KR101203037B1 - High yield and rapid syntheses methods for producing metallo-organic salts - Google Patents

Abstract

The present invention relates to a novel process for the preparation of salts of metal cations and organic acids, in particular of alkaline earth metal ions of the Periodic Table II and divalent salts of carboxylic acids. The method involves the use of high temperatures (at least about 90 °) and optionally high pressure to obtain higher yields, higher purity and faster reaction rates than are obtained by known synthetic methods. In particular, the present invention relates to the preparation of strontium salts of carboxylic acids. Novel strontium salts are also provided by the process of the invention.

Strontium, Strontium Salts, Metal Cations, Organic Acids, Alkaline Earth Metals, Carboxylic Acids

Description

HIGH YIELD AND RAPID SYNTHESES METHODS FOR PRODUCING METALLO-ORGANIC SALTS

The present invention relates to a process for the preparation of salts of metal cations and organic acids, in particular of alkaline earth metal ions of the periodic table group II and of carboxylic acids. In particular, the present invention relates to the preparation of strontium salts of carboxylic acids. New procedures and conditions are disclosed herein for carrying out such synthesis with higher purity, higher yields and shorter processing times than previously possible. Novel strontium salts are also provided by the process of the invention.

Alkaline earth metals and alkali metals are almost always found in oxidized state as components of metal organic salts due to the highly reactive nature of such elements. Salts of such metal ions are widely distributed throughout nature. The distribution and relative abundance of the various metal ions are very common elements, such as calcium, magnesium, potassium and sodium, to less common elements such as strontium, barium, lanthanum and gallium, and very rare elements such as rubidium, cesium And beryllium.

Salts of alkaline earth metals and alkali metal compounds are used in many industrial processes and in the production of food, pharmaceuticals, pharmaceutical ingredients, vitamins and other health-related products, personal care products, as well as many industrial products such as fertilizers, building materials, glass , Iron and steel and many other products. Thus, the efficient preparation of pure metal organic salts is of great commercial interest.

For many practical uses of alkaline earth metals, certain salts must be prepared that have the properties necessary for the intended use. Of particular interest in the present invention is the situation in which the metal-ion salts must be prepared with high purity, organic counter-ions not found in nature. The preparation of such salts is generally carried out by a variety of aqueous processes, and it is generally difficult to control the homogeneity and purity of the reaction product, which requires recrystallization and other purification steps, which in turn is described by Briggman B & Oskasson (1977). ), Schmidbaur H et al. (1989) and Schmidbaur et al. (1990) lower the yield of the desired salt.

The present invention discloses novel methods for the synthesis and isolation of organic salts of metal ions, in particular alkaline earth metals. In the production process according to the invention, high temperatures and optionally high pressures are used to ensure higher yields, purity and reaction rates than those obtained by the presently known synthetic methods for the production of alkaline earth metals and organic salts of alkali metals.

Accordingly, the present invention relates to a process for the preparation of metal salts of organic acids, wherein the method comprises preparing a hydroxide or halogen salt of the metal ions with an organic acid (anion) in an aqueous medium, about 60 minutes or less, for example about 30 minutes or less. Or reacting at a temperature of at least about 90 ° C., for example at least about 100 ° C., at least 120 ° C., or at least about 125 ° C. for a period of about 20 minutes or less, such as about 15 minutes.

In certain embodiments, the reaction may be carried out in a closed vessel at a temperature of at least 100 ° C. and a pressure of at least 1 bar.

The present invention provides examples that demonstrate the importance of the reaction temperature and provide guidelines for establishing the optimum temperature for the synthesis of certain organometallic salts, in particular the strontium salts. The synthesis allows the production of some entirely new salts, where time, temperature and pressure are the main parameters of compound purity. The synthesis method can be applied to the preparation of organic salts of most metal ions, but in particular the carboxylic acid salts of alkaline earth metals can be produced in accordance with the invention in higher yields and purity than can be obtained by other methods. .

An important point in the process according to the invention is to avoid the formation of relatively large amounts of insoluble carbonate. In fact, the carbonate salt is very difficult to circumvent because of its poor solubility and rapid precipitation from solution upon formation, contaminating the desired reaction product. Furthermore, starting materials for the synthesis of metal organic salts include metal hydroxides or metal halogenides, which allow favorable conditions for the formation of carbonates in aqueous media. If the organic acid of the metal organic salt is a carboxylic acid (which is often the case), generally only slowly heating to a temperature slightly above room temperature will be acceptable due to the risk of decarboxylation of the carboxylic acid and subsequent increase in carbonate levels. I realize that I can. Thus, the present invention allows the use of reaction temperatures much higher than room temperature, the higher yields of the salts of interest (compared to known methods), while at the same time maintaining the formation of carbonates at very low limits. It provides a manufacturing method. The yield of divalent metal salts produced by the process according to the invention is at least 70%, for example at least about 75%, at least about 80%, at least about 85%, at least about 90% or at least about 95%. The amount of precipitated carbonate is less than 1%, for example less than 0.75% or less than 0.5% or even 0.2% or less of the amount of the desired metal organic salt prepared by the above production method.

The process according to the invention may further comprise the step of filtering the hot reaction product immediately after stopping heating to remove the precipitated carbonate from the reaction mixture.

Furthermore, the inventors have found that in order to accelerate the crystallization of the divalent metal salt, a small amount of alcohol, for example 5 to 10 vol / vol% to 50 to 60 vol / vol%, preferably 5 to 40 vol / vol It was found that the addition of%, more preferably 10-25 vol / vol% methanol or ethanol led to marked precipitation acceleration of the desired salt. The addition of alcohols is particularly important in the synthesis of salts having solubility in excess of 2 g / l at room temperature.

The production process according to the invention can be applied to a wide variety of chemicals. Particularly suitable is the use of the desired metal organic salt in foods, pharmaceutical ingredients, personal care products such as creams, lotions and toothpastes, and human products such as vitamins and other nutritional supplements. In such cases, a high purity product is required and the manufacturing process disclosed in the present invention provides significant advantages over all other available methods.

Suitable metals for use in the method according to the invention are selected from metal atoms and ions tested or used for pharmaceutical use. Such metal atoms or ions belong to the group representing alkali metals, alkaline earth metals, light metals, transition metals, post-transition metals or semi-metals (according to the periodic table).

Preferred metals are alkaline earth metals such as beryllium, magnesium, calcium, strontium and barium and radium. The method is particularly suitable for metals in which the production of carbonate is problematic or unnecessary.

As is evident from the embodiments of the present invention, a particularly suitable embodiment of the present invention uses the chloride salt of metal ions as starting material. However, as is evident from the examples of the present invention, it has also been found that metal hydroxides are also very suitable as starting reagents for the synthesis of metal organic salts.

The molar ratio between metal ions and organic acids is important for achieving the best yield possible. Typically, the molar ratio is at least about 0.8: 1, for example at least about 1: 1, preferably at least 1.1: 1, for example 1.2: 1.

In principle, the organic acid can be any organic acid. In certain embodiments, the organic acid is a mono-, di-, tri- or quattro-carboxylic acid. Examples of suitable organic acids for use in the process according to the invention include, for example, acetic acid, C ₂ H ₅ COOH, C ₃ H ₇ COOH, C ₄ H ₉ COOH, (COOH) ₂ , CH ₂ (COOH) ₂ , C ₂ H ₄ (COOH) ₂ , C ₃ H ₆ (COOH) ₂ , C ₄ H ₈ (COOH) ₂ , C ₅ H ₁₀ (COOH) ₂ , fumaric acid, maleic acid, malonic acid, lactic acid, citric acid, tartaric acid, Oxalic acid, ascorbic acid, ibuprofen acid, benzoic acid, salicylic acid, phthalic acid, carbonic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, camphoric acid, gluconic acid, L- and D-glutamic acid, pyruvic acid, L- and D-aspart Acids, trifluoroacetic acid, ranelic acid, 2,3,5,6-tetrabromobenzoic acid, 2,3,5,6-tetrachlorobenzoic acid, 2,3,6-tribromobenzoic acid, 2,3, 6-trichlorobenzoic acid, 2,4-dichlorobenzoic acid, 2,4-dihydroxybenzoic acid, 2,6-dinitrobenzoic acid, 3,4-dimethoxybenzoic acid, abietic acid, acetoacetic acid, acetonedicarboxylic acid, aco Nitric acid, acrylic acid, adipic acid, alpha-ketoglutaric acid, Anthranilic acid, benzyl acid, arachidic acid, azelaic acid, behenic acid, benzenesulfonic acid, beta-hydroxybutyric acid, brasidic acid, capric acid, chloroacrylic acid, cinnamic acid, citraconic acid, crotonic acid, cyclopentane- 1,2-dicarboxylic acid, cyclopentanecarboxylic acid, cystathionine, decanoic acid, erucic acid, ethylene-diaminetetraacetic acid, fulvic acid, fumaric acid, gallic acid, glutamic acid, glutaric acid, gulonic acid, glucosamine sulfate, Heptanoic acid, hexanoic acid, humic acid, hydroxystearic acid, isophthalic acid, itaconic acid, lanthionine, lauric acid (dodecanoic acid), levulinic acid, linoleic acid (cis, cis-9,12-octadecadenoic acid) , Malic acid, m-chlorobenzoic acid, melisic acid, mesaconic acid, methacrylic acid, monochloroacetic acid, myristic acid, (tetradecanoic acid), nonanoic acid, norvaline, octanoic acid, oleic acid (cis-9-octadecenoic acid ), Ornithine, oxaloacetic acid, palmitic acid (hexadecanoic acid), p-aminobenzoic acid, p-chlorobenzoic acid, petroleic acid, phenylacetic acid, p-hydroxybenzoic acid, pimelic acid, propiolic acid, propionic acid, p-butylbenzoic acid, p-toluenesulfonic acid, pyruvic acid, sarcosine, sebacic acid, serine, Sorbic acid, stearic acid (octadecanoic acid), suberic acid, succinic acid, terephthalic acid, tetrolic acid, threonine, L-threonate, tyronine, tricarblylic acid, trichloroacetic acid, trimellitic acid, tri Mesic acid, tyrosine, ulmic acid and cyclohexanecarboxylic acid.

