LV13484B - Method for production of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate - Google Patents

Abstract

Invention relates to a new manufacturing method of 3-(2,2,2-trimethylhydrazinium)propionate by basic hydrolysis with bases in alcohols or other proper solvents. More complete precipitation of inorganic salts is achieved by saturation of reacting mixture with carbon dioxide or sulphur dioxide. Halogenides, methylsulphates or acid salts of alkyl- or aralkylesters of 3-(2,2,2-trimethylhydrazinium)propionate are used as raw materials. Potassium or sodium hydroxides or other proper basic agents are used as bases. They are used in ratio of 1.05 - 2.2 equivalents against inorganic acid anion.

Description

Process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate dihydrate

The invention relates to processes for the preparation of pharmaceutically active substances, in particular to the preparation of the active ingredient Meldonium 3- (2,2,2-trimethylhydrazinium) propionate dihydrate (THP). Meldonium is a cardiovascular preparation with an average dose of 1.0 grams per day. Because the product is intended for a wide range of patients, there is a need for manufacturing techniques that allow large volumes of the preparation to be conveniently and cheaply produced. The techniques known so far are not well suited to Meldonia's large-scale production processes.

Therefore, the present invention is directed to a method of obtaining Meldonium which would allow the production costs of Meldonium to be reduced and would be convenient for large scale production.

Several methods of obtaining this substance are known. They use one common principle scheme: in the first step, the reaction of 1,1-dimethylhydrazine with the acrylic acid esters yields the 3- (2,2-dimethylhydrazinopropionic acid) ester, which is further alkylated with a suitable methylating agent (methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate or other). methylating reagents). The resulting 3- (2,2,2-trimethylhydrazinium) propionic acid ester halide or methyl sulfate is further hydrolyzed and deionized. The different methods of obtaining Meldonium differ fundamentally in the manner in which the corresponding 3- (2,2,2-trimethylhydrazinium) propionic acid ester salt is hydrolyzed and / or deionized and the resulting cost of Meldonium also differs.

Thus, solutions of 3- (2,2,2-trimethylhydrazinium) propionic acid ester halides or methyl sulfates are treated with highly basic anionites which exchange the inorganic anion with the hydroxylanion, followed by hydrolysis of the spontaneous ester groups / 1 /. This method has several major drawbacks which make it disadvantageous to produce large quantities of Meldonia. One of the major disadvantages of this method is that strong basic anionites are unstable in basic media and rapidly deteriorate. Consequently, after 6 to 10 regeneration cycles, these resins need to be replaced with new ones, which greatly increases production costs. Another disadvantage is that the strongly basic anion exchange resin has a low ion exchange capacity, which means that large amounts of resin, large amounts of solvent-eluent (usually ethanol) are needed both in the reaction process and in the product isolation process. As a result, large amounts of solvent have to be evaporated, which also increases the production cost of the product. Another major disadvantage of this technique is the high cost of preparation and regeneration of the anionites themselves, since the resin has to be swollen in deionized water for at least 12 hours before use, washed with hydrochloric acid, rinsed with sodium hydroxide, rinsed with distilled water. and alcohol, and the column should be rinsed immediately with hydrochloric acid and deionised water at the end of the process. It requires large amounts of sodium alkali, hydrochloric acid, alcohol and deionized water, and requires additional measures for solvent recovery and waste disposal.

Some of the above disadvantages can be overcome if the salts of 3- (2,2,2-trimethylhydrazinium propionic acid ester are deionized by electrodialysis.) At least two technical solutions have been proposed for the electrodialysis process in Meldonium production / 2,3 /. implementation requires specialized electrodialysis equipment, with increased demands on the materials used (platinum titanium electrodes, highly calibrated diameter porosity and high mechanical strength and capacity dialysis membranes, special ceramic coating for the apparatus body, etc.). current, flow rate, working solution concentrations, inter-electrode distances, chamber shape, etc. The membrane becomes contaminated and degraded during the manufacturing process and therefore needs to be changed frequently. Along with the deionization process, water electrolysis also occurs, which leads to the formation of explosive gas and renders the large-scale production process hazardous and requires additional safety measures to prevent risks. Therefore, even using this process, Meldonia's cost price is relatively high.

