DD273062A1 - PROCESS FOR PREPARING HYDROXYBENZOESAEURE (CHINOXALIN-2-YLMETHYL) ETHANTS AND ETHERS - Google Patents

Abstract

The invention relates to a process for the production of hitherto inaccessible hydroxybenzoic acid (quinoxalin-2-ylmethyl) ether and esters (formula II-V), which are applicable as intermediates for the preparation of biologically active preparations. The synthesis takes place by reaction of the hydroxybenzoic acids or their esters with 2- (halomethyl) quinoxalines in the presence of a base. Depending on the reaction conditions and the molar ratio of the starting materials, either ethers (eg, formula III), esters (eg, formula II), or compounds having both structural features (eg, formula IV) are formed which, in turn, form others Derivatives such as acids, salts, ethers, esters, hydrazides (eg, formula V) can be converted.

Description

Field of application of the invention

The invention relates to a process for the preparation of hydroxybenzoic acid (quinoxalin-2-ylmethyl) ethers and esters, which are applicable as intermediates for the preparation of biologically active preparations.

Characteristic of the known technical solutions

, Hydroxybenzoic acid (quinoxalin-2-ylmethyl) ethers and esters are unknown; Thus, there is still no process for their preparation.

The formation of ethers from phenolates and halomethylquinoxalines is known. Also known is the formation of esters from the salts of carboxylic acids and halomethylquinoxalines (eg PS DE 27 22 777

from 8.12.1977). These two methods can not readily be applied to dia hydroxybenzoic acids because the

Hydroxybenzoic acids containing both the functional group of a phenol and a dio carboxylic acid and it first

It is undetermined which of the two functional groups reacts, and thus the possibility of forming different ones

Products or mixtures thereof. Also, the conversion of hydroxybenzoic acid esters to the corresponding ethers can not be after the above mentioned. known Procedures are carried out as this is carried out in an aqueous-alkaline medium, whereby the esters at least

partially saponified.

Object of the invention

The aim of the invention is to find a process for the preparation of quinoxalin-2-ylmethyl ethers and esters of hydroxybenzoic acids and their derivatives, since such compounds are not previously available.

Explanation of the essence of the invention

- Aufgüt of the invention is to find a method by which the previously inaccessible hydroxybenzoic acid (quinoxalin-2-ylmethyl) ethers and esters can be produced.

Features of the invention

According to the invention the object is achieved in that hydroxybenzoic acids A or their esters E with the general formulas I and II, in which the two functional groups can be in o-, m- or p-position and at AR = H or ER = Alkyl or aryl and Q represents a quinoxalin-2-yl radical, which preferably corresponds to the formula Vl, in the presence of a base B with 2- (halomethyl) quinoxalines C of the general formula Hal-CH ₂ -Q, in which shark preferred Cl or Br and Q represents a quinoxalin-2-yl radical which corresponds to Formula VI corresponds to hydroxybenzoic acid (quinoxalin-2-ylmethyl) ethers or esters with the proviso that

When using the ester E of the general formula I or II, the reaction in anhydrous solvent, preferably in absolute alkenol ROH, acetone, butanone or DMF, in the presence of Alkalialkanolat, preferably RONa, or alkali carbonate, preferably anhydrous K ₂ CO ₃ performed is while the starting materials in an equimolar ratio (E: B: C = 1: 1: 1) are used, the reaction product compounds of general formula III or IV, in which R and Q have the same meaning as in the starting materials, arise and

• when using the acids A of the general formula I with R = H, the same solvents and bases as boim use of the ester E can be used, but preferably commercially available ethanol or e <n other ethanol-water mixture al * solvent and KOH or NaOH be used as base and bsi a molar ratio of the starting materials of A: B: C = 1: 1: 1, the ester group general formula II, at the ratio A: ß: C = 1: 2: 1, the ethers of general formula II! with R = H or K or Na and at the ratio of A: B: C = 1: 2: 2, the compounds of the general formula IV, where in each case Q has the same meaning as in the reaction partner C used, arise and the resulting Chirioxalin- 2-ylmethoxybenzobenzoic acids or their esters may then be converted to other derivatives using polar or nonpolar solvents, preferably from commercial ethanol or other ethanol-water mixtures, provided that

• the quinoxalin-2-ylmethoxybenzoic acid esters of the general formula III and IV with R = alkyl or aryl by the action of alkali metal hydroxide or carbonate in the salts of the general formula III where R = Na or K, from which by acidification the acids of the general formula III be formed with R «H, and be converted by the action of hydrazine in the hydrazides of general formula V, wherein Q each has the same meaning as in the precursors, and

The quinoxalin-2-ylmethoxybenzoic acids of the general formula III where R =H or their alkali metal salts react with the reactant C in a molar ratio of 1: 1 to give the compounds of the general formula IV in which Q has the same meaning as in the respective precursors, wherein, in the case of using an acid, one equivalent of base is added before the reaction.