In certain embodiments, the organic acid is an amino carboxylic acid, for example a natural or synthetic amino acid.

Other divalent metal salts which may be prepared according to the invention consist of an anion selected from the group of pharmaceutically active compounds having divalent metal ions and acid or amine groups: for example salicylates, for example acetyl Salicylic Acid, Pyroxycam, Tenoxycam, Ascorbic Acid, Nistatin, Mesalazine, Sulfasalazine, Olsalazine, Glutamic Acid, Repaglinide, Methotrexate, Reflonomide, Dimethylnitrosamine, Azatriopine, Hydroxychloroquine , Cyclosporin, minocycline, salaziprine, penicylamine, diclofenac, propionic acid, for example naproxen, flurbiprofen, phenpropene, ketoprofen and ibuprofen, pyrazolone, for example phenylbutazone, phena Mate, for example mephenamic acid, indomethacin, schindall, meloxycamp, afazone, pyrazolone, for example phenylbutazone, bisphosphonate, for example Azoledronic acid, minandronic acid, incadronic acid, ibandronate, alendronate, risedronate, olpadronate, cladronate, tiludronate and pamideronate, COX-2 selective cyclo-oxygena Inhibitors, for example celecoxib, valdecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib and deracoxib, pantothenic acid, eoprostenol, iloprost, tyropiban, tran Samsan, folic acid, furosemide, bumetanide, carrenic acid, capopril, rasagiline, enalapril, ricinopril, ramipril, posinopril, trandolapril, baltan, telmisartan, pravastatin, fluvostatin , Atorvastatin, cerivastatin, sulfadiazine, trethionine, adapalene, azelaic acid, dinoprostone, levothyroxine, thyronine, doxycycline, limecycline, oxytetracycline, tetracycline, ampicillin, a Moxycillin, clavulanic acid, taxobactam, nalidixic acid fucidinic acid and reclopelone [2,2-dimethyl-6- (4-chlorophenyl) -7-phenyl-2,3-dihydro-1H-P As well as lollyzin-5-yl] -acetic acid, any pharmaceutically active derivatives of these compounds.

Other examples of acids suitable for the preparation of strontium salts for use in pharmaceutical compositions can be found in WO 00/01692, which is incorporated herein by reference.

A wide range of metal salts can be prepared using the process according to the invention. In certain embodiments of the present invention, the metal salt may be formed between an organic acid containing one or more carboxylic acid functional groups and an alkaline earth metal selected from the group comprising strontium, calcium and magnesium. In particular strontium is considered as a component of interest in the treatment of various diseases, in particular diseases involving abnormal control of bone and / or cartilage metabolism (see detailed discussion below), and in certain embodiments of the invention, the metal Is strontium.

In order to illustrate the possibility of the process according to the invention, a detailed description is given of the application of the process in the preparation of organic strontium salts. However, this merely illustrates the possibility of the present invention and does not limit the range in any way.

strontium

Strontium is a stable element that is non-radioactive and can only be found in nature. Although 26 isotopes of strontium have been disclosed, only stable non-radioactive strontium is found on Earth. Natural strontium is a mixture of four stable isotopes Sr-84, Sr-86, Sr-87 and Sr-88, of which isotope Sr-88 is the most common and accounts for 82.5% of all stable strontium on earth. The average molar weight of natural non-radioactive strontium is 87.62 Da. Other known, non-natural strontium isotopes are radioactive, of which strontium-90 and Sr-89 are the most important. These are powerful beta-emitters with a variety of commercial uses. Sr-89 is used in some medical applications, while Sr-90 is primarily used in auxiliary nuclear power units for use in very professional applications, such as for generating electricity in satellites and remote power plants. The medical use of Sr-89 is primarily related to the potential of strontium to target mineralized bone tissue, where the radioactive Sr-89 isotopes are used for the destruction of bone tumors.

In fact, strontium is practically always found oxidized as a double-cation, and consequently as a salt complexed with inorganic anions, such as carbonates, sulfates and phosphates. A relatively limited number of strontium salts have been chemically characterized in detail, with sufficient analysis of their structure and chemical properties. In general, the strontium salts studied above exhibit similar properties to the corresponding salts of the other second main group, alkaline earth metals. This means that the properties of a given strontium salt can be expected to resemble the corresponding calcium, magnesium and barium salts.

Natural salts of strontium, such as carbonate and sulfate salts, have very low solubility in water (up to 0.15 g / l at room temperature). This solubility is lower than the corresponding calcium and magnesium salts, as the ionic and positron properties of strontium are greater than for calcium. An important example of the exemption of this rule is found in the solubility of hydroxides, where strontium hydroxide is more soluble. Thus, a general observation is that the water solubility of most inorganic strontium salts is lower than that of similar calcium salts. This is the result of lower polarization of ionic strontium compared to calcium and magnesium ions (which have greater polarization due to their smaller nucleus radius (0.99 kPa for calcium compared to 1.12 kPa of strontium). However, it should be emphasized that many inorganic strontium salts are highly soluble. By way of example, strontium chloride, strontium hydroxide, strontium nitrate and strontium oxide are highly soluble and have solubility in water in the range of 225 to 800 g / l. For some strontium salts, for example hydroxide salts, the solubility is higher than the corresponding calcium or magnesium salts.

Although organic strontium salts have been disclosed, the literature reports for this type of compound are limited to considerably fewer materials. These are all strontium salts of anion-containing carboxylic acids. The physicochemical properties of the organic strontium salts were reported to be similar to the corresponding magnesium, calcium and barium salts (Schmidbaur H et al., Chem Ber. (1989) 122: 1433-1438). Strontium salts of carboxylic acids are crystalline non-volatile solids with strong electrostatic forces that keep ions in the crystal lattice. Most of the organic strontium salts in crystalline form contain varying amounts of crystal water, which acts to coordinate coordination with strontium ions in the crystal lattice. The temperature required to melt the salt is very often too high that the carbon-carbon bonds of the organic anions may break before reaching the melting, and the molecules are generally decomposed at temperatures between 300 and 400 ° C. (Schmidbaur H et al. Chem Ber. (1989) 122: 1433-1438.

All alkaline earth metal salts of carboxylic acids are soluble to some degree in aqueous solution, but the solubility of certain salts varies greatly in size and hydrophobicity as well as the electrostatic properties of organic anions. One of the simplest organic carboxylic acids, acetate, produces a well defined crystalline salt of strontium (which is highly soluble in water; 369 g / l at room temperature). Larger organic anions usually have significantly lower solubility depending on the hydration enthalpy and lattice enthalpy of the salt. However, since the various strontium salts do not necessarily form the same type of crystal structure and their crystal lattice energies are not known, it is not possible to theoretically calculate the solubility of such salts, which should be determined empirically. will be. Furthermore, a given salt may exist in different crystal structures, in which the important properties, for example the amount of bound crystal number, change, so that different crystal forms will have different lattice and hydration enthalpy and thus solubility.

Properties of Carboxylic Acid Salts of Strontium

Carboxylic acid salts of divalent earth metals such as strontium, and in particular dicarboxylic acids, have some unique properties as they may have a partial chelating effect in solution. In this case, the salt is present as a complex in solution, wherein the divalent metal ion complexes with the carboxyl group of the anion. Such complexing may be important in biological systems, where the alkaline earth metals, especially calcium and magnesium, play a biophysiological role. The majority of divalent metal ions may exist in complex bound form, rather than free and unbound ionic form in the aqueous environment of the biological system. Complex formation rates with alkaline earth metals in aqueous solutions are higher for amino acids than for hydroxy-carboxylic acids and related non-carboxylic acids, suggesting that amino groups may play a role in complex formation. In general, the difference in dissociation constant and hydration enthalpy for various ligands becomes smaller as the radius of the metal increases. Therefore, the stability of the strontium complex with dicarboxylic acid is lower than the stability of the complex with calcium and magnesium. This means that the chelated dicarboxylic acid in aqueous solution has a propensity to preferentially bind calcium and magnesium rather than the larger ions of strontium and barium.

Organic strontium salts have little commercial use and therefore such compounds are not available for large scale chemical production (> 1000 kg batch size). Recently, however, ranelate, a strontium salt of tetracarboxylic acid, has been developed for pharmaceutical use in the treatment of metabolic bone diseases such as osteoporosis. The chemical properties of strontium ranelate are similar to the dicarboxylic acid salts of many strontium. It has a water solubility of 0.76 g / l at 22-24 ° C. with a slight increase in solubility at higher temperatures and lower pH. In aqueous solution, the ranelate ions act as chelates and complex with divalent metal ions as described above. The core 3-cyano-4-carboxymethylthiophene structure of the ranelate ion is chemically stable under physiological conditions, but the nitrile group is hydrolyzed to form various α-hydroxy acid or unsaturated acid derivatives of ranelate. Can be.

Synthesis of Carboxylic Acid Salts of Strontium

Organo-strontium salts of carboxylic acid anions can be synthesized by a number of different routes. A conventional method for preparing such organic strontium salts is to use a reaction between the organic acid and strontium hydroxide in an aqueous solution. By way of example, the following scheme represents the neutralization reaction of malonic acid and strontium hydroxide salts:

[Reaction Scheme 1]

^{Sr 2 + (aq) + 2OH} - (aq) + C 3 H 2 O 4 2 - (aq) + 2H + (aq) → Sr (C 3 H 2 O 4 2 -) (aq) + 2H 2 O ( l)

After the reaction which occurs rapidly upon dissolution of the solid, the suspension of dissolved strontium malonate can be induced to precipitate by evaporation of water and subsequently to raise the concentration of the salt. Crystals of strontium malonate will slowly form and precipitate from the solution.

Another approach is to use sodium or potassium salts of suitable carboxylic acids and strontium chloride. Since all organic strontium salts will dissolve less than the highly soluble chloride salts, the organic strontium salts will precipitate under these conditions leaving behind NaCl and excess SrCl ₂ in solution. The following scheme illustrates, by way of example, a scheme using a reaction between SrCl ₂ and sodium-malonate, wherein the reaction product is added in equimolar amounts.