Another process for the preparation of Meldonium is known, in which the trimethylsilyl ester of acrylic acid is used as a starting material for the first stage condensation with 1,1-dimethylhydrazine. The idea behind the patent is based on the well-known fact that trimethylsilyl esters of carboxylic acids are spontaneously hydrolyzed in water. Therefore, it is expected that trimethylsilyl-3- (2,2,2-trimethylhydrazinium) propionate halide in water will readily hydrolyze even in the absence of a base. The major disadvantage of this method is the much higher price and more difficult availability of silylated acrylic acids compared to acrylic acid methyl ester, which is a cheap high tonnage product. It should also be noted that the description of the proposed process is not feasible in practice due to the fact that the Meldonium extraction from aqueous solutions of ether described in the process is not possible because Meldonium is insoluble in ether but very soluble in water.

The classical process for the hydrolysis of carboxylic acid esters by simple treatment with alkali has not been successfully carried out so far in the case of alkyl 3- (2,2,2-trimethylhydrazinium) propionate halides or other salts, since 3- (2,2,2-trimethylhydrazinium) propionate forms relatively persistent double salts with variable composition / 5,6 /. In some cases, such double salts are quite stable and can also be used as pesticides in agriculture.

All known attempts to disrupt the double salt structure of, for example, NaCl and 3- (2,2,2-trimethylhydrazine) propionate by simply dissolving it and / or heating it in alcohol or other solvents in which NaCl is insoluble and could be expected to be precipitated out of solution have succeeded. These manipulations fail to completely precipitate the entire amount of NaCl, since part of it remains in the form of a bound double salt and a pharmaceutically pure product (with a content of> 99.5%) is not obtained.

We have unexpectedly found that the double salt structure of 3- (2,2,2-trimethylhydrazinium) propionate can still be completely destroyed if their solutions of alcohol in the inorganic salts are treated with carbon dioxide or sulfur dioxide. Thus, for example, even the KBr double salts of 3- (2,2,2-trimethylhydrazinium) propionate in alcohol can be completely destroyed in this way and the inorganic salts component can be removed by simple filtration. Thus, Meldonium is obtained which is free of inorganic salts and is easily purified to> 99.5% purity by conventional crystallization methods.

This process can conveniently be carried out using as starting material the alkyl 3- (2,2,2-trimethylhydrazinium) propionate chloride, bromide or methylsulfate, as well as any other hydrolyzable 3- (2,2,2-trimethylhydrazinium) propionate ester salt, for example, benzyl esters. The amounts of alkali in this reaction can be varied from 1.05 to 2.1 equivalents per mole of ester, thereby controlling the rate of hydrolysis.

The acid hydrolysis products of the salts of the 3- (2,2,2-trimethylhydrazinium) propionate esters can also be used in the process, that is, the Meldonium salts with the acids used to hydrolyze them, such as hydrochloric acid, sulfuric acid, etc., neutralized with suitable alkali (e.g. calcium alkali, or other alkaline agents such as soda, potash, lithium or cesium carbonates, sodium or potassium bicarbonates, etc.) and the resulting double salts are destroyed by a patented process with carbon or sulfur dioxide treatment.

The patented process for the production of Meldonium thus achieves the objective of developing a large-scale, convenient and inexpensive process for the production of Meldonium, characterized in that the double salt structure resulting from the hydrolysis of 3- (2,2,2-trimethylhydrazinium) propionate esters is destroyed by carbon or sulfur dioxide. , which offers a number of advantages over known methods of obtaining Meldonium. In contrast to these, the patented Meldonium process allows the use of available and inexpensive reagents (sodium or potassium or other suitable alkali or alkaline agents, carbon dioxide or sulfur dioxide, ethyl alcohol and isopropyl alcohol), conventional chemical, which is cheaper and more readily available than special design electrodialysis machines, the process is fast, the product is high yielding, easy to disperse and purify by conventional methods (filtration, crystallization). As a result, the patented Meldonia extraction process allows large quantities to be produced at low cost and high quality.

