RO131042A2 - Process for preparing fluorophores as 3-substituted benzocoumarin derivatives - Google Patents

Abstract

The invention relates to a process for preparing fluorophores as 3-substituted benzocoumarin derivatives. According to the invention, the process comprises the condensation of 2-hydroxy-1-naphthaldehyde with diethylmalonic ester, in the presence of morpholine catalyst, in ethanol medium, for 2h, at the reflux temperature, followed by the condensation of the ethyl ester of the 5,6-benzocoumarin-3-carboxylic acid formed with an amine in ethanol medium, for 3 h, at reflux, and the cooling of the resulting solution at the environmental temperature for crystallization of amide, which is then separated by filtration and purified by recrystallization from ethanol.

Description

PROCESS FOR OBTAINING 3-SUBSTITUTED BENZOCUMARIN-DERIVED FLUOROPHORES

The present invention relates to a process for obtaining high purity fluorophores, derived from 3-substituted benzocoumarin, which correspond to the general formula:

\ H / ^{R Ί} wherein: R and R ₂ may be the same or different and can be hydrogen, an alkyl or aryl radical, a heterocyclic amine residue or R and R ₂ may form a morpholinyl ring.

Being an important class of fluorescent organic heterocycles !, coumarin derivatives have been widely studied for their biological activity and especially for their antioxidant and anti-inflammatory properties. The remarkable optical properties of coumarin derivatives make them useful in a wide range of applications such as: optical brighteners, laser dyes, chromophores in nonlinear optics, electroluminescent materials, solar energy collectors, fluorescent marking materials in biology and medicine Benzo-substituted coumarin derivatives, known as benzocoumarins, have been less studied. Akira Takadate et al., In studies performed to highlight the fluorescent properties of coumarins and benzocoumarins, observed that benzocoumens, which have position 3 as various heterocyclic substituents, are highly fluorescent.

The production of benzocoumarin compounds can be accomplished by various known processes, such as by reacting hydroxyaphthaldehydes with carboxylic acids or esters thereof, which contain an active methylene group in the position adjacent to the carboxyl group. For the synthesis of compounds of this structural type can be used as naphtaldehydes 2-hydroxy-1-naphtaldehyde, 1-hydroxy-2-naphtaldehyde, 1-hydroxy-4-methoxy-2-naphthalaldehyde, 1-hydroxy-4-methoxy-2-naphtaldehyde, 1- hydroxy-4-chloro-2-naphtha dehydride or 1-hydroxy-4-bromo-2-naphtaldehyde, and as carboxylic acids containing an active methylene group in the position adjacent to the carboxyl group may be mentioned malonic acid, cyanoacetic acid, phenylacetic acid and acetoacetic acid.

The preparation of 3-substituted benzocoumarins is described, for example, in US 2,878, wherein the synthesis of 5,6-benzocoumarin ethyl ester is carried out. The choice between diethylmalonic ester and 2-hydroxy-1-naphthaldehyde is carried out. at a molar ratio of 1,01.0 di ethyl alcohol, at a concentration of 29% of 2-hydroxy-1-naphtaldehyde in aucuresii

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15-1D-20H reaction mass, using piperidine as catalyst. The 5,6-benzocoumarin-3-carboxylic acid ethyl ester obtained can be used for the optical bleaching of various polycondensed synthetic materials such as polyesters, polyamides or polyurethanes.

PL 56,780 discloses a process for the synthesis of benzocoumarins by condensing 2-hydroxy-1-naphtaldehyde with a compound with an active methylene group, in the presence of ethyldiaminotetraacetic acid and an aliphatic or heterocyclic secondary amine. Similarly, German Patent DE 1,275,983 relates to the production of 5,6-benzocoumarin-3 substituted by the reaction of 2-hydroxy-1 naphthalaldehyde with compounds containing active methylene groups, in the presence of catalytic amounts of secondary amines, in the medium of aliphatic alcohols, ketones. or pyridine.