Scheme 2

^{Sr 2 + (aq) + 2Cl} - (aq) + 2Na + (aq) + C 3 H 2 O 4 2 - (aq) → Sr (C 3 H 2 O 4 2 -) (aq) + Cl - (aq ) + Na ⁺ (aq)

In these two alternative synthetic routes, recrystallization will be necessary to obtain the desired strontium salt in sufficiently pure form. In turn, the yield is due to the lack of complete precipitation of strontium from the solution during recrystallization, due to the formation of precipitated strontium carbonate and due to the very low solubility of the metal carbonate which renders the precipitated strontium unavailable for further reaction. Will decrease as a result of losses. In alkaline solutions, carbonates are formed by dissolution of atmospheric carbon dioxide according to the following scheme:

Scheme 3

^{_{CO 2 (g) + 2OH -}} (aq) → CO 3 2 - (aq) + H 2 O (l)

Since strontium carbonate is easily formed and has a low solubility product, Scheme 3 shifts to the right, which extracts strontium from the carboxylate product, ie Scheme 1 (or 2) shifts to the left. Thus, repeated recrystallization will reduce the yield of the desired strontium carboxylate, while the presence of strontium carbonate contamination will increase.

The schemes shown above (Scheme 1 and 2) depict the final preparation reaction of the organic strontium salt with simple reaction of the inorganic strontium salt, which is available in free acid form or as a salt, with the desired organic anion. Therefore, it is necessary to be able to obtain the organic acid commercially in order to carry out this reaction. In the case of more complex and / or unique anions, they will have to be synthesized prior to the preparation of the strontium salt, which can then incorporate the formation of the strontium salt by the scheme as outlined above into the final synthesis step. In either case, the methods and procedures disclosed in this patent can be used to improve the yield and purity of the desired reaction product.

According to the process of the invention, any strontium salt, or salt consisting of an organic anion and a metal cation, for example an alkaline earth metal or an alkali metal cation, in particular an alkaline earth metal cation, is optionally subjected to a higher pressure at elevated temperature under an inert atmosphere. This can be done more efficiently with higher yields, better purity and shorter processing times. Specifically we demonstrate that the yield and purity of the strontium salts produced in this manner are dramatically improved over the previous synthetic methods disclosed in the prior art literature.

The present method of preparation can be used for the preparation of strontium salts of dicarboxylic acid organic anions, which salts can be used for the prophylactic and / or therapeutic treatment of metabolic bone diseases.

Large amounts of strontium intake have been associated with altered bone mineralization and increased skeletal strength in several animal studies. The effect is believed to be due to direct or substrate mediated inhibition of pre-osteoblast maturation, migration and activity, and osteoclast activity by strontium. In other words, strontium acts as both an inhibitor of absorption and an assimilation agent on bone tissue.

Various salts of strontium are known from the prior art, for example strontium ranelate (2- [N, N-di (carboxymethyl) amino] -3-cyano-4-carboxymethyl-thiophen-5-carboxylic acid Disodium salt of) is disclosed in EP-B 0 415 850. Other known strontium salts are, for example, strontium tartrate, strontium phosphate, strontium carbonate, strontium nitrate, strontium sulfate and strontium chloride. We have found that the strontium salts of some dicarboxylic acids, such as strontium malonate, strontium fumarate, strontium succinate, strontium glutamate and strontium aspartate, are more soluble than other dicarboxy strontium salts of similar molecular size. In pure aqueous solutions of such salts, strontium is present in partially complexed form. When administered to an animal, for example a mammal, ie a rat, dog, monkey or human, strontium complexed to carboxylic acid anions as well as ionic strontium will be absorbed from the intestinal lumen by both passive and active transport mechanisms. In this case strontium will be replaced from the complex by the available calcium and magnesium forming a much more stable complex with ionized amino acids. Some dicarboxylic acids may act to preferentially bind / complex with the available free calcium, thus promoting both the gut absorption of the calcium ions and their role in the regulation of the physiology of the ions, in particular bone turnover, thereby preventing bone disease. It may be particularly suitable for pharmaceutical and / or therapeutic interventions.

Specific salts of interest include fumaric acid, maleic acid, malonic acid, lactic acid, citric acid, tartaric acid, ascorbic acid, salicylic acid, acetyl-salicylic acid, pyruvic acid, L- and D-aspartic acid, gluconic acid, L- and D-glutamic acid, ranelic acid. , Alpha-ketoglutaric acid, arachidic acid, cyclopentane-1,2-dicarboxylic acid, malic acid, myristic acid (tetradecanoic acid), pyruvic acid, sarcosine, serine, sorbic acid, threonine, tyronine and Strontium salt formed with an acid such as tyrosine.

In certain embodiments the salts formed are strontium malonate, strontium lactate, strontium succinate, strontium fumarate, strontium ascorbate of L and / or D-type, strontium aspartate of L and / or D-type, L And / or D-type strontium glutamate, strontium pyruvate, strontium tartrate, strontium threonate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate and mixtures thereof.

Novel strontium salts such as strontium L-diglutamate pentahydrate and strontium D-glutamate hexahydrate are also provided by the present invention. The salts are described below for the first time, and the convenient high purity preparation of alkaline salts of the salts and / or alkaline earth metals of organic acids, which have not been disclosed previously, demonstrates the possibility of the above-described preparation process for efficient synthesis of difficult organic metal salts.

Strontium malonate

Strontium malonate has been disclosed previously in the literature. However, the method of synthesis of strontium malonate in its pure form has not been disclosed in detail above.

One report discloses anhydrous strontium malonate salts. The authors report the slow evaporation of aqueous solutions of malonic acid and strontium hydroxide at room temperature over several days to produce colorless single crystals. This crystal was analyzed by X-ray crystallography, which appeared to be an orthorhombic unit cell with no crystal number bound (Briggman B & Oskasson Å 1977, Acta Cryst. B33; 1900-1906). 2 and Table 1 below graphically show the analyzed crystal structure of the anhydrous strontium malonate salt.

[Table 1]

Distance [Å] and angle [°] for malonate ions in anhydrous crystalline form of strontium malonate as disclosed by Briggman & Oskasson 1977 (see FIG. 2 for atomic nomenclature).

Street

Angle

Two or more crystalline forms of strontium malonate exist in anhydrous forms as disclosed in Table 1 and FIG. 2 above and in the form with one water molecule per unit cell in the crystal. In situations where the high strontium content of the salt is intended, for example in pharmaceutical applications, the use of anhydrous salts is preferred since strontium constitutes 45.7% of the salt on a molar basis. Therefore, the manufacturing process which makes it possible to reproduce and control the high purity and high yield preparation of the salts is very valuable.

In the synthesis of strontium malonate, the total yield of the product varies with temperature and synthesis time. Thus, the synthesis can be improved by testing the synthesis in an autoclave system that maintains below the decomposition temperature of the organic anion residue of the strontium salt for temperature purposes. As an example, malonic acid decomposes under neutral or acid conditions at 132 to 134 ° C., therefore the synthesis of strontium malonate should be carried out at temperatures lower than 132 ° C. However, alkaline conditions improve the stability of malonate, which may allow synthesis at temperatures above conventional decomposition temperatures.

More suitable is the fact that carboxylate decarboxylates on heating (Q) and releases gaseous carbon dioxide. The reactions shown in Schemes 4 and 5 demonstrate that the decarboxylation of malonic acid is facilitated by the addition of an acid that facilitates the reaction through an intermediate of carbon anions:

[Reaction Scheme 4]

^{_{HOOCCH 2 COO - (aq) +}} Q → CO 2 (g) + HOOCCH 2 - (aq)

Scheme 5

^{_{HOOCCH 2 - (aq) + H}} + (aq) → CH 3 COOH (aq)

At low temperatures, the decarboxylation is not significant because the reaction of Scheme 4 is slow. However, by raising the temperature and adding acid, the reaction can proceed to completion. In the synthesis of strontium malonate, it has been found that this can be made in high yield by using a closed reaction vessel with an inert gas or vapor pressure under alkaline conditions by an optimization procedure. This optimization result depends on the reactions of Schemes 4 and 5, which predict that both reactions will shift to the left to promote the stability of malonate ions. Steam and argon have been used to lower the risk of decarboxylation, but other inert gases may also be used.

Thus, strontium malonate is synthesized by reacting strontium hydroxide with elevated pressure (at least 1 bar) at a temperature maintained at 100 ° C. or higher and 130 ° C. or lower to avoid decomposition of malonic acid in a sealed container. can do. By this method high yields of pure strontium malonate can be obtained after a reaction time of only 15 minutes and a single filtration step.

Strontium glutamate

Strontium L-glutamate was prepared by previously reacting strontium hydroxide and L-glutamic acid under reflux for 3 hours, followed by cooling and slow crystallization over a period of up to 2 weeks.

In the process according to the invention the strontium L-glutamate hexahydrate and the strontium hydroxide and glutamic acid at a temperature in the range from about 120 ° C. to about 135 ° C. and a pressure from about 1 to about 1.7 bar, optionally under an inert gas atmosphere for about 15 minutes. Prepared by reacting for a period of from about 60 minutes to obtain strontium glutamate. The method may also include filtering the hot reaction mixture immediately after stopping heating to remove precipitated calcium carbonate from the reaction mixture. Further details and instructions for optimizing the reaction are shown in Example 8.

As mentioned above, by using the method according to the invention, the inventors have prepared a new strontium glutamate salt (strontium L-diglutamate pentahydrate) different from known strontium glutamate.

Detailed description of the preparation of the novel salts and the crystal structure is given in Example 5 of the present invention. The following provides a detailed description of the novel salts.

X-ray crystallographic analysis (FIG. 1) revealed that the strontium glutamate salt synthesized differs from the strontium L-glutamate hexahydrate disclosed previously, as disclosed in FIGS. 1 and 2 and Tables 2 and 3.