This technique can also be combined with known deionization techniques

- treatment with strongly basic anionites or electrodialysis. In this case, bases which are slightly soluble in halides and are not expected to precipitate completely (eg NaBr) may also be used. In the case of combined processes, deionization techniques are used for the complete desalting of the final product after removal of the double salts and removal of the inorganic salt backbone. The invention is illustrated but not limited by the following examples:

1. To 66.8 g KOH (containing 90% by weight of the substance) in 450 ml ethanol at 18-20 ° C is added 120.5 g methyl 3- (2,2,2-trimethylhydrazinium) propionate bromide with vigorous stirring for 5-10 min. Stirring is continued at 18-20 [deg.] C. until complete hydrolysis of the ester (according to TLC analysis). The reaction mixture is then cooled to +2 - +4 ° C and filtered off with KBr precipitate, which is washed with 2x20 ml of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the inorganic salt precipitate is washed with 3x20 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (89 g of product with a Meldonium content of 94% (92% of theory)) which is recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

2. To 34 g of KOH (content 90% by weight) in 450 ml of ethanol is added 120.5 g of methyl 3- (2,2,2-trimethylhydrazinium) propionate bromide at 18-20 [deg.] C. with vigorous stirring for 5-10 min. Stirring is continued at 18-20 [deg.] C. until complete hydrolysis of the ester (according to TLC analysis). The reaction mixture is then cooled to +2 - + 4 ° C and the KBr precipitate is filtered off and washed with 2x20 ml of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the inorganic salt precipitate is washed with 3x10 ml ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (90 g of product with a Meldonium content of 93% (92% of theory)) which is recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

3. To 33 g of KOH (content 90% by weight) in 450 ml of ethanol are added 136 g of methyl 3- (2,2,2-trimethylhydrazinium) propionate methyl sulphate under vigorous stirring for 5 to 10 minutes. Stirring is continued at 18-20 [deg.] C. until complete hydrolysis of the ester (according to TLC analysis). The reaction mixture is then cooled to +2 +4 ° C and filtered off the inorganic salt precipitate which is washed with 2x20 ml of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the precipitate is washed with 3x10 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (89.5 g of product with a Meldonium content of 91% (89% of theory)) which is recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

4. Add 33 g of methyl 3- (2,2,2-trimethylhydrazinium) propionate methyl sulfate to 33 g of KOH (content 90%) in 450 ml of ethanol at 18-20 [deg.] C. with vigorous stirring for 5-10 min. Stirring is continued at 18-20 [deg.] C. until complete hydrolysis of the ester (according to TLC analysis). The reaction mixture is then cooled to +2 +4 ° C and filtered off the inorganic salt precipitate which is washed with 2x20 ml of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the precipitate is washed with 3x10 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (89.5 g of the product with a Meldonium content of 91% (89% of theory)). The resulting mass is dissolved in water and further purified by known electrodialysis techniques and recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

5. To 24 g of NaOH in 450 ml of ethanol are added 92 g of methyl 3- (2,2,2-trimethylhydrazinium) propionate chloride with vigorous stirring for 5-10 minutes at 18-20 ° C. Stirring is continued at 18 to 20 oC until the hydrolysis of the ester is complete (according to TLC analysis). The reaction mixture is then cooled to +2 - +4 ° C and filtered off with a NaCl precipitate, which is washed with 2x20 mL of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the precipitate is washed with 3x10 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (91 g of product with 95% Meldonium content, (95% of theory)) which is recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

6. To 23 g of NaOH in 450 ml of ethanol at 18-20 [deg.] C. is added 92 g of methyl 3- (2,2,2-trimethylhydrazinium) propionate chloride with vigorous stirring for 5-10 min. Stirring is continued at 18 to 20 oC until the hydrolysis of the ester is complete (according to TLC analysis). The reaction mixture is then cooled to +2 - + 4 ° C and filtered off with a NaCl precipitate, which is washed with 2x20 ml of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the precipitate is washed with 3x10 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (95 g of product with 95% Meldonium content, (95% of theory)). During the recrystallization of the resultant product from isopropyl alcohol, a strongly basic anionite OH ', such as Amber Lithium IRA-400, is added to the hot solution in an amount corresponding to 1.2 equivalents of the remaining Cl' anion. After 5 min, the ion exchanger is filtered off and the solution is cooled. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content> 99.5%.

