Field of the Invention

The present invention relates to novel heterocyclic dyes and their application as well as to a efficient process for their manufacture using (i) ammonium formate as reactant and solvent and (ii) citric acid and/or aconitic acid and/or salts of the aforementioned acids.

Background

Many nitrogen heterocyclic compounds have proven to be excellent dyes or valuable intermediates for a broad range of applications. As an example, citrazinic acid (2,6- dihydroxyisonicotinic acid), itself being a yellow powder, was used in the synthesis of azo dyes for use in cellulosic and nylon fiber dyeing [see G.H. Elgemeie, M.H. Helal, H.M. El-Sayed, Pigm. Resin Technol. 30 (2001)], in the synthesis of fluorescent molecules [see N. Chandrasekhar, R. Chandrasekar, J. Org. Chem. 75 (2010) 4852] and the preparation of various amine derivatives used as reactive dyes [see US 3,000,897],

As a dihydro-pyridine ring with a carboxylic acid and hydroxy group substitution, citrazinic acid has numerous possible resonating structures allowing a high variability in the design of dyes, a high solubility in polar solvents, ^-stacking capabilities, good compatibility with biological systems, tunable reactivity towards common fabrics and high thermal stability.

The compound is also known to form dimers which are likewise useful and exhibit interesting optical properties [see S. Mura et al, ..Modulating the Optical Properties of Citrazinic Acid through the Monomer-to-Dimer Transformation", J. Phys. Chem. A 2020, 124, 197-203], Dimers and higher stacked species are further used as a fluorophore for carbon quantum dots (CQD), see [C. Reckmeier et al., ..Aggregated Molecular Fluorophores in the Ammonothermal Synthesis of Carbon Dots", Chem. Mater. 2017, 29, 10352-10361],

Citrazinic acid may be prepared according to the process described in US 2,728,773 which however just yields 44 % in a multistep synthesis. In view of the aforementioned prior art, there is still a strong need to provide further dyes having similar structural advantages like citrazinic acid but with different or enhanced optical properties.

Preferably, such dyes should have a high color strength and light fastness, be water soluble, and exhibit low toxicity to allow their use in food and beverage industry or related packaging.

As a further goal there was a need to provide an efficient process for their manufacture starting from readily available compounds without the need to involve toxic or hazardous organic intermediates.

Summary of the Invention

According to one aspect of the invention, there are now provided compounds of formula (I) wherein

Cat each independently denotes a cation including a proton, in a preferred embodiment either a proton, a monovalent cation or 1/n equivalent of a n-valent cation.

In addition, there is provided a process for the preparation of compounds of formula (I) by reacting citric acid and/or aconitic acid and/or salts of the aforementioned acids with ammonium formate. Detailed description of the Invention

The invention also encompasses all combinations of preferred embodiments, ranges parameters as disclosed hereinafter with either each other or the broadest disclosed range or parameter.

Formula (I) also encompasses any rotational isomers and resonance structures of the depicted molecules.

Whenever used herein the terms “including”, “for example”, “e.g.”, “such as” and “like” are meant in the sense of “including but without being limited to” or “for example without limitation”, respectively.

As used herein the term “citric acid” includes both the anhydrous form as well as the monohydrate, whereby the anhydrous form is preferred.

As used herein the term “aconitic acid” includes both the cis- and trans-isomer as well as any mixture thereof.

The compounds of formula (I) are dark solids that are readily soluble in water, formic acid, dimethylformamide, dimethylsulfoxide and other highly polar solvents. Their solubility in les polar solvents such as acetone, ethanol, methanol and dichloromethane is low.

Solutions of compounds of formula (I) exhibit a bright rose color.

Fig 1. shows the LIV/VIS spectrum of an aqueous solution of the tetraammonium salt i.e. a compound of formula (I) wherein each Cat identically represents ammonium in neutral solution (solid line), after acidification (dotted line), and after adding a base (dashed line)

Fig 2. shows the FTIR spectrum of the tetraammonium salt. The pyrazine structural unit with the vibrational mode at 1560 cm ^-1 can be assigned to the C=N or C=C bond vibrations in substituted pyridines. The band at around 1700 cm ^-1 corresponds to C=O vibrations in aromatic ketones or carboxylic acids.