Another novel strontium glutamate salt prepared by the process according to the invention is strontium D-glutamate hexahydrate. The nature and crystal structure of the salts are disclosed in Example 10.

In the case of strontium D-glutamate hexahydrate and strontium di-L-glutamate pentahydrate, both of these novel novel crystal forms and high purity are applicable to X-ray analysis by the high temperature production method disclosed in this patent. The rapid preparation of strontium organic salts provides an illustration of the applicability of methods for preparing difficult organometallic salts.

Strontium aspartate

Strontium L-aspartate was also prepared earlier by reacting L-aspartic acid with strontium hydroxide. The reaction was carried out over 3 hours under reflux and the resulting reaction mixture was cooled over 3 days to initiate crystal formation. X-ray crystallography was performed to reveal the crystal structure of the resulting strontium L-aspartate crystals (H. Schmidbaur, P. Mikulcik & G. Muller (1990), Chem Ber. 123; 1599-1602). See). The investigation revealed that the strontium L-aspartate salt isolate was formed in trihydrate form.

In summary, the inventors have found that different strontium salts require different synthetic routes, and for some strontium salts an optimized synthesis and preparation process has been identified. Particularly in connection with the present invention, the synthesis of strontium salts and strontium malonates of dicarboxyl amino acid aspartate and glutamate (D- or L-form) is very difficult, in accordance with conventional reaction routes, and generally of low yield and purity. It was found that crystalline salts were obtained. In order to facilitate the large scale preparation of pure strontium salts of dicarboxylic acid amino acids, for example for pharmaceutical use, we have studied various synthetic routes of these specific strontium salts. Surprisingly, therefore, the synthesis of well defined and pure strontium glutamate in the form of hexahydrate is most conveniently carried out in the free acid form of glutamate and strontium hydroxide, with elevated temperatures, for example above 80 ° C, or more preferably 100 ° C or It was found that even a temperature of 120 ° C. or most preferably above 130 ° C. is required (see Examples 5 to 17). Furthermore, the inventors have found that addition of a small amount of alcohol can accelerate the formation of crystals of the dissolved aqueous organic strontium salt (see Example 3). Furthermore, the present invention discloses strontium salts of dicarboxylic acids in new crystalline form (see Examples 5, 6 and 10).

Strontium salts prepared according to the invention can be used in medicines, for example creams, lotions, ointments, tablets, capsules, gels and the like. As mentioned above, strontium is believed to have an effect on cartilage and / or bone diseases and / or other diseases, and thus the salts are difficult to regulate cartilage and / or bone diseases and / or cartilage and / or bone metabolism in mammals, For example osteoporosis, fracture healing, stabilization of orthopedic implants, osteoarthritis, rheumatoid arthritis, leg-Calbe-Perse disease, steroid-induced osteoporosis, other therapies such as chemotherapy or highly active retroviral suppression therapy ( HAART) or systemic lupus erythematosus (SLE) can be used to prepare pharmaceutical compositions for the treatment and / or prevention of bone loss. The pharmaceutical composition may further comprise one or more physiologically acceptable excipients.

For the treatment and / or prevention of cartilage and / or bone diseases and / or diseases which cause dysregulation of cartilage and / or bone metabolism in mammals, varying amounts of strontium and malonate, alpha-ketoglutarate, where appropriate Or the possibility of administering each of amino acids such as glutamic acid and / or aspartic acid may be required. The amount of strontium (and, for example, malonate, alpha-ketoglutarate or amino acid) in the pharmaceutical composition according to the invention can be controlled by adding an additional amount of strontium in the form of a strontium-containing compound to the composition. The strontium-containing compound may be selected from the salts described above.

In the following, a more detailed description of the preparation of the individual salts according to the invention is provided. All details concerning strontium also apply to all other alkaline earth metal salts or salts of alkali metals according to the invention.

Furthermore, the respective details and specifications for strontium are applied mutatis mutandis whenever appropriate, as well as for the individual strontium salts, as generally applicable, in accordance with the details and specifications set out below. Every time the strontium salt is applied. Furthermore, the method of the present invention applies equally to the preparation of other metal organic salts.

1 and 2 show diffraction plots for X-ray analysis of two strontium salts. The top diffraction plot shows strontium glutamate hexahydrate at high temperature but as synthesized by strontium hydroxide and L-glutamic acid using the reaction conditions disclosed in Example 2. The salt and resulting diffraction plots correspond to the strontium L-glutamate hexahydrate salts disclosed above (H. Schmidbaur, I. Bach, L. Wilkinson & G. Muller (1989), Chem Ber. 122; 1433-1438). The bottom diffraction plot shows the strontium glutamate hexahydrate salt synthesized from strontium chloride and L-glutamic acid as disclosed in the examples of the present invention. The novel strontium glutamate salt was identified as strontium di-L-glutamate pentahydrate consisting of one strontium ion and two mono-quantized glutamate ions.

2 shows Briggman B & Oskasson Å 1977, Acta Cryst. B33; 1900-1906, showing the molecular structure of strontium malonate (anhydrous) in crystalline form. The lower part shows the crystal with atoms depicted in an arbitrary radius

3 shows the crystal packing of strontium (L−) diglutamate pentahydrate as viewed along the b axis. Strontium 9 configuration is shown as a polyhedron of gray tint. H atoms are omitted for clarity.

4 illustrates asymmetric units of strontium (L-) diglutamate pentahydrate crystals, showing an elliptic substitution probability and atomic numbering of 75%. H atoms are represented by circles of arbitrary size.

FIG. 5 shows an X-ray powder diffraction plot of the crystals of strontium glutamate hexahydrate prepared by the method disclosed in Example 8. FIG.

FIG. 6 shows an X-ray powder diffraction plot of the crystals of strontium malonate prepared by the method disclosed in Example 9 and analyzed as disclosed in Example 18. FIG.

Figure 7 illustrates the crystal packing of strontium D-glutamate hexahydrate (left panel) and the asymmetric unit of the crystal (right panel), showing an elliptic substitution probability and atomic numbering of 75%. H atoms are represented by circles of arbitrary size. The right side looks at the crystals below the α-axis in the left panel and shows the Sr 9-configuration as polyhedron.

Example  1-for comparison

Dissolved strontium chloride and suitable Carboxy  Use of known methods for preparing crystalline salts of strontium by precipitation from dissolved sodium salts of anions

In a 100 ml volume glass beaker, 5 g of the sodium salt of carboxylic acid were dissolved in a small portion of water and heated slightly at a temperature of 30-50 ° C. or less. Final volume was 25-50 ml. In another beaker SrCl ₂ (SrCl ₂ hexahydrate, Sigma-Aldrich 43,966-5) was dissolved in 100 ml of water. The latter solution was slowly decanted to the final solution of the dissolved sodium salt. The transfer was continued until an initial cloud was observed, resulting in a total volume of 50-100 ml. The solution was incubated for several days at room temperature (22-24 ° C.) until a significant amount of crystallized precipitate of the organic strontium salt appeared.

The advanced reaction is illustrated by the reaction between strontium ions and sodium fumarate (Scheme a and b):

Scheme a

_{NaOOCCHCHCOONa (s) + H 2 O} (l) → - OOCCHCHCOOH (aq) + 2Na + (aq) + OH - (aq)

Scheme b

^{- OOCCHCHCOOH (aq) + Sr 2} + (aq) → Sr (OOCCHCHCOO) (aq) + H + (aq)

After the precipitation, the solution was filtered on a Buchner funnel using a suction flask and the crystals were flushed with a small portion of ethanol. The crystals of some of the salts were very soluble, so that the crystals were allowed to settle for a longer time, for example 30 to 60 minutes or longer, in order to improve the yield of the crystals. Repeated crystallization produced about 50% yield. The strontium salts of L-aspartate and lactate were very soluble and the water solubility at room temperature exceeded 25 g / l.

The lactate and L-glutamate salts of strontium were precipitated out of solution by excess strontium chloride and the solvent was slowly evaporated to obtain large crystals of the lactate salts.

Example  2-for comparison

strontium On hydroxide  by Carboxylic acid  General preparation of crystalline salts by neutralization

A small amount of suitable organic acid (0.75-3 g, see table below) was completely dissolved in water by heating to 30-50 ° C. temperature. Strontium hydroxide (Sigma Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0, approximately 10 g / L) was then added slowly. Then, a magnetic stir bar was added and stirring and gentle heating (ie 30-50 ° C.) of the suspension was started. After some time, the solution becomes clear and all solid material is dissolved. The heating is maintained and after 3 hours of incubation, the solution is filtered when hot on a Buchner funnel. Very small amount of impurities remained in the filter.

The filtrate was subsequently cooled at room temperature overnight to grow fine powdered crystals of the desired strontium salt. Further purification of the salt can be carried out by repeated recrystallization (Table 2).

[Table 2]

The amount of starting reagent used for the synthesis and recovery of organic strontium salts in the synthesis of eight specific organic strontium salts using the free acid form of the anion and strontium hydroxide according to the general reaction route

Strontium salt of (free acid used) Sr (OH) ₂ *
8H ₂ O Free acid Yield Evaluation yield ^* Melting temperature Solubility Crystal structure Fumarate ¹ 2.044 g 1.140 g 0.999 g 21% > 380 ℃ O X α-ketoglutarate ² 2.017 g 1.441 g 0.828 g 16% > 380 ℃ O X Succinate 2.098 g 1.177 g 0.958 g 20% 230 ℃ O O L-ascorbate ³ 2.094 g 1.805 g 2.005 g 32% > 380 ℃ O X L-glutamate 2.017 g 1.453 g 0.175 g 4% > 380 ℃ O O Citrate 2.057 g 1.918 g 1.123 g 15% > 380 ℃ O O L-aspartate 2.190 g 1.316 g 0.167 g 3% > 380 ℃ X X Tartrate 2.070 g 1.502 g 2.005 g 36% > 380 ℃ O O

footnote:

^* ) Recovery calculated as% of strontium content in Sr (OH) ₂ * 8H ₂ O and stoichiometry corresponding to the minimum content of the corresponding acid, eg 1: 1 ratio in tartrate. The strontium salts of Table 2 (above) were characterized by powder X-ray crystallography and the corresponding diffraction plot (not shown) showed that the product was relatively impure and of poor quality (ie, heterogeneous crystalline form). Thus, the maximum yield of the room temperature synthesis was estimated to be 30%, which was calculated from the magnitude of the characteristic peaks in the X-ray diffraction plot. Thus, the weight was multiplied by a factor of 0.3 to obtain the estimated recovery and the molecular weight of the strontium salt was used according to the appropriate amount of bound crystals. Although unclear, the method reveals that the white powder of Table 2 did not contain the desired product for high yield. The remaining fraction of the product consisted mainly of unreacted reagents (ie strontium hydroxide) and strontium carbonate. If the strontium salt of Table 2 contains six water molecules in the crystal structure, the yield will be further reduced by even some 10-50% compared to the values provided. This difficulty of evaluation and measurement arises from the formation of significant amounts of strontium carbonate when the salts are separated by recrystallization.

