(19) &   

(11) EP 2 247 572 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 241/02 (2006.01) C07C 243/40 (2006.01) 03.08.2011 Bulletin 2011/31 (86) International application number: (21) Application number: 09713008.2 PCT/EP2009/051996

(22) Date of filing: 19.02.2009 (87) International publication number: WO 2009/103773 (27.08.2009 Gazette 2009/35)

(54)NE- A O POT PROCESS FOR PREPARING 3-(2,2,2-TRIMETHYLHYDRAZINIUM)PROPIONATE DIHYDRATE EIN-TOPF-VERFAHREN ZUR HERSTELLUNG VON 3-(2,2,2-TRIMETHYLHYDRAZINIUM) PROPIONAT-DIHYDRAT PROCÉDÉ DE PRÉPARATION EN ENCEINTE UNIQUE DE DIHYDRATE DE 3-(2,2,2- TRIMÉTHYLHYDRAZINIUM)-PROPIONATE

(84) Designated Contracting States: • OSVALDS, Pugovics AT BE BG CH CY CZ DE DK EE ES FI FR GB GR LV-1004 Riga (LV) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • CERNOBROVIJS, Aleksandrs PT RO SE SI SK TR LV-2114 Olaine (LV) Designated Extension States: • IEVINA, Agnija AL BA RS LV-1004 Riga (LV) • LEBEDEVS, Antons (30) Priority: 19.02.2008 LV 080022 LV-3600 Ventspils (LV) 19.02.2008 LV 080023 (56) References cited: (43) Date of publication of application: WO-A-2005/012233 US-A- 4 481 218 10.11.2010 Bulletin 2010/45 • GILLER S.A. ET AL,.: CHEMISTRY OF (73) Proprietor: Grindeks, a joint stock company HETEROCYCLIC COMPOUNDS, vol. 11, no. 12, Riga 1057 (LV) 1975, pages 1378-1382, XP002534780

(72) Inventors: • KALVINS, Ivars LV-15052 Ikskile (LV)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 247 572 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 247 572 B1 2

Description [0006] US4481218 discloses a preparation of 3-(2,2,2- trimethylhydrazinium)propionate dihydrate, which com- Technical Field prises passage through a column with a strongly basic ion exchange resin. [0001] The present invention relates to one-pot proc- 5 ess for preparing 3-(2,2,2- trimethylhydrazinium)propion- Disclosure of Invention ate dihydrate (international non- proprietary name - "Mel- donium") from 3-(2,2-dimethylhydrazino)propionate es- [0007] We have unexpectedly found, that preparation ters having general formula (I). of the 3-(2,2,2-trimethylhydrazinium)propionate dihy- 10 drate is possible to carry out in a one-pot process using as a starting material 3-(2,2-dimethylhydrazino)propion- ate esters of the general formula (I),

15

wherein R represents CH 3, C2H5, C3H7, i-C3H7, C4H9, i- 20 C4H9 and C6H5CH2 and from the corresponding acid (R represents H). wherein R represents CH 3, C2H5, C3H7, i-C3H7, C4H9, i- Background Art C4H9 and C6H5CH2, hydrolyzing the 3-(2,2-dimethylhy- drazino)propionate esters of the formula (I) in a solvent, [0002] 3-(2,2,2-Trimethylhydrazinium)propionate di- 25 followed by the reaction with dimethyl carbonate (DMC). hydrate is known for its cardioprotective properties under Surprisingly, we have also found that a direct one-pot the International Non- proprietary Name of Meldonium. A synthesis of the 3-(2,2,2-trimethylhydrazinium)propion- number of methods for the preparation of 3-(2,2,2-tri- ate dihydrate by the hydrolysis of the 3-(2,2-dimethylhy- methylhydrazinium)propionate dihydrate are known. drazino)propionate esters of the formula (I) and simulta- [0003] Generally, the process involves 1,1-dimethyl- 30 neous reaction of the formed intermediate with DMC can hydrazine reaction with acrylic acid esters leading to also be performed with high yields of the desired product. 3-(2,2-dimethylhydrazino)propionate esters, further [0008] According to the present invention, the solvent alkylated with a methyl halide or dimethylsulphate to give for the invented process is selected from the group, com- the appropriate methyl-3-(2,2,2-trimethylhydrazinium) prising water and water-containing solvents e. g. lower propionate halogenide or methylsulphate, which are then 35 alcohols, acetone, ethyl acetate, acetonitrile, dioxane, hydrolyzed and deionized. dimethylformamide, dimethylsulphoxide, alkylketones [0004] A standard alkaline hydrolysis method of car- and mixtures thereof. bonic and sulphuric acid esters in case of the alkyl- [0009] In one embodiment of the current invention, hy- 3-(2,2,2-trimethylhydrazinium)propionate salts was not drolysis of 3-(2,2- dimethylhydrazino)propionate esters of successfully realized till now because of the problems of 40 the formula I was carried out at 70-100°C in water until separation of 3-(2,2,2- trimethylhydrazinium) propionate complete conversion of the starting ester to the corre- dihydrate and the resulting inorganic salts. It is known sponding acid, controlled chromatographically. After the that 3-(2,2,2-trimethylhydrazinium)propionate dihydrate conversion was completed, the process was continued, forms relatively stable double salts of the variable com- without isolation of the intermediates, by adding to reac- position (SU849724). 45 tion mixture dimethyl carbonate and methanol. Reaction [0005] WO 2008/028514 A (SILVA JORGE)was continued at the same temperature until the conver- 13.03.2008, disclosed a method of producing the sion was completed (with chromatographic control), then 3-(2,2,2-trimethylhydrazinium) propionate dihydrate by methanol, dimethyl carbonate and water were removed hydrolyzing 3-(2,2,2-trimethylhydrazinium)propionate by distillation at a reduced pressure. The distillation res- halide or methyl sulphate esters under acidic conditions, 50 idue was treated with hot isopropyl alcohol, filtered and catalyzed by HCl, sulphuric acid, phosphoric acid etc., dried, yielding of 90-98% of the desired 3-(2,2,2- trimeth- followed by neutralization by an appropriate inorganic ylhydrazinium)propionate dihydrate. base (for example, sodium, potassium, calcium or mag- [0010] In another embodiment of the current invention, nesium hydroxide or another appropriate base, for ex- 3-(2,2-dimethylhydrazino)propionate ester of the formula ample sodium, potassium, lithium or cesium carbonate 55 I was dissolved in water, and methanol and dimethyl car- or bicarbonate etc.) and the double salts thus obtained bonate were added to this solution. The reaction mixture can be separated by the invented process using satura- was heated at 80-100°C with chromatographic control tion of the solution with carbon dioxide or sulphur dioxide. until the full conversion of the starting ester. After removal