In formula (I) each Cat independently represents a cation. In one embodiment suitable cations include a proton, ammonium, guanidinium, pyridinium, a primary, secondary, tertiary or quarternary organic ammonium ion, in particular those of formula [N(Ci-Cis- alkyl) _s Ht] ⁺ wherein s is 1 ,2, 3 or 4 and t is (4-s) as well as monovalent metal ions such as lithium, sodium, potassium and cesium, one half equivalent of a divalent metal ion such as magnesium, calcium, strontium or barium. A preferred cation is ammonium. Preferred compounds of formula (I) are the tetra ammonium, the tetra sodium and the tetra potassium salts, i.e. those therein each Cat identically represents ammonium or sodium or potassium.

Compounds of formula (I) are useful as or as a component of dyes for example for food, beverages, cosmetics, pharmaceuticals, packaging such as packaging with food contact, printed articles, polymers, fabric, textiles. They are further useful as or as a component of inks, laquers, pigments, crayons, markers, as precursor material for carbon quantum dots and intermediate or precursor of compounds, such as dyes, comprising a structural element as depicted in formula (I) less one or two hydrogen atoms.

The invention therefor also encompasses food, beverages, cosmetics, pharmaceuticals, packaging materials, printed articles, polymers, fabric, textiles, inks, laquers, pigments, crayons and markers comprising compounds of formula (I).

The compounds of formula (I) can be prepared via a green and very efficient process which is also encompassed by the invention.

Such process comprising at least the steps of a) providing a mixture comprising at least i) citric acid and/or aconitic acid and/or a salt of the aforementioned acids and ii) ammonium formate b) heating the mixture provided in step a) at a reaction temperature of 140°C or more.

In step a) citric acid and/or aconitic acid and/or a salt of the aforementioned acids are used to provide a reaction mixture. Suitable salts include ammonium, guanidinium, pyridinium, a primary, secondary, tertiary or quarternary organic ammonium salts, in particular those of formula [N(Ci-Ci8-alkyl) _s H _t ] ⁺ wherein s is 1 ,2, 3 or 4 and t is (4-s) as well as lithium, sodium, potassium and cesium, magnesium, calcium, strontium or barium salts, each of the foregoing either as mono-, di- or tri-salt considering the three carboxylic groups of citric acid and aconitic acid.

Where used below any amounts of salts are calculated on the basis of anhydrous salts even though hydrates might exist.

Where used below any amounts of citric acid are calculated on the basis of anhydrous citric acid even if the monohydrate is employed. Where used below the water forming the abovementioned hydrates of citric acid and salts are calculated to be part of the water content of mixtures provided in step a).

In a preferred embodiment citric acid is employed, more preferably anhydrous citric acid.

In one embodiment the molar ratio between ammonium formate and the sum of citric acid, aconitic acid and salts of the aforementioned acids is for example from 1.5 to 100, preferably from 1.8 to 20, more preferably from 1.9 to 10 and even more preferably from 2.0 to 5.0 for example from 2.0 to 2.5 or from 2.0 to 2.2, in particular 2.0.

Higher molar ratios are possible but provide no advantage. Lower molar ratios than 1.5 are possible but significanty decrease the yield of compounds of formula (I) due to consumption of two molar equivalents of ammonium formate per equivalent of citric acid, aconitic acid or salts of the aforementioned acids during the reaction.

It is an important finding of the invention that mixing citric acid and/or aconitic acid and/or salts of the aforementioned acids and ammonium formate and in particular of citric acid and/or aconitic acid and ammonium formate leads to a significant decrease in the melting point of the mixture compared to the single components, so that ammonium formate may serve as a reagent and as a solvent simultaneously without the necessity to add further other solvents.

Therefore the invention also encompasses the use of ammonium formate to prepare citrazinic acid or its salts or compounds of formula (I).

Such decrease in melting point is also known from mixtures of formic acid with ammonium formate and formic acid is actually also formed during the reaction.