1) Fumaric acid is water insoluble and ethanol is added to the suspension until complete dissolution is achieved. Synthesis is continued using this material.

2) The strontium-AKG salt has a slightly brownish appearance.

3) In addition to the indicated amounts of strontium hydroxide and L-ascorbate, additionally 4.087 g of SrCl ₂ * 6H ₂ O dissolved in water is added to the reaction mixture.

In conclusion, known methods for the preparation of strontium salts produce relatively poor yields (up to 40%). Furthermore, the data of this example demonstrate that strontium carbonate formation, heterogeneous crystal formation, and the presence of unreacted starting product in the reaction product are a common phenomenon when forming strontium salts by the methods disclosed in the prior art literature. The following examples provide guidance on how to prepare strontium salts in higher yields. The examples provided below are for illustrative purposes and are not to be construed as limiting the invention in any way. Moreover, those skilled in the art will find instructions for the preparation of other alkaline earth metal or organometallic compounds of interest according to the present invention.

Example  3

Improvement of known synthetic methods for the preparation of metal organic salts by use of ethanol precipitation

As an improvement of the process disclosed in Examples 1 and 2, the inventors have used a small amount of alcohol, such as from 5 to 10 vol / vol% to 50 to 60 vol / vol% methanol or ethanol, to accelerate the crystallization. It was found that addition led to marked acceleration of the desired strontium salt precipitation. The addition of ethanol is particularly important for the synthesis of strontium salts having solubility in excess of 2 g / l at room temperature (22 to 24 ° C.), and therefore the addition to the synthesis of strontium salts of L-aspartate, L-glutamate and lactate. Will provide significant advantages. In order to obtain the required product in a short time, it was necessary to observe the initial crystallization or the initial clouding in solution immediately in the first step.

The following examples provide guidelines for determining the solubility of strontium salts to obtain information as to whether alcohol precipitation can be advantageously applied to accelerate and increase the crystallization of certain strontium salts during the preparation according to the invention.

Example  4

Determination of Solubility of Organic Strontium Salts

Synthesis of Strontium Salts

The majority of strontium salts can be obtained by reacting the sodium salts of organic acids with strontium chloride and following the general synthetic method described in Example 1. However, strontium citrate, strontium tartrate, strontium succinate and strontium α-ketoglutarate were obtained by synthesizing from the free acid form of carboxylic acid and strontium hydroxide as described in Example 2 for solubility investigation. The solubility of the carboxylic acid strontium salt was measured in purified water. The solubility of these salts was also measured as a function of temperature. This was done by culturing a saturated solution of the salts in a temperature controlled incubator. Furthermore, the solubility of the salts was investigated in 0.05M ammonium carbonate buffer solution with physiological pH of 7.5 as well as pure distilled water.

The buffered solutions were immersed in a water bath of controlled temperature at room temperature (22-24 ° C) or 30 ° C or 40 ° C. The test tubes were stirred and the solutions were subsequently incubated in an incubator for 24 hours. In order to eliminate the potential impact of any residual strontium chloride in solubility measurements, all precipitates were collected at the base of the test tube and the solution on the precipitates was carefully removed and replaced with fresh solution. After substitution of the solution, the test tubes were stirred again and allowed to stand for an additional 24 hours. From these solutions, the dissolved portion of the strontium salt was collected in a volume of 1 ml at the specified temperature. The solution was diluted to 50 ml before analysis by Flame Atomic Absorption Spectrometry (F-AAS). Prior to subsequent series of sampling, the solution was equilibrated at the next temperature for 24 hours.

Strontium Analysis by Flame Atomic Absorption Spectroscopy F-AAS

Two methods were used to quantify strontium in solution: flame atomic absorption spectroscopy (F-AAS), and more sensitive inductively coupled plasma mass spectrometry (ICP-MS). For most investigations the F-AAS method had sufficient sensitivity.

Some of the highly soluble strontium salts were further diluted prior to analysis by F-AAS. Measurements were performed using a Perkin-Elmer 2100 with hydrogen lamp for correction of background signal. Strontium was measured at a slit width of 0.2 mm and the wavelength was 460.8 nm operating at energy of 58 and current of 8 mA.

Temperature and pH Effects on Organic Strontium Salt Solubility

For the majority of the organic strontium salts listed in Table 3, the temperature change in the 20-40 ° C. interval had only a minor effect on solubility (Table 3). However, for strontium L-glutamate, a significant change in temperature with respect to solubility was observed in the range of 20 ° C. to 40 ° C. The solubility of the salts increased by more than three times in the intervals examined in contrast to most other salts. It is noted that the solubility under physiological conditions (37 ° C.) is suitable for the pharmaceutical use of the material, so that a surprising increase in strontium glutamate solubility at higher temperatures can have therapeutic results with great potential.

The solubility of the strontium salt in ammonium carbonate buffer solution at pH 7.5 was generally higher than the solubility measured in pure water (Table 3). However, there were some notable exceptions, for example strontium malonate had reduced solubility in the buffer solution. Thus, as shown in Table 3, it was found to be most suitable to compare the solubility of the strontium salt by comparing the values obtained in water.

Relative solubility

Table 3 shows the water solubility of the organic strontium salts at room temperature and 40 ° C. The strontium salts of L-aspartate and lactate had solubility in excess of 50 g / l, which prevented accurate measurement of solubility by the experimental procedure used.

The results are consistent with the observations in the synthesis experiments in which citrate, fumarate and tartrate immediately precipitate upon synthesis by the preparation procedures disclosed in Examples 1 and 2. This indicates insufficient solubility of the strontium salt, as manifested by the lower solubility of the salt compared to other organic strontium salts at both 22 ° C. and 40 ° C.

The glutamate salts exhibited higher solubility than other salts, especially at temperatures of 40 ° C. During the synthesis of the salts, the inventors found that, as disclosed in Example 3, the yield of the salts can be significantly improved by adding alcohol to the solution. The addition of the alcohol promoted the onset of crystal growth. Other studied strontium salts precipitated only after evaporation of the solvent for several days at room temperature. Alcohol addition was not required for crystal formation and initiation of precipitation, significantly promoting the precipitation, thus improving the synthesis method and yield of the desired salt.

[Table 3]

Relative solubility in water buffered solutions of pH 7.5 at 40 ° C. and room temperature (22-24 ° C.) of the irradiated strontium-salts, as measured by F-AAS.

Strontium salt Solubility (mg / L) at room temperature (22-24 ℃) Solubility at 40 ℃ (mg / L) Negative ion Underwater pH 7.5 Underwater pH 7.5 Malonate ^** 1474 2816 1441 2127 L-glutamate ^** 2111 3022 7093 7195 L-aspartate ^** > 25000 > 25000 > 25000 > 25000 Pyruvate ^* 2204 1946 1929 1829 α-ketoglutarate ^** 1316 2252 3534 3809 Fumarate ^** 571 1215 444 977 Maliate ^** 3002 1680 2527 1457 Tartrate ^** 883 1831 1028 1400 Ranelate ^*** 760 890 1450 1970 Succinate ^** 1137 926 1116 2233 Citrate ^*** 107 388 147 430

^* ) Mono-carboxylic acid

^** ) dicarboxylic acid-glutamate salt is hexahydrate salt

^*** ) tri-carboxylic acid

^**** ) tetra-carboxylic acid

Example  5

Novel salt strontium (L-) by synthesis at 100 ° C. according to the invention Diglutamate Pentahydrate  Produce

Initially, 100 ml of Millipore water in a 250 ml beaker was charged with solid L-glutamic acid (Sigma Aldrich, C ₅ H ₉ NO ₄ , MW 187.14 g / mol, CAS no. 142-47-2, lot number 426560/1, Code 43003336) was added to 14.703 g (0.1 mol) to prepare a suspension of glutamic acid (white). To the suspension was added 26.66 g (0.1 mol) of solid SrCl ₂ (SrCl ₂ hexahydrate, Sigma-Aldrich 43,966-5, MW 266.6). Then, a magnetic stir bar was added and stirring and heating were started and maintained until the suspension reached the boiling point. The final suspension is also opaque white and continues stirring by maintaining a medium rotational speed of the stirring device. In order to prevent carbon dioxide from entering the solution, the beaker was covered with a cover glass.

After several minutes of boiling and stirring, the solution became clear and all solid material dissolved. The boiling was maintained and additional water was added as needed to replace the water lost by boiling. After 3 hours of boiling, the solution was filtered while boiling on a Buchner funnel. Very small amount of impurities remained on the filter. The filtrate was subsequently cooled to room temperature and ethanol was added, resulting in the growth of finely powdered crystals of strontium L-diglutamate pentahydrate. Precipitation of the final product proceeded in the filtrate within 1 hour. The product was filtered, dried at 110 ° C. for 1/2 hour in an oven and then dried over silica orange in a dryer for 12 hours. Prior to analysis by X-ray crystallography and FAAS, the salts were ground to a fine powder by mortar.