The reactions are carried out at temperatures of -8O ⁰ C to 2OO ° C, but preferably in the range of 1O ⁰ C to 11O ⁰ C, and under a pressure of 1OhPa to 10MPa, but preferably carried out at atmospheric pressure.

The required starting materials are either commercially available or are not disclosed in the literature (eg BZobSi.chim.29 (1959) 2763, J.org.Chemistry 31 [1966] 2613, Z. Chem., 1982, 282, J.Amer.Chem Soc., 1963, 1830, Helv., 1986, Acta 29 (194611247, J. Chem. Soc., 1955, 303).

COOR COOR CONHNH ₂ OCH ₂ QK -H-OCH ₂ Q

I i

COOCH ₂ Q COOCH ₂ Q

OCH ₂ Q

I E 21

AusfOhrungsbelsplele example 1

2-O-methyl-quinoxalin-2-ylmethoxy) -benzoic acid methyl ester

In an alkanolate solution prepared from 2.3 parts by weight. Sodium and 180Tl. absolute methanol, dissolve 15.3Tl. Salicylic acid methyl ester and finally adds the solution of 23.7Tl. 2- (bromomethyl) -3-methyl-quinoxaline in 400 μl. absolute Methanol added. The mixture is refluxed for 3 hours and then filtered hot. The solution is concentrated in vacuo

The product, which crystallizes out in the cold, sucks and recrystallizes from methanol and / or heptane.

Yield: 50% of theory Melting temperature: 110-112 ⁰ C Example 2

2- (3-methyl-chinoxalln-2-ylmethoxy) benzoate

One puts one from 160Tl. absolute ethanol and 2.3Tl. Sodium-produced alkanolate solution with 17Tl. salicylate

and adds the solution of 23.7Tl. 2- (Bromorethyl) -3-methyl-quinoxaline in 400 μl. added to absolute ethane. The mixture becomes a

Cooked under reflux and then filtered hot. The solution is concentrated in vacuo, sucked in the cold

crystallizing product and crystallized from ethanol and / or heptane to.

Yield: 53% of theory Melting temperature: 101-104 ° C Example 3

2- (3-methyl-quinoxalin-2-ylmethoxy) phenyl benzoate

23,7Tl. 2- (bromomethyl) -3-methylquinoxaline and 23.7Tl. Salicylic acid phenyl esters are dissolved in 320 μl. Acetone dissolved and with 20Tl.

Potassium carbonate added. While stirring, the mixture is refluxed for 4 hours, filtered hot and distilled Solvent off. The remaining residue is recrystallized from acetone or cyclohexane. Yield: 34% of theory Melting point: 112-114 ⁰ C

Example 4 Ethyl 3- (3-methyl-quinoxalin-2-ylmethoxy) benzoate

a) Analogously to Example 2 with 17Tl. S-hydroxy-benzoic acid ethyl ester Yield: 84% of theory

Melting temperature. 87.5-89.5 ⁰ C (from hexane)

b) Analogously to Example 3 with 17Tl. 3-Hydroxy-benroic acid ethyl ester and 320Tl. butanone; the crude product obtained as oil is brought to crystallization by stirring with a little ethanol.

Yield: 65% of theory Example 5

4- (3-methyl-chlnoxalln-2-ylmethoxy) benzoic acid 'methyl ester

Analogously to Example 2 or 3 with 17Tl.4-hydroxy-benzoic acid ethyl ester

Yield: 72 and 71% of theory, respectively

Melting temperature: 123-124.5 * 0 (bus heptane or ethanol)

Example β

4- (3-methyl-quinoxalin-2-ylmethoxy) benzoesäurepropylester

From 200Tl. Propanol and 2.3Tl. Sodium is prepared an alkanolate solution containing 19 μl. 4-hydroxy-benzoic acid propyl ester is added. Add the hot solution of 23.7Tl. 2- (bromomethyl) -3-methyl-quinoxaline in 200 μl. Add propanol and treated the mixture as in Example 2.