U.S. Pat. No. 3,075,996 discloses a process for melting 5,6-benzocoumarin-3-carboxylic acid aw3'-dimethylaminopropylamide by reaction between 5,6-benzocoumarin-3-carboxylic acid ethyl ester and 3-dimethylamino-propylamine. the result being used for mass optical bleaching of artificial fibers.

Patent PL84999 claims a process for the production of 5,6-benzocoumarin-3-carboxylic acid ethylamide by the reaction of 2-hydroxy-1-naphthaldehyde and diethylmalonic ester, at a molar ratio of 1: 1.25, in the presence of piperidine catalyst, followed by amidation of the ester formed with 1.2 moles of ethylamine. According to this process, 5,6-benzocoumarin-3-carboxylic acid ethylamide is obtained in a yield of 68.2%.

Patent RO107409 relates to the production of 5,6-benzocoumarin-3-carboxylic acid alkyl esters or alkylamides by condensing 2-hydroxy-1-naphthaldehyde with diethyl malonate, at a molar ratio of 3.3: 1, in the presence of the morpholine catalyst, followed by amination of the resulting ester with 1.4 moles of ethyl amine. In order to obtain a product with a high degree of purity, it is proposed that sulfur dioxide be bubbled into the reaction mass or that a salt generating sulfur dioxide and charcoal be introduced. 5,6-benzocoumarin-3-carboxylic acid ethylamide is conditioned in the form of a stable dispersion, which can be used for the optical bleaching of textile substrates from acetate, triacetate and polyacrylbnitrile.

The procedures presented have the following disadvantages:

-high concentrations of reactants in the reaction mass ensure high reaction rates, but also favor the formation of by-products difficult to remove from the finished product and obtaining yields below 70%;

-timpiflOTigrcfe ^ favors the obtaining of colored by-products that remain embedded and it has a significantly diminished fluorescence;

fc 'WE ARE BLIND. />% ^Buc î ^res ql O 14-- OD 76 8 - L 1 5 -10- 2DU

- the use in the phase of obtaining the ethyl ester of 5,6-benzocoumarin-3-carboxylic acid of quantities of reactants over the equimolar quantities favors the obtaining of reaction by-products that negatively influence the purity and implicitly the fluorescence of the finished product;

-use sulfur dioxide or salts generating sulfur dioxide, Corrosive and toxic substances, to obtain products with a high degree of purity.

According to the invention, 3-substituted benzocoumarin derivatives corresponding to general formula (I) are obtained by a process which involves two steps, as follows:

a) Knoevenagel condensation of 2-hydroxy-1-naphthaldehyde with diethylmalonic ester. The reaction takes place in ethyl alcohol, at reflux, for 3-4 hours and in the presence of catalytic amounts of a secondary alkylamine or heterocyclic amine.

b) Condensation of ethyl ester of 5,6-benzocoumarin-3-carboxylic acid resulting from ammonia, aliphatic primary or secondary amines, aromatic amines or heterocyclic amines in the reaction mass from the Knoevenagel condensation of 2-hydroxy-1-naphtaldehyde with the ester diethylmalonate.

Compared to the processes described in the literature [1-8], the process according to the invention has the following advantages:

- ensures the obtaining of pure products;

-leads to an increase in yield of 10-15%, by eliminating intermediate leaks;

- shortens the synthesis process by approx. 10 hours, by excluding the operation of isolating 5,6-benzocoumarin-3-carboxylic acid ethyl ester.

The following are 7 examples of carrying out the process according to the invention.

Example 1. 90 ml of ethyl alcohol, 15.5 ml (0.1 mol) of diethylmalonic ester and 17.2 g (0.1 mol) of water are charged to a reaction vessel equipped with a stirrer, thermometer, reflux refrigerant and heating-cooling bath. hydroxy-1-naphthaldehyde. The reaction mixture was gradually warmed to 50-55 ° C and 0.026 mol of morpholine was added as an alkaline catalyst. Continue heating, with stirring, to reflux temperature, where it is kept for 2 hours to complete. Finally, the reaction is diluted with 45 ml of ethyl alcohol and introduced at 65-70 ° C

8.2 ml of 25% (0.11 mol) ammonia solution. After 3 hours at reflux maintained masaje_reacţie cooled to crystallize the formed amide which is isolated by filtration and purified in ^{a co} ° l l ether. 21 g of 5,6-benzocoumarin-3-carboxamide are obtained, which are the physicochemical properties of Table 1.