X-ray crystallographic analysis (see FIG. 1) revealed that the strontium glutamate salt synthesized differs from the strontium L-glutamate hexahydrate salts disclosed previously (H. Schmidbaur, I. Bach, L. Wilkinson & G. Muller (1989). ), Chem Ber. 122; 1433-1438). The strontium glutamate hexahydrate previously disclosed by Schmidbaur et al. Has a very low solubility (0.023 g / l), whereas the strontium glutamate salt prepared by the method disclosed in this example has a solubility of at least 2 g / l. Reported to have. These latter parameters are of great importance for the potential medical use of the strontium salt as disclosed herein. The salts have been identified as novel glutamate salts of strontium: strontium L-diglutamate, pentahydrate, containing two monohydrated glutamic acid residues complexed to one strontium ion. Coordination of the salts was identified as follows:

Strontium (L-) diglutamate pentahydrate is a uniform crystal belonging to the monoclinic P2 ₁ spacing group having a unit size of a = 8.7097 Å, b = 7.2450 Å and c = 14.5854 Å, volume: 904.891 (0.158) Å ³ Formed. See Example 18 for a detailed description of the X-ray crystallography process.

The strontium (L-) diglutamate pentahydrate crystal-composition is shown in FIGS. 3 and 4.

[Table 4]

Main interatomic distance for strontium (L-) diglutamate pentahydrate crystals. The atomic numbering used is as shown in FIG. 5.

All H atomic parameters were initially freely purified. In the final cycle of Rietweld purification, the H atoms of the CH ₂ and CH groups were placed in calculated positions with CH distances of 0.97 kPa and 0.98 kPa, respectively, and purified as boarding atoms. For some molecules in the crystal structure, the OH distance was constrained to 0.84 mm 3 and the NH distance was 0.89 mm 3. The substitution parameters were set to 1.2 (CH and NH) or 1.5 (OH) x U _eq of the corresponding C, N or O atoms.

[Table 5]

Geometry of hydrogen bond of strontium (L-) diglutamate pentahydrate (Å, °). The atomic numbering used is as shown in FIG. 5.

TABLE 6

Torsion angle (°) of strontium (L-) diglutamate pentahydrate. The atomic numbering used is as shown in FIG. 5.

Further improvements to the synthesis of strontium (L-) diglutamate pentahydrate include degassing with nitrogen or argon of water and all aqueous solutions, which ultimately results in contact with carbon dioxide which can lead to the formation of strontium carbonate impurities To prevent. Subsequently, those skilled in the art will be able to easily adapt the procedure to proceeding under inert gas atmosphere.

Example  6

Strontium by synthesis at 100 ° C. according to the invention Aspartate Trihydrate  Produce

Initially, 100 ml of Millipore water in a 250 ml beaker was added to solid L-aspartic acid (Fluka, C ₅ H ₉ NO ₄ , MW 133.11 g / mol, CAS no. 56-84-8, lot number 432866/1, Fill cord 52603495) is added to 13.311 g (0.1 mol) to prepare a suspension of aspartic acid (white). To the suspension was added 26.571 g (0.1 mol) of solid strontium hydroxide (Sigma-Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0). Then, a magnetic stir bar was added and stirring and heating were started to reach the boiling point of the suspension. The final suspension is also white and the stirring is continued by maintaining a medium rotational speed of the stirring device. In order to prevent carbon dioxide from entering the solution, the beaker was covered with a cover glass.

After several minutes of boiling and stirring, the solution became clear and all solid material dissolved. The boiling was maintained and additional water was added as needed to replace the water lost by boiling. After 3 hours of boiling, the solution was filtered while boiling in the gaseous phase with Buchner funnel. Very small amount of impurities remained on the filter. Subsequent cooling of the filtrate to room temperature resulted in the growth of fine powdered crystals of strontium aspartate trihydrate. Precipitation of the final product proceeded in the filtrate within 1 hour. The product was filtered, dried at 110 ° C. for 1/2 hour in an oven and then dried over silica orange in a dryer for 12 hours. Prior to analysis by X-ray crystallography and FAAS, the salts were ground to a fine powder by mortar.

The overall yield of strontium aspartate trihydrate was approximately 98% before recrystallization, with the majority of impurities consisting of the residue of reagents and strontium carbonate. The yield is significantly higher than the yield obtained by synthesis under conventional conditions (only 3% obtained) (see Example 2). Thus, the high temperature synthesis process as disclosed herein provides a significant increase in yield and reduced synthesis time while producing higher purity strontium aspartate salts. The product was analyzed by X-ray crystallography, data from the results of the Cambridge Crystallograph database and described in H. Schmidbaur, P. Mikulcik & G. Muller (1990), Chem Ber. 123; 1599-1602], it was clearly confirmed that it is strontium aspartate trihydrate. See Example 18 for a detailed description of the X-ray crystallography process.

Further improvements to the synthesis include degassing with nitrogen or argon of water and all aqueous solutions, which prevents contact with carbon dioxide which can eventually lead to the formation of strontium carbonate impurities. Subsequently, those skilled in the art will be able to easily adapt the process to proceeding under inert gas atmosphere.

Example  7

Strontium by synthesis at 100 ° C. according to the invention Malonate  Preparation of Anhydride

Initially, 100 ml of millipore water in a 250 ml beaker was added to 10.406 g (0.1 mol) of solid malonic acid (Fluka, MW 104.06 g / mol, CAS no. 141-82-2, lot number 4495031/1, fill code 44903076). In addition, a suspension of malonic acid (white) is prepared. To the suspension was added 26.571 g (0.1 mol) of solid strontium hydroxide (Sigma-Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0). Then, a magnetic stir bar was added and stirring and heating were started to reach the boiling point of the suspension. The final suspension is also white and the stirring is continued by maintaining a medium rotational speed of the stirring device. In order to prevent carbon dioxide from entering the solution, the beaker was covered with a cover glass.

After several minutes of boiling and stirring, the solution became clear and all solid material dissolved. The boiling was maintained and additional water was added as needed to replace the water lost by boiling. After 3 hours of boiling, the solution was filtered while boiling on a Buchner funnel. Very small amount of impurities remained on the filter. Subsequent cooling of the filtrate to room temperature resulted in the growth of fine powdered crystals of strontium malonate. Precipitation of the final product proceeded rapidly during filtration and most of the product was found in the filter (not heated). Only in rare cases did precipitation proceed in the filtrate. The product was filtered, dried at 110 ° C. for 1/2 hour in an oven and then dried over silica orange in a dryer for 12 hours. Prior to analysis by X-ray crystallography and FAAS, the salts were ground to a fine powder by mortar.

The overall yield of strontium malonate was approximately 98% before recrystallization, with the majority of impurities consisting of the residue of reagents and strontium carbonate. The product was clearly identified by X-ray crystallography as strontium malonate by comparing the data to the results of the Cambridge Crystalgraphic Database (see description of Example 18).

In a further refinement of the synthesis, anhydrous strontium malonate was produced on the 10 kg scale according to the method of the present invention, indicating that the method can be applied to larger scale synthesis. 15.80 kg of Sr (OH) ₂ * 8H ₂ O was dissolved in 63.2 L of purified water and heated to 95-100 ° C. 5.63 kg of malonic acid was dissolved in 4.1 L of purified water and filtered, after which additional 1.4 L of water was added and the solution was heated to 95-100 ° C. The two solutions were mixed in a closed reaction vessel under an inert nitrogen atmosphere and stirred under reflux for 20 minutes. Subsequently the heating was stopped and the solution was cooled to 40-50 ° C. for 2-4 hours during which strontium malonate precipitated. The precipitate was filtered off and the salt was further washed with 13.2 L of water and dried completely at a temperature of 70 ° C. under vacuum. 9.4 kg of very pure strontium malonate was obtained as a uniform microcrystalline white powder, corresponding to a yield of 94%. The product was clearly identified by X-ray crystallography as strontium malonate (anhydrous) by comparing the data to the results of the Cambridge Crystalgraphic Database. See Example 18 for a detailed description of the X-ray crystallography process.

Example  8

According to the invention, using a temperature of 100 ℃ or more Dicarboxylic acid  Process for preparing strontium salt

In accordance with the methods previously developed and described in detail in Examples 1 and 2, the synthesis of the strontium salts of dicarboxylic organic acids and especially the strontium salts of amino acids, on a larger scale, due to the lower yield and difficulty in separating the desired reaction product from contaminants (Ie> 1 kg) can be difficult to produce. Of particular concern is the strontium salt of carbonate, since the reaction will form as an impurity if it occurs in an atmosphere containing the usual levels of carbon dioxide. In Examples 4-7, we demonstrated that when the strontium salt of dicarboxylic acid is prepared from the free acid form of the anion and strontium hydroxide, the overall yield of the product varies with synthesis temperature and time. In order to complete the reaction, it is necessary to boil a mixture of suitable amino acids and strontium hydroxides in water, which unless strontium in the reaction mixture is air, unless other means or procedures are used to inhibit the unnecessary formation of strontium carbonate. Allow sufficient time to react with carbon dioxide in the air. In this embodiment, we provide optimized reaction conditions, in which the temperature is increased above 100 ° C. in a closed vessel and the reaction time is significantly reduced, and the inert atmosphere of the carbon dioxide free gas can be easily introduced. By this, a method for further improving the synthesis is disclosed.

This example provides typical data from optimal conditions for the synthesis of strontium L-glutamate hexahydrate in an autoclave system. In contrast to the conditions used in Example 5, strontium hydroxide was used as starting material, resulting in the formation of strontium L-glutamate hexahydrate. Although strontium L-glutamate is used as an example, the optimizations disclosed in this example can also be applied to the synthesis of other strontium salts, where the exact reaction conditions can be optimized as disclosed in this example. The reaction temperature should be maintained below the melting point or below the decomposition temperature of the organic anion residue of the desired strontium salt.

Strontium L-glutamate was used as the strontium compound model in the optimization experiment. The purity of the product was monitored by comparison to crystallographic data and by measurement of strontium content. Ideally, the content of strontium is 25.7% in strontium L-glutamate hexahydrate, the product formed in the experiment. Subsequently other strontium salts can be prepared in high purity and high yield by similar methods.