As a consequence the mixture provided in step a) may also additionally contain formic acid. A suitable form to use formic acid and ammonium formate is to employ or form a mixture of formic acid and ammonium formate comprising between 18 and 50 mol.-% of ammonium formate calculated on the sum of ammonium formate and formic acid which leads to mixtures being liquid already at room temperature. This facilitates handling.

If was found that the reaction is not very sensitive to the presence of water, actually water is presumed to be formed during the reaction. As a consequence certain amounts of water in the reaction mixture provided in step a) are tolerable.

Therefore, in one embodiment the sum of citric acid (calculated as anhydrous citric acid) and/or aconitic acid and/or salts of the aforementioned acids and ammonium formate, formic acid and water is from 95 to 100 wt.-%, preferably from 98 to 100 wt.-% with regard to the total weight of the mixture provided in step a), the remainder typically being impurities from the starting materials employed.

In another embodiment the sum of citric acid (calculated as anhydrous citric acid) and ammonium formate and water is from 95 to 100 wt.-%, preferably from 98 to 100 wt.-% with regard to the total weight of the mixture provided in step a), the remainder typically being impurities from the starting materials employed.

In yet another embodiment the sum of anhydrous citric acid and ammonium formate is from 95 to 100 wt.-%, preferably from 98 to 100 wt.-% with regard to the total weight of the mixture provided in step a), the remainder typically being impurities from the starting materials employed.

Providing the reaction mixures comprising the compounds set forth above may occur in any manner known to those skilled in the art, in any order of addition and in any vessel known to skilled in the art to allow the reaction as defined above.

In step b) the reaction temperature is 140°C or more, preferably 160°C or more and even more preferably 170°C or more.

In one embodiment the reaction temperature is in the range of 140°C to 190°, preferably from 160°C to 185°C and even more preferably from 175 to 185°C.

It is known that ammonium formate decomposes beginning at temperatures above 180°C, so higher temperatures as those mentioned before are possible but will give rise to increased formation of undesired side products such as formamide. At temperature lower than 140°C the reaction becomes too slow to obtain compounds of formula (I) as main product.

The pressure conditions are not specifically limited, and the pressure in step b) may be from 500 hPa to 50 MPa, preferably from 1000 hPa to 1 MPa. Due to the potential decomposition of ammonium formate and the formation of lower boiling components like water and formic acid however, the reaction is carried out under the pressure building up upon confining the reaction mixture in step a) and heating it up to the desired temperature i.e. under isochoric or close to isochoric conditions.

The process according to the invention, in particular step b) thereof can be carried out in any vessel or reactor suitable for that purpose and known to those skilled in the art.

Preferably the reaction is carried out in an autoclave or a reactor allowing for performance of the process under isochoric or nearly isochoric conditions. Reaction times in step b) are for example at least 60 minutes, preferably at least 2 hours, more preferably at least 4 hours.

In one embodiment reaction times in step b) are 60 minutes to 48 hours, preferably 2 hours to 24 hours and even more preferably from 4 to 16 hours.

Longer reaction times are possible but virtually don't add any advantage, shorter reaction times, though possible reduce the yield of the desired compounds of formula

(I).

Without wanting to be bound by theory it is assumed that, where citric acid or its salts are employed ammonium citrate is formed in step b) which then is converted to citric acid triamide which is further condensed to citrazinic acid ammonium salt of formula

(II). Four molecules of the latter are then self-condensed via nucleophilic attack of a hydroxyl group at the 5-position as depicted below to form compounds of formula (I):

In step b) a reaction mixture comprising compounds of formula (I) is obtained.

An analogous reaction sequence is assumed for aconitic acids and its salts.

Depending on the starting materials employed different salts of compounds of formula (I) are obtained. Where citric acid is used as a starting material the tetra ammonium salt is obtained.

Water, formic acid and, where present, volatile by-products like formamide can be removed by distillation, fractionation or in vacuo from the crude reaction mixture to obtain raw compounds of formula (I). To and where an excess of ammonium formate was employed, washing the crude compounds of formula (I) with isopropanol, ethanol or methanol has shown to be very efficient.