7. To 33 g of KOH (content 90% by weight) in 450 ml of ethanol at 18-20 ° C, add 113.5 g of 3- (2,2,2-trimethylhydrazinium) propionate hydrobromide bromide with vigorous stirring for 5-10 min. Stirring is continued at 18-20 [deg.] C. until complete hydrolysis of the ester (according to TLC analysis). The reaction mixture is then cooled to +2 - +4 ° C and filtered off with KBr precipitate, which is washed with 2x20 ml of ethanol. The salts are combined and saturated with carbon dioxide to a pH of 8.1 to 8.5 (based on pH meter reading). The resulting mass is filtered again, the precipitate is washed with 3x10 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (90 g of product with a Meldonium content of 94% (93% of theory)) which is recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

8. To 33 g of KOH (content 90% by weight) in 450 ml of ethanol are added 136 g of methyl 3- (2,2,2-trimethylhydrazine) propionate methyl sulphate under vigorous stirring for 5 to 10 minutes. Stirring is continued at 18-20 [deg.] C. until complete hydrolysis of the ester (according to TLC analysis). The reaction mixture is then cooled to +2 + 4 ° C and filtered off the inorganic salt precipitate which is washed with 2x20 ml ethanol. The salts are combined and saturated with sulfur dioxide to pH 8.1-8.5 (pH meter reading). The resulting mass is filtered again, the precipitate is washed with 3x10 ml of ethanol and the salts are concentrated in vacuo at room temperature. A semi-crystalline mass is obtained (89 g of product with 94% Meldonium content (92% of theory)) which is recrystallized from 2-propanol, ethanol or another suitable solvent. Obtains Meldonia with k.t. 85-87 ° C (capillary) and content of the parent substance> 99.5%.

LITERATURE

1. Eremeev A., Kalvinsh L, Semenikhina V., Liepinsh E.E., Latvian Γ.Γ., Anderson P.P., Astapenok E.B., Spruzh Υ.Υ., Trapentsiers P.T., Podoprigora G.L., Giller S.A. 3- (2,2,2-Trimethylhydrazinium) propionate and method for preparation and use of formula // Pat. 4481218 US., A.c. 529155 CCCP., IlaTeHT Pocchh 529155., Pat. LV 5224 Latvia., Pat. 2057432 UK, Patentschr. 642060 Schweiz., Brevet d'invent. 2478087 Fr., Patentschr. 2953334 BRD., Brevet d'inv. 880831 Belg., Pat. 1244003 Japan,

2. ΡΙβΜ-δα Χ.Κ., ΚραΜ3ακα Π.Ρ., AŪ36ajimc B.C., KaaeuHbiu H.PL, Mendepz Lī.B., Cudopoe A.B. 3ap and A.A. Cnoco6 noJiyHeHHfl 3- (2,2,2-TpnMeTHJi-rn, itpa3HHHH) nponnoHaTa nnranpaTa // A.c. 1262900 CCCP., IlaTeHT Pocchh 1262900., Pat. LV 5046 Latvia.

3. BacuJibee 5.H., OMenbMeHKO IO.H., Τκαμ H.H., ΠγτοΒΗΗ O.B., KajtBHHbiu Ι4.Ή .. 3neKTpoMeM6paHHbiH CHHTe3 3- (2,2,2-TpHMeTHnrHApa3HHHHa) nponHOHa. TKypHaji npHienartHOH χημηη, 1992, βμπ.12, tom 65, οτρ. 2823-2825.