Experiment

Preparation of solution: 100 ml of Millipore water in 250 ml beaker was added to solid L-glutamic acid (Sigma Aldrich, C ₅ H ₉ NO ₄ , MW 187.14 g / mol, CAS no. 142-47-2, lot number 426560 / 1, Fill Code 43003336) was added to 14.703 g (0.1 mol) to prepare a suspension of glutamic acid (white). Solid strontium hydroxide (Sigma-Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0) 22.257 g, 26.571 g or 31.885 (0.08 mol, 0.1 mol, 0.12) Mole).

Optimization experiment

After preparation of the salts, nine optimization experiments were performed according to the settings in Table 7. In this table, the term 'base-acid ratio' refers to the molar ratio between strontium hydroxide and glutamic acid.

[Table 7]

Parameters and Key Results of the Optimization Process for the Synthesis of Strontium L-Glutamate

Experiment
number Autoclave Temperature (℃) Synthesis time
(minute) Base-to-acid ratio Total volume
(ML) Autoclave pressure (bar) yield% % Sr
(AAS) One 125 15 0,8 50 1,55 94 25 2 124 30 One 75 One 112 22 3 124 60 1,2 100 1,6 121 21 4 127 15 One 100 1,2 118 22 5 132 30 1,2 50 1,55 120 25 6 132 60 0,8 75 1,6 50 22 7 134 15 1,2 75 1.65 108 24 8 134 30 0,8 100 1.65 76 14 9 132 60 One 50 1.65 82 24

The pressure was monitored but not used in the optimization process. Strontium content (% Sr) was measured by FAAS but was not used as a quality parameter. The theoretical strontium content of strontium glutamate hexahydrate is 25.7%. Yield (%) was applied as a quality parameter.

process

1. The calculated amount of acid was weighed and transferred to a Bluecap autoclave bottle and Millipore water was added. The bottle was closed and shaken to obtain a suspension with fine particles.

2. The calculated amount of strontium hydroxide octahydrate was weighed and added to the acid solution of (1) and the bottle was vigorously vortexed until all coarse mass of mass had turned to fine particle powder.

3. The bottle was placed in an autoclave and the temperature was set. During this time no further agitation was carried out in the autoclave.

4. At t = 100 ° C., close the valve of the autoclave and start timing.

5. During autoclaving, actual temperature and actual pressure were monitored.

6. After autoclaving, the steam was released as soon as possible for safety precautions.

7. Open the autoclave at approximately 110 ° C. to recover the solution. Again, shake the bottle to obtain a high degree of mixing.

8. The solution was immediately hot filtered on a Buchner funnel after autoclaving, leaving only a residual amount of carbonate in the filter. The product precipitated out of the solution while cooling to room temperature.

9. After precipitation, the product was filtered off and dried in an oven at 110 ° C. for 1/2 hour. This was then dried over silica gel orange in a dryer. Finally the product was ground to a fine powder in a mortar.

10. After grinding, the product was weighed and the total yield calculated.

Strontium Content (% Sr):

0.2 g of sample was dissolved in 100 ml of 0.1 M HNO ₃ prepared in Millipore water. The solution was further diluted to a factor 500 with 1% KCl solution and the content of strontium was measured by FAAS. The measurement was carried out using a Perkin-Elmer 2100 equipped with a hydrogen lamp for background signal correction. Strontium was measured at a slit width of 0.2 nm and the wavelength was 460.8 nm operating at an energy of 58 and a current of 8 mA.

X-ray crystallography

A second purity test was performed by powder X-ray crystallography using a Huber G670 as described in more detail in Example 18. A characteristic diffraction plot of strontium glutamate is shown in FIG. 5.

Results and discussion

From the results shown in Table 7, it is clear that some of the synthesis conditions resulted in a relatively low yield and low purity of strontium glutamate as evident from the mole percent of strontium in the reaction product. The product of Experiment 8 was produced in a relatively low yield, which did not contain the expected 25.7% strontium. However, in general, the results of the optimization experiments are close to the expected product. Incomplete reaction gives too low content of strontium product. The conditions used in Experiments 1 and 5 provided strontium content that best matched the expected values.

By studying the influence of the individual parameters on the overall yield (Table 4), it becomes clear that the total volume is less important while the temperature, reaction time and base-acid ratio are important for the synthesis. Yields higher than 100% (observed in experimental conditions 2, 3, 4, 5 and 7 (Table 7)) originate from incomplete drying, but these results are almost excluded when considering the mean value.

Maximum yields were obtained by using high temperature (133 ° C.), short reaction time and excess strontium hydroxide. Thus, temperature is more important than time but it is comparable in importance to the base to acid ratio. To confirm the maximum yield of the optimization experiments, a tenth experiment was conducted to control the optimization, and the results of this experiment were consistent with the findings reported in Table 7.

Further refinements of the synthesis include the introduction of an inert atmosphere into the synthesis environment as well as the degassing of all solutions with nitrogen gas or argon gas, in order to reduce the formation of carbonate salts. Such salts can be readily formed in conventional air atmospheres and will precipitate easily in the reaction mixture due to the very poor solubility of the carbonate salts of most alkaline earth and alkali metals.

Example  9

Strontium using a temperature of at least 100 ° C. according to the invention Malonate  Manufacturing method

In order to confirm the applicability of the disclosed high temperature synthesis method to strontium salts other than strontium L-glutamate, strontium malonate was prepared by the above high temperature synthesis method. Basically, the reaction conditions found for the preparation of strontium L-glutamate (Example 8) were used. 100 ml of Millipore water in a 250 ml beaker is added to 10.41 g (0.1 mole) of solid malonic acid (Fluka 63290, MW 104.1, CAS no. 141-82-2) to prepare a suspension of malonic acid (white). Solid strontium hydroxide (Sigma-Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0) 22.257 g, 26.571 g or 31.885 (0.08 mol, 0.1 mol, 0.12) Mole). The reaction procedure disclosed in Example 8 was carried out and the temperature was maintained at 130 ° C. or lower while maintaining the reaction time at 15 minutes to avoid decomposition of malonic acid.

The maximum yield was obtained by this synthesis method using a molar ratio of Sr (OH) ₂ to acid of 1.2.

An X-ray powder diffraction plot of strontium malonate obtained by the high temperature synthesis method disclosed in this example is shown in FIG. 7. See Example 18 for a detailed description of the X-ray crystallography process.

The revealed X-ray diffraction plot of the synthesized strontium malonate salt is consistent with the anhydrous crystalline strontium malonate disclosed above. It is clear that the crystal form of the malonate salt is uniform and pure from the separation of stable baselines and well defined diffraction peaks. Thus crystalline pure and well defined strontium malonate can be readily obtained by the above high temperature synthesis method.

Example  10

Preparation of Novel Strontium Salts of D-Glutamic Acid by High Temperature Synthesis Method

Further experiments were conducted to confirm the applicability of the high temperature synthesis method to the preparation of other racemic strontium salts. Strontium D-glutamate was selected. The salt was not prepared previously. The salt, 100 ml of Millipore water in a 250 ml beaker was added to solid D-glutamic acid (Sigma Aldrich, HO ₂ CCH ₂ CH ₂ CH (NH ₂ ) CO ₂ H, MW 147.13, CAS no. 6893-26-1) 14.713 It was synthesized by adding g (0.1 mol) to prepare a suspension of D-glutamic acid. To the suspension was added 31.898 g (0.12 mol) of solid strontium hydroxide (Sigma-Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0). The reaction procedure described in Example 8 was carried out, the temperature was maintained at 132 ° C. and the reaction time was maintained at 15 minutes. After completion of the reaction, the strontium D-glutamate salt was filtered, dried and X-ray diffraction analysis was performed to reveal the structure as disclosed in Example 18.

Strontium D-glutamate hexahydrate was formed into uniform crystals belonging to the tetragonal P2 ₁ 2 ₁ 2 ₁ spacing group with unit size of a = 7.3244 mm 3, b = 8.7417 mm 3 and c = 20.0952 mm ³ , volume: 1286.65 mm ³ . The crystal form of the strontium D-glutamate hexahydrate was similar to that of the strontium L-glutamate hexahydrate disclosed above (H. Schmidbaur, I. Bach, L. Wilkinson & G. Muller (1989), Chem Ber. 122; 1433). -1438). 8 shows the structure of the crystal and the unit cell appearance.

The following coordinations were obtained (Tables 8 and 9):

[Table 8]

Main interatomic distance of strontium D-glutamate with Å distance

TABLE 9

Coordination of Strontium D-Glutamate

Coordination of hydrogen atoms is included in the table, and atomic numbering is as shown in FIG. 5.

Example  11

strontium Formate  synthesis

The reaction conditions found for the preparation of strontium L-glutamate (Example 8) were used. 100 ml of Millipore water in a 250 ml beaker is added to 4.603 g (0.1 mol) of solid formic acid (FLUKA 33015, MW 104.1, CAS 64-18-6) to prepare a suspension of malonic acid (white). To the suspension was added 31.898 g (0.12 mol) of solid strontium hydroxide (Sigma-Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0). The reaction procedure described in Example 8 was carried out.

Example  12

magnesium Malonate  synthesis

Magnesium malonate in pure form was synthesized in high yield and purity using the reaction conditions found for the preparation of strontium malonate (Example 9). A suspension of sodium malonate (white) was added to 100 ml of Millipore water in a 250 ml beaker to 16.605 g (0.1 mol) of solid sodium malonate dibasic monohydrate (SIGMA M1875-100G, MW 166.05, CAS 26522-85-0). To prepare. To the suspension was added 24.410 g (0.12 mol) of solid magnesium chloride hexahydrate (FLUKA 63068, MgCl ₂ * 6H ₂ O, MW 203.3, CAS 7791-18-6). The reaction procedure described in Example 8 was carried out.