Yield: 53% of theory

Melting point: 88 to 89.5 ⁰ C (from isopropanol)

Example 7

2- (3-methyl-quinoxalin-2-ylmethoxy) benzoic acid

The solutions of 30.8Tl. Methyl 2- (3-methyl-quinoxalin-2-ylmethoxy) benzoate in 600 μl. Ethanol and of 35Tl. Soda in1500Tl. Water is combined and gradually heated to boiling. The mixture is refluxed for 15 minutes, and the ethanol is distilled off in vacuo. The precipitated red by-product (melting range 222-224 ⁰ C, from Pyriuin) is filtered off with suction and washed with sodium carbonate solution. The combined filtrates are slowly acidified with acetic acid to precipitate the desired product. It is filtered off with suction and crystallized from ethanol.

Yield: 54% of theory

Melting point: 198-200 ⁰ C

Example 8 3- (3-Methylquinoxalin-2-ylmethoxy) benzoic acid

a) With heating, dissolve 32.2Tl. Ethyl 3- (3-methyl-quinoxalin-2-ylmethoxy) benzoate in 400 μl. Ethanol or 8Tl. Potassium hydroxide in 200Tl. Ethanol. Both solutions are combined and refluxed for 1 hour. By adding 5% aqueous acetic acid, the reaction solution is slightly acidified. It is left overnight in the cold and sucks the desired acid. Further purification can be carried out by recrystallization from ethanol. Yield: 92% of theory

Melting temperature: 204-207 ⁰ C

b) The solution of 13.8Tl. m-hydroxy-benzoic acid and 11.2Tl. Potassium hydroxide in 100 parts Ethanol gradually becomes with the warm solution of 23.7Tl. 2- (bromomethyl) -3-methyl-quinoxaline in 400 μl. Ethanol added. While stirring, the mixture is kept for 30 minutes at 50 ⁰ C, heated for a further 30 minutes to boiling and filtered hot. The filtrate is acidified with dilute acetic acid and placed in the refrigerator overnight. It sucks the solid material and dissolves for cleaning in excess boiling sodium carbonate solution. After separation of insoluble constituents, the desired product is formed by acidification with acetic acid, which is separated off and recrystallized from ethanol.

Yield: 44% of theory

Example 9

Potassium salt of 4- (3-methyl-quinoxalin-2-ylmethoxy) benzoic acid

The hot solution of 32.2Tl. Ethyl 4- (3-methyl-quinoxalin-2-ylmethoxy) benzoate in 400 μl. Ethanol is treated with 8 l of solution. Potassium hydroxide in 400Tl. Ethanol added. The mixture is refluxed for 15 minutes using a boiling water bath, allowed to cool to room temperature, filtered off with suction and washed twice with ethanol.

Yield: 84% of theory

Melting temperature: from 325 ⁰ C with decomposition

Example 10 4- (3-Methylquinoxalin-2-ylmethoxy) benzoic acid

a) The potassium salt of 4- (3-methyl-quinoxalin-2-ylmethoxy) benzoic acid is dissolved in 10 times the mass of 5% 'ger sodium bicarbonate solution hot. By acidification with dilute acetic acid, the desired product is formed, which is filtered off with suction, washed with water and recrystallized from ethanol.

Jte curing ^e ': 90% of theory Melting point: 206-209 ⁰ C.

b) To dissolve 13.8 parts. p-hydroxybenzoic acid and 11.2Tl. Potassium hydroxide in 400Tl. Ethanol, with stirring, the warm solution of 23.7 TI. 2- (bromomethyl) -3-methyl-quinoxaline in 400 μl. Ethanol gradually added. On the water bath is boiled for 15 minutes under reflux and allowed to cool. It sucks the resulting product, it dissolves again in 850Tl. boiling 5% sodium bicarbonate solution and separating the insoluble by-product. The filtrate is acidified with dilute acetic acid to form the desired product, which is suction filtered cold and finally recrystallized from ethanol.

Yield: 68% of theory

Example 11

Salicylic acid-β-methyl-quinoxaline-1-methyl methoxide The solution of 23.7 g of 2- (bromomethyl) -3-methyl-quinoxaline in 40% TiO. Ethanol is mixed with the solution of 5.6 μl. Potassium hydroxide and 13.8 parts Salicylic acid in 200Tl. Ethanol and boiled for 2 hours with stirring and reflux. Filter the hot solution and concentrate in vacuo. The precipitated product is filtered off, washed with water and recrystallized from ethanol.