4. JIonbieB Β. A, KoMapoB Β. Γ, Bopohkob Μ. Γ., LOpeBHH Β. Π., HaxMaHOBHH A C., KoMapoBa T. H., EaoxHHa Β. H., KapHayxoBa P. Β., ΕφρεΜΟΒ Β. Γ., HopsHOB Γ. Π., ΠορχιΐΗΗ Γ. B., libiateB C. B., CaBuyK Β. H. CnocoS nonyneHna nurnapara 3- (2,2,2-TpnMeTHJirnnpa3HHHH) nponHOHaTa. illaT.PoccHH 95118258.04

5. Tpanenuuep Π.Τ., Kajieumui Η.Ρί, LLfymoe Γ.Κ., EpeMamtc Γ.Α., ilpuede Χ.Κ., Meji6epe JJ.B., Kaycc B.JL, flupnenc B.B. Cojih 3- (2,2,2-τρΗΜετΗΠ γη / φβ3ηηηη) προπηοηοβοη KHCJIOTbl, oSnanatouine pocToperynHpyK) meH aKTHBHocTbio b OTHomeHHH monHHa // A.c. 849724 CCCP, 23.03.81.

6. Jīomīpee B.A., fl, omyiuuH Γ.Β., Bopomoe Μ.Γ. ΠρακΛαόπαπ xumim l, l-duMenrumudpa3UHa u e? O npou36odnbix. ) KypHaji npHKnaflHOH χημηη, 1998, Bbin.8, vol 71, οτρ. 1233-1248.

Claims (17)

1. Process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate from the salts of 3- (2,2,2-trimethylhydrazinium) propionate esters using alkaline hydrophyses in alcohol or other suitable solvents, characterized in that complete precipitation of inorganic salts is achieved. , reaction mixtures with carbon dioxide. 2. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate by prt, wherein the base is an alkaline agent selected from the group consisting of sodium, potassium, lithium, cesium, calcium and magnesium oxides, hydroxides, carbonates, or hydrogen carbonates. 3. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 1, wherein the base is potassium hydroxide. 4. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 1, wherein the base is sodium hydroxide. 5. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 1, wherein alkyl 3- (2,2, 2-Trimethylhydrazinium propionate halides. 6. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 1, wherein alkyl 3- (2,2, 2-trimethylhydrazinium) propionate methyl sulfates. 7. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 1, characterized in that 3- (2,2,2-trimethylhydrazinium) is used to obtain 3- (2,2,2-trimethylhydrazinium) propionate. acid salts of propionate. 8. Process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate from the salts of 3- (2,2,2-trimethylhydrazinium) propionate esters by alkaline hydrolysis in alcohols or other suitable solvents, except that complete precipitation of inorganic salts is achieved. treating mixtures with sulfur dioxide. 9. Process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate from the salts of 3- (2,2,2-trimethylhydrazinium) propionate esters by alkaline hydrolysis in alcohols or other suitable solvents, except that complete precipitation of inorganic salts is achieved. treating mixtures with sulfur dioxide. 10. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, wherein the base is potassium hydroxide. 11. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, wherein the base is sodium hydroxide. 12. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, wherein the alkyl 3- (2,2,2-trimethylhydrazinium) propionate is used for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate. -trimethylhydrazinium) propionate halides. 13. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, wherein the alkyl 3- (2,2,2-trimethylhydrazinium) propionate is used for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate. -trimethylhydrazinium) propionate methyl sulfates. 14. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, characterized in that 3- (2,2,2-trimethylhydrazinium) is used for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate. ) acid salts of propionate. 15. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, characterized in that the final purification of 3- (2,2,2-trimethylhydrazinium) propionate involves additional treatment with strong basic anionites. 16. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to claim 9, characterized in that the final purification of 3- (2,2,2-trimethylhydrazinium) propionate uses an additional deionization method, electrodialysis. 17. A process for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate according to any one of claims 2 to 4, wherein the base is used in an amount of 1.05 to 2.15 equimolar to the anion of an inorganic acid.