2 3 EP 2 247 572 B1 4 of the solvents the residue was treated with hot isopropyl Example 2 alcohol, filtered and dried, yielding of 90-98% of the de- sired 3-(2,2,2-trimethylhydrazinium)propionate dihy- [0014] Preparation of 3-(2,2,2-trimethylhydrazinium) drate. Thus, according to the current invention, it is pos- propionate dihydrate Methyl-3-(2,2-dimethylhydrazino) sible to obtain 3-(2,2,2-trimethylhydrazinium)propionate 5 propionate (146 g, 1 mol) was dissolved in water (270 dihydrate from methyl-3-(2,2-dimethylhydrazino)propi- mL), then methanol(170 ml) and dimethylcarbonate (843 onate in a one-pot reaction, without isolation of any in- mL, 10 mol) were added to the solution. Reaction mixture termediates and significantly increasing the reaction rate was heated at 95°C in a reactor until the reaction was and total yield of the final product. complete (controlled by HPLC). Methanol, dimethyl car- [0011] In yet another embodiment of the current inven- 10 bonate and water were removed by distillation at a re- tion, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate duced pressure. The distillation residue was dissolved in can also be obtained from the 3-(2,2- dimethylhydrazino) hot isopropyl alcohol (500 ml), and evaporated again. propionic acid, which forms as an intermediate in the in- Obtained 3-(2,2,2-trimethylhydrazinium)propionate di- vented process, reacting the 3-(2,2-dimethylhydrazino) hydrate was dried under reduced pressure. The yield was propionic acid with DMC in a solvent, followed by evap- 15 171 g (93.9%). oration of the liquids, treatment of the residue with hot isopropyl alcohol, filtration and drying of the crude Example 3 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, with 95-98% yields of the desired product. Methods of [0015] Preparation of 3-(2,2,2-trimethylhydrazinium) the current invention overcomes the disadvantages of 20 propionate dihydrate 3-(2,2- Dimethylhydrazino)propion- the method disclosed in WO 2008/028514 A (SILVA ic acid (132 g, 1 mol) was dissolved in water (180 mL), JORGE) 13.03.2008 by presenting the one-pot process thereafter methanol (170 ml) and dimethyl carbonate for obtaining 3-(2,2,2-trimethylhydrazinium)propionate (843 mL, 10 mol) were added to the reaction mixture. dihydrate from 3-(2,2-dimethylhydrazino)propionate es- Reaction mixture was heated at 95°C in a reactor until ters and/or 3-(2,2-dimethylhydrazino)propionic acid, re- 25 the reaction was complete (controlled by HPLC). ducing the number of reaction steps and eliminating the [0016] Methanol, dimethyl carbonate and water were problemof formation of the double salts. Thus, the current removed by distillation at a reduced pressure. The distil- invention provide for an inexpensive and convenient lation residue dissolved in hot isopropyl alcohol (500 ml), large scale manufacturing process of 3-(2,2,2- trimethyl- and evaporated again. Obtained 3-(2,2,2-trimethylhy- hydrazinium)propionate dihydrate under use of inexpen- 30 drazinium)propionate dihydrate was dried under reduced sive and available reagents with high yields and purity of pressure. The yield was 175 g (96.0%). the final product. [0012] The present invention will be described in more detail by referring to the following nonlimiting examples. Claims The scope of the invention should not be limited to the 35 working examples, which are for demonstration purpos- 1. A one-pot process for preparing 3-(2,2,2-trimethyl- es. One skilled in the art can practice the invention based hydrazinium)propionate dihydrate from 3-(2,2- on the disclosures in the present patent application. dimethylhydrazino)propionate esters, having gener- al formula (I) Example 1 40

[0013] Preparation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate Methyl-3-(2,2-dimethylhydrazino) propionate (146 g, 1 mol) was dissolved in water