Yield: 58% of theory Melting temperature: 144-145 ⁰ C

Example 12

S-hydroxy-benzoic acid O-methyl-quinoxaline-1-methyl-methyl ester Analogous to Example 11 with 13.8 parts of 3-Hydroxy-benzoic acid Yield: 69% of theory Melting temperature: 192-195 ⁰ C

Example 13

.; 4-hydroxy-benzoic acid (3-methyl-quinoxalin-2-ylmethyl ester Analogously to Example 11 with 13,8Tl ethanol yield 4-hydroxy-benzoic acid in 300TL: 76% of theory Melting point: 206-210 ⁰ C.

Example 14

2- (3-methyl-quinoxalin-2-y ^l-methoxy) benzoic acid (3-methyl-quinoxalin-2-ylmethyl) ester In 1750Tl. Ethanol was 29.4 parts. 2- {3-methyl-quinoxalin-2-ylmethoxy) benzoic acid> and 5.6 part. Potassium hydroxide dissolved under heating. Add the solution of 23.7 parts. 2- (bromomethyl) -3-methyl-quinoxaline in 400 μl. Ethanol, refluxed for 2 hours and concentrated in vacuo. The precipitated product is filtered off with suction, washed with water and recrystallized from N, N-dimethylformamide.

Yield: 76% of theory Melting temperature: 174-176.5 ⁰ C

Example 15 S-O-Methyl-quinoxaline-1-methylmethoxybenzoic acid-O-methyl-quinoxaline-1-methylmethyester

a) Analogously to Example 14 with 29.4 parts. 3- (3-methyl-2-chloro-2-ylmethoxy) benzoic acid and 5.6 parts Potassium hydroxide in BOOTI. Ethanol Yield: 73% of theory Melting temperature: 144.5-146.5 ⁰ C

b) The solutions of 13.8Tl. 3-hydroxybenzoic acid and 11.2Tl. Potassium hydroxide in 300 μl. Ethanol and from 47.4Tl. 2- (bromomethyl) -3-methyl - <; hinoxaline in 800 μl. Ethanol are combined and boiled under reflux for 2 hours. It is then filtered hot and concentrated in vacuo. The cold-sucked product is washed with water and recrystallized from Ν, Ν-dimethyl-formamide or ethanol.

Yield: 75% of theory

c) From 2.3Tl. Sodium and 100Tl. Absolute ethanol is prepared an ethanolate solution, which is used to dissolve 29.4Tl. 3-Hydroxy-benzoic acid (3-methyl-quinoxalin-2-ylmethyl) ester in 700 μl. absolute ethanol is added. Finally, it is mixed with the solution of 23.7Tl. 2- (bromomethyl) -3-methyl-quinoxaline in 400 μl. absolute ethanol and reflux for 2 hours. It is then concentrated in vacuo, filtered off with suction, washed with water and recrystallized. Yield: 53% of theory

Example 16 4- (3-Methyl-quinoxalin-2-ylmethoxy) benzoic acid (3-methyl-quinoxalin-2-ylmethyl) ester

a) 33.2Tl. Potassium salt of 4- (3-methyl-quinoxalin-2-ylmethoxy) benioesäure be hot dissolved in about 10 times the mass of 50% aqueous ethanol and with the solution of 23.7Tl. 2- (bromomethyl) -3-methyl-quinoxaline in 400 μl. Ethanol added. While stirring, it is refluxed for 2 hours. It is allowed to cool, filtered off with suction, washed with water and recrystallized from Ν, Ν-dimethylformamide.

Yield: 81% of theory Melting point: 175.7 to 177 ⁰ C.

b) Dissolve 13.8 parts. 4-hydroxybenzoic acid and 11.2Tl. Potassium hydroxide in 400Tl. Ethanol and mixed with the solution of 47.4Tl. 2- (bromomethyl) -3-methylquinoxelin in 80% Ti. Ethanol. While stirring, the mixture is refluxed for 3 hours. After cooling, it is filtered off with suction, washed with water and crystallized.

Yield: 65% of theory

Example 17

2- (3-Melhyl-quinoxalin-2-ylmethoxy) benzoic acid hydrazide The ethanoic solution of 2- (3-methyl-quinoxalin-2-ylmethoxy) benzoic acid methyl ester is treated with excess 72% hydrazine hydrate and refluxed for 4 hours. After cooling, the mixture is filtered off with suction and recrystallized from pyridine.

