of reaction by-products.

Claims (8)

2- (benzoylamino) represented by Structural Formula (4) by reacting benzoyl aminocyanoacetic acid alkylester represented by Structural Formula (2) with 4-halomethyl-1H-quinolin-2-one represented by Structural Formula (3) ) -2-cyano-3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid ester is prepared, and then the compound is hydrolyzed and optionally decarboxylated to formula (1). A process for preparing the 2- (benzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid derivative represented. In the above formula, R means phenyl, 4-chloro phenyl or 4-methoxy phenyl, R ₁ means cyano and methyl or ethyl ester, X means chlorine or bromine. The method according to claim 1, wherein the solvent used in synthesizing the compound of formula (4) is selected from methanol or ethanol. The method according to claim 1, wherein the base used in synthesizing Structural Formula (4) is selected from sodium amide, sodium hydride, potassium hydride or sodium metal. The method according to claim 1, wherein the base used in the decarbonation process for synthesizing Structural Formula (1) is selected from sodium hydroxide, sodium carbonate, potassium hydroxide or calcium carbonate, and the acid is selected from hydrochloric acid or sulfuric acid. . The production method according to claim 1, wherein the temperature of the reaction for synthesizing Structural Formula (1) is 70 to 120 ° C. Cyano after dissolving the acid alkyl ester (8) in glacial acetic acid / water mixed solvent is added sodium nitrite create a reaction of the intermediate, 2-hydroxy-2-amino-dicyano derivative, and then, using a reducing agent to change the amine paste benzoyl derivative formula ( 2) the manufacturing method to obtain. In the above structural formula, the definitions of R and R ₁ are as defined in claim 1. 7. The process according to claim 6, wherein the solvent used in the synthesis of the compound of formula (2) is selected from water, glacial acetic acid, ether, dichloromethane, dichloroethane or tetrahydrofuran. 7. The process according to claim 6, wherein the reducing agent used in the synthesis of the compound of formula (2) is selected from sodium borohydride, lithium aluminum hydride, lanney nickel or zinc.