Example  13

Zinc L- Glutamate Dihydrate  synthesis

Basically, the reaction conditions found for the preparation of strontium L-glutamate (Example 8) were used. A suspension of sodium glutamate (white) was prepared by adding 100 ml of Millipore water in a 250 ml beaker to 18.714 g (0.1 mole) of solid L-glutamic acid monosodium salt monohydrate (ALDRICH G2834, MW 187.14, CAS 142-47-2). do. To the suspension was added 13.628 g (0.1 mol) of solid zinc chloride (FLUKA, 96469, MW 136.28, CAS 7646-85-7). The reactions were placed in a closed vessel in an autoclave, the temperature was increased to 132 ° C. for 15 minutes and then the reaction was stopped and after the reaction mixture reached 92-98 ° C., it was filtered on a Buchner funnel and the desired Zinc L-glutamate salt easily precipitated from the filtrate. The yield is approximately 95% and the purity exceeds 96%.

Example  14

zinc Malonate Dihydrate  synthesis

Basically the reaction conditions found for the preparation of zinc L-glutamate were used (Example 13). A suspension of sodium malonate (white) was added to 100 ml of Millipore water in a 250 ml beaker to 16.605 g (0.1 mol) of solid sodium malonate dibasic monohydrate (SIGMA M1875-100G, MW 166.05, CAS 26522-85-0). To prepare. To the suspension was added 13.628 g (0.1 mol) of solid zinc chloride (FLUKA, 96469, MW 136.28, CAS 7646-85-7). Subsequent preparation steps were as described in Example 13.

Example  15

Barium L- Glutamate  synthesis

Basically the reaction conditions found for the preparation of strontium L-glutamate (Example 8) were used. A suspension of L-glutamic acid (white) is prepared by adding 100 ml of Millipore water in a 250 ml beaker to 14.713 g (0.1 mol) of solid L-glutamic acid (FLUKA 49449, MW 147.13, CAS 56-86-0). To the suspension was added 37.86 g (0.12 mol) of solid barium hydroxide octahydrate (FLUKA 11780, Ba (OH) ₂ * 8H ₂ O, MW 315.5, CAS 12230-71-6). The reaction procedure described in Example 8 was carried out.

Example  16

Calcium L- Glutamate  synthesis

Basically the reaction conditions found for the preparation of strontium L-glutamate (Example 8) were used. A suspension of sodium glutamate (white) was prepared by adding 100 ml of Millipore water in a 250 ml beaker to 18.714 g (0.1 mole) of solid L-glutamic acid monosodium salt monohydrate (ALDRICH G2834, MW 187.14, CAS 142-47-2). do. To the suspension was added 17.6424 g (0.12 mol) of solid calcium chloride dihydrate (FLUKA, 21097, MW 147.0, CAS 10035-04-8). The reaction procedure described in Example 8 was carried out.

Example  17

calcium Malonate  synthesis

Basically the reaction conditions found for the preparation of strontium malonate (Example 9) were used. A suspension of sodium malonate (white) is prepared by adding 100 ml of Millipore water in a 250 ml beaker to 16.605 g (0.1 mole) of solid sodium malonate dibasic monohydrate (SIGMA M1875-100G, MW 166.05). To the suspension was added 17.6424 g (0.12 mol) of solid calcium chloride dihydrate (FLUKA, 21097, MW 147.0, CAS 10035-04-8). The reaction procedure described in Example 8 was carried out.

Example  18

X-ray On diffraction  Measurement of crystal structure

summary

We define the crystalline material as having a three-dimensional repeating structure, ie by three-dimensional translation, there is a unit cell that is at least the same unit that matches any part of the crystal. The unit cell dimensions are typically 3 to 25 mm 3 for inorganic and organic materials. Such a three-dimensional arrangement of unit cells will also contain a lattice plane combination that connects all the corners of the unit cell. In such a combination the distance between the grid planes will be from 0 to the maximum dimension of the unit cell itself. Therefore, the plane distance is about the same size as the X-ray wavelength used for diffraction, 0.5 to 2.4 GHz. Such crystals, when placed on X-ray rays, will act as a grating to produce a characteristic interference or diffraction pattern. The location of the recorded diffracted radiation is measured by the lattice plane distance, ie the size of the unit cell, while the recorded diffracted intensity is measured by the position and symmetry of the atoms in the unit cell. For practical purposes, this means that the unique crystal structure creates a unique diffraction pattern that can be used for identification or measurement of the crystal structure. There are two general methods commonly used for structural analysis: single-crystal method and powder diffraction method.

Single-crystal method

This method is mainly used to measure the crystal structure of unknown materials. Since the name contains only one crystal, a size of less than 0.3 mm is typically used. The crystals can be loaded onto a single-crystal diffractometer that can rotate in an independent direction and a complete three-dimensional diffraction pattern can be collected for about 10 hours. From the location of the diffraction points, the unit cell dimension can be calculated, and the atomic arrangement within the unit cell can be analyzed from the intensity of the point. The analyzed structure is unique in accuracy and typically has an interatomic distance of better than 0.01 mm 3, and the method is also sensitive to absolute molecular structure identification. Together with modern diffractometers and software, the method is 99% successful for organic and metal organic compounds.

powder diffraction

The powder sample will ideally contain an infinite amount of micrometer sized crystals in a random orientation. When irradiated by X-rays, each crystallite will diffract independently and contribute to the diffraction pattern. The result will be a one-dimensional projection of the three-dimensional single-crystal pattern of the powder diffraction pattern. The interpretation of the powder diffraction pattern is much less straightforward than the single-crystal pattern. Depending on the unit cell size and symmetry, the powder diffraction pattern exhibits varying degrees of reflection overlap. Nevertheless, the peak position is still a function of unit cell dimensions and the intensity is a function of unit cell content. The powder diffraction pattern is a fingerprint of roughly irradiated structure, and we can collect data in 10 minutes using the powder diffraction database and an effective irradiation-comparison program and a few minutes analysis safely confirms the known structure. . Powder diffraction has generally played an important role for the structural characterization of materials. Apart from phase identification, the method is commonly used for structural degradation, structural purification and crystallization studies, crystallite size and size distribution, stress / strain, and the like. The method is mainly used for solid crystalline materials, but information from amorphous and fibrous materials and thin films is also easily obtained.

powder diffraction  equipment

Diffractometer: Hoover G670 powder diffractometer operating with Guinier (transmission) geometry and equipped with a primary quartz focusing monochromator and an image plate detector with an integrated laser / photoelectron multiplier reading system

X-ray generator: 40 kV and 30 mA

Radiation: CuKα1 1.54059 Å

Instrument Adjustment: Intensity and 2θ-scale tested with Si-Standard (NBS) matched through complete pattern Rietvelt tablets. Adjust approximately once a week and after any adjustment of the diffractometer.

Sample holder: flat plate Scotch tape, 10 x 10 mm working area in Scotch tape

Measurement: Range: 2-100 ° in 2θ. The detector reads in steps of 0.05 ° at 2θ. The exposure time is 15 to 120 minutes depending on the scattering powder.

Measurement Procedure: Samples are ground with agate mortar and pestle and placed on a sample holder on Scotch tape. The sample holder is loaded on a powder diffractometer stage and the vibration motor is started. In the data collection program, provide a filename (typically a sample name) and describe any other mention or observation. Write down the measurement time and start data collection. Write in the notebook the file name, measurement time and performer. After the measurement is completed, the powder diffraction pattern is printed and the practitioner signs. Usually you will want to confirm using the survey-comparison program.

references

Briggman B & Oskasson Å 1977, Acta Cryst. B33; 1900-1906

Schmidbaur H et al. Chem Ber. (1989) 122: 1433-1438

Schmidbaur, H. P. Mikulcik & Muller (1990), Chem Ber. 123; 1599-1602

The present invention relates to a method for producing a salt of a metal cation and an organic acid, in particular an alkaline earth metal ion of a periodic table group II and a carboxylic acid, and particularly, can be used for the preparation of a strontium salt of a carboxylic acid.

Claims (33)

A process for the preparation of strontium salts of organic acids containing at least one carboxylic acid group, wherein at least one of the hydroxide and / or halogen salts of strontium ions is combined with an organic acid (anion) in an aqueous medium at a temperature of at least 90 ° C. for a period of up to 60 minutes. Reacting and the molar ratio of the strontium ions to the organic acid is 1: 1 to 1.2: 1. The method of claim 1, A process for producing a strontium salt, wherein the yield is 95% or more. 3. The method according to claim 1 or 2, The molar ratio of the strontium ion and the organic acid is 1.05: 1 to 1.2: 1 characterized in that. The method of claim 1, The molar ratio of the strontium ion and the organic acid is 1.1: 1 to 1.2: 1, characterized in that. The method of claim 1, The molar ratio of the strontium ion and the organic acid is 1: 1. The method of claim 1, The organic acid is a mono-, di-, tri- or tetra-carboxylic acid production method. The method of claim 1, The organic acid is fumaric acid, maleic acid, malonic acid, lactic acid, ascorbic acid, L- and D-glutamic acid, pyruvic acid, L- and D-aspartic acid, ranelic acid, alpha-ketoglutaric acid, succinic acid and L-tsu A method of manufacture selected from the group comprising leonate. delete delete The method of claim 1, The salt is a strontium malonate production method. The method of claim 1, The halogen salt is a chloride salt. The method of claim 1, The reaction is carried out in a closed vessel at a temperature of 100 ℃ or more and a pressure of 1 bar or more. The method of claim 1, The amount of precipitated carbonate is less than 1% of the amount of divalent metal salt. delete delete delete delete delete delete delete The method of claim 3, wherein Preparation comprising reacting strontium hydroxide with dicarboxylic acid at a temperature in the range of 120 ° C. to 135 ° C. and a pressure of 1 to 1.7 bar for a period of 15 to 60 minutes to obtain a strontium salt of the dicarboxylic acid used. Way. 22. The method of claim 21, And immediately filtering off the hot reaction mixture to remove precipitated strontium carbonate from the reaction mixture. The method of claim 1, A process for improving the precipitation of the strontium salt from the reaction mixture by adding 5 to 60 vol / vol% alcohol to the solution. 24. The method of claim 23, Said alcohol is ethanol. 24. The method of claim 23, Wherein said alcohol is methanol. delete delete delete delete delete delete delete delete

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