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Example 2. Proceed as in Example 1, except that the wet reaction mass containing 5,6-benzocurnarin-3-carboxylic acid ethyl ester is cooled and the precipitate obtained is isolated by filtration and the resulting cake is washed on the filter with 30 ml of alcohol. ethyl and approx. 200 ml of water. After drying, approx. 24 g straw-yellow powder subjected to aniline amidation, in a molar ratio of 5 _w 6-benzoCumarin-3-carboxylic acid ethyl ester: 1: 1.1 aniline. Finally, after drying, 23 g of 3-phenylcarboxamido-5,6-benzocoumarin are obtained. Physico-chemical characteristics of the two products, ethyl ester of acid

5,6-benzocoumarin-3-carboxylic and 5,6-benzocoumarin-3-phenylcarboxamide are shown in Table 1.

Example 3. The procedure is as in Example 1, except that 12.7 ml of cyclohexylamine (0.11 mol) are used for amide synthesis. 28 g of 5,6-benzocoumarin-3-cyclohexylcarboxamide are obtained for which the physico-chemical characteristics given in Table 1 have been determined.

Example 4. Proceed as in Example 1 except that 11 ml of n-butylamine (0.11 mol) is used for amide synthesis. 21 g of 5,6-benzocoumarin-3-n-butylcarboxamide having the physico-chemical characteristics of Table 1 are obtained.

Example 5. Proceed as in Example 1 except that 11 ml of iso-butylamine (0.11 mol) are used for amide synthesis. 21 g of 5,6-benzocoumarin-3-isobutylcarboxamide are obtained, the physico-chemical characteristics of which are shown in Table 1.

Example 6. Proceed as in Example 1 except that 11.3 ml of 3-methoxypropylamine (0.11 mol) are used for amide synthesis. 28 g of 5,6-benzocoumarin-3- (3'-methoxypropyl) carboxamide are obtained for which the physico-chemical characteristics in Table 1 have been determined.

Example 7. Proceed as in Example 1 except that 9.7 ml of morpholine (0.11 mol) are used for amide synthesis. 25 g of 5,6-benzocoumarin-3-morpholinylcarboxamide with the physicochemical properties of Table 1 are obtained.

7 6 8 Table 1: Physico-chemical characterization

Note, -IR spectra were recorded on a Jasco FTIR 6300 spectrophotometer;

-UV-VIS spectra were recorded on a Jasco UV-VIS / NIR V570 spectrophotometer;

-fluorescence spectra were recorded on a JASCO FP-6500 spectrofluorimeter with V-500 integrating sphere.

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PROCESS FOR OBTAINING 3-SUBSTITUTED BENZOCUMARIN-DERIVED FLUOROPHORES

Claims (1)

CLAIM Process for obtaining fluorescent compounds! of high purity, acid amides 5,6-benzocoumarin-3-carboxylic acid, consisting of the condensation of 2-hydroxy-1-naphthaldehyde with diethylmalonic ester in the presence of the morpholine catalyst, at a molar ratio of 2-hydroxy-1-naphthaldehyde: diethylmalonic ester of 1: 1, in ethyl alcohol medium at reflux for 2 hours, followed by condensation of 5,6-benzocoumarin-3-carboxylic acid ethyl ester formed with aniline, ammonia, cyclohexylamine, n-butylamine, iso-butylamine, morpholine or 3-methoxypropylamine , at a molar ratio of 3-carboxyethyl-5,6-benzocoumarin: amine of 1: 1.1, in ethyl alcohol, at reflux for 3 hours and cooling of the resulting solution at room temperature to crystallize the amide, which is separated by filtration and is purified by recrystallization from ethyl alcohol.