Yield: 58% of theory Melting temperature: 226-227'C

Example 18

3- (3-Methyl-quinoxalin-2-ylmethoxy) benzoic acid hydrazide Analogous to Example 17 with S-O-methyl-quinoxaline-1-methylmethoxybenzoic acid ethyl ester Yield: 67% of theory

Melting temperature: 177-178'C

Example 19

4- (3-Methyl-quinoxalin-2-ylmethoxy) benzoic acid hydrazide 4- (3-Methyl-2-chloro-2-ylmethoxy) -benzoic acid (3-methyl-2-oxo-2-ylmethyl) -ester is dissolved in warm pyridine and after Boiled with excess 72% hydrazine hydrate for 4 hours under reflux. After cooling, the mixture is filtered off with suction and recrystallized from pyridine / ethanol.

Yield: 42% of theory

Melting temperature: 192-194 "C

Claims (8)

1. A process for the preparation of hydroxybenzoic acid (quinoxalin-2-ylmethyl) ethers and esters, characterized in that hydroxybenzoic acids (A) or their esters (E) in the presence of a base (B) with 2- (halomethyl) quinoxalines (C) to hydroxybenzoic acid (quinoxalin-2-ylmethyUern) or esters react and the resulting quinoxalin-2-ylmethoxybenzoic acids or their esters can then be converted into other derivatives. 2. The method according to item 1, characterized in that the hydroxybenzoic acids used as starting materials A or their esters E correspond to the general formulas I and II, in which the two functional groups can be in the o-, m- or p-position and in AR = H or ER = alkyl or aryl and Q represents a quinoxalin-2-yl radical, which preferably corresponds to the formula VI. 3. The method according to item 1, characterized in that are used as reactants C 2- (Halogenmethy!) Quinoxalines of the general formula Hal-CH ₂ -Q, in the shark preferably Cl or Br and Q is a quinoxalin-2-yl Rest represents, which preferably corresponds to the formula Vl. 4. The method according to item 1, characterized in that when using the esters of the general formula I or II, the reaction in anhydrous solvent, preferably in absolute alkanol ROH, acetone, butanone or DMF, in the presence of Alkalialkanolat, preferably RONa, or alkali metal carbonate , preferably anhydrous K ₂ CO ₃ , is carried out while the starting materials in an equimolar ratio (E: B: C = 1: 1: 1) are used, wherein the reaction product compounds of the general formula III or IV, in which R and Q have the same meaning as in the starting materials (see point 2 and 3I) arise. 5. The method according to item 1, characterized in that when using the acids of general formula I with R = H, the same solvents and bases asunterstellpunkt 4 can be used, but preferably commercially available ethanol or other ethanol-water mixture as a solvent and KOH or NaOH Base are used and at a molar ratio of the starting materials of A: B: C = 1: 1: 1, the esters of the general formula II, at the ratio A: B: C = 1: 2: 1, the ethers of general formula III with R = H or K or Na and the ratio of A: B: C = 1: 2: 2, the compounds of the general formula IV, wherein each Q has the same meaning as in the reaction partner C used arise. 6. The method according to item 1, characterized in that the resulting quinoxalin-2-ylmethoxybenzoesäureester of the general formula III and IV using polar or nonpolar solvents, preferably of commercial ethanol or other ethanol-water mixture, by the action of alkali metal hydroxide or carbonate into the salts of the general formula III where R = Na or K, from which the acids of the general formula III are formed by acidification with R = H, and are converted into the hydrazides of the general formula V by the action of hydrazine, where Q each has the same meaning as in the ester used. 7. The method according to item 1, characterized in that the resulting quinoxalin-2-ylmethoxybenzoic acids of the general formula III or their alkali salts with the reactant C in a molar ratio of 1: 1 using the solvent mentioned in point 5 to the compounds of general formula IV, in which Q has the same meaning as in the starting materials, wherein in the case of the use of an acid one equivalent of base is added before the reaction. 8. The method according to item 1, characterized in that the reactions at temperatures of -8O ⁰ C to 25O ⁰ C, but preferably in the range of 1O ⁰ C to 110 ° C, and under a pressure of 1OhPa to 10MPa, but preferably at Normal pressure, be carried out.