If desired formic acid and excess ammonium formate can be recycled to step a). To obtain other salts either (I) salts of citric acid other than the ammonium salt may be used as starting material in the process for the preparation of compounds of formula (I) or (II) after preparing the tetrammonium salt metal hydroxides or carbonates may be added, e.g. 1 to 4 molar equivalents calculated on the metal content, to the tetraammonium in an aqeous solution. Subsequent evaporation to dryness or alternatively precipitation by adding a water miscible solvent wherein the compounds of formula (I) are not or only sparingly soluble such as methanol, ethanol and isopropanol will then yield the desired salts.

To obtain compounds of formula (I) wherein Cat represents a proton, aqueous solutions can be treated with a strongly acidic cation exchanger in its protonated form.

The compounds of formula (I) are typically obtained as a nanopowder. The color strength and brilliance can be varied depending on the state of aggregation as known for other dyes. Undesired aggregation can be stopped by adding a gum or other compounds known by those skilled in the art for this purpose.

A major advantage of the present invention is the provision of novel compounds being useful as colorants and dyes in various applications. They exhibit a high colour strength, are tasteless, are easy to prepare via the inventive efficient process for their preparation described herein.

In the following, the present invention is illustrated by examples which however not intended to limit the scope of invention.

Experimental section:

I General Information:

Materials.

Ammonium formate (> 98 %) was purchased from Alfa Aesar; citric acid (>99.5) was purchased from Sigma Aldrich. All chemicals were used without further purification.

Characterization.

Elemental analysis (EA) was accomplished as combustion analysis using a Vario Micro cube CHNOS Elemental Analyzer.

Scanning electron microscopy (SEM) images were obtained on a LEO 1550-Gemini microscope.

Optical absorbance spectra of powders were measured on a Shimadzu UV 2600 equipped with an integrating sphere. The emission spectra were recorded on LS-50B, Perkin Elmer instrument. The excitation wavelength was 240 nm.

Fourier-Transformed Infrared Sprectra (FTIR) were measured using a Nicolet iS5 FTIR spectrometer equipped with an ATR/iD5 with a horizontal cell (Thermo Scientific®, EUA).

LC-MS was performed using a Dionex UltiMate 3000 LIHPLC system. Elution was performed on a Thermo Scientific Accucore C18 column. The components were detected using an LTQ Orbitrap XL linear ion trap quadrupole mass spectrometer equipped with a Heated Ion Max electrospray ionization (H-ESI) source.

II Preparation of compounds of formula (I)

Example 1: Preparation of the tetra-ammonium salt

3.78 g of ammonium formate were mixed with 5.76 g of citric acid to result in a molar ratio 2:1 of the corresponding components. The mixture was thoroughly ground in a mortar to obtain homogeneous viscous paste. The viscous mixture was transferred into a Teflon® beaker and sealed with the Teflon® cap. The beaker was placed into a high- pressure stainless steel reactor from Parr. The reactor was kept at 180°C for 4 hours. Thereafter, the reaction was stopped by cooling the autoclave in an ice bath. The resulting raw product was obtained as a viscous solution with dark color. The raw product was dried in an oven at 80 °C overnight. A dry dark violet solid was obtained and ground in a mortar to obtain a powder. The powder was transferred to a 10 mL plastic centrifuge tube and 7 mL of ethanol was added. The mixture was thoroughly shaked and subsequently sonicated for 15 min in a lab sonicator. The purfied product was separated by centrifuging at 6000 RPM for 3 min. The washing procedure with ethanol was repeated tree times, until no organic molecules were detected in the washing solution by NMR. The purfied residue was dried in the oven at 60 °C overnight to obtain the pure tetraammonium salt.

Purity was confirmed by LC-MS using a column C18, mobile phase 60% B (0.1% formic acid in water) + 40% D (methanol) at 0.3 ml/min flow, UV-vis detection at 210 nm and MS detection showing the calculated peak at 634 M/z for [M-H ⁺ ],

Further elemental analysis was performed twice for CHN.

The results are given in table 1

Figs. 3 and 4 show SEM images of a compound of formula (I) with Cat identically being ammonium (the tetraammonium salt).

As can be seen in the images the compounds of formula (I) are typically obtained as an aggregated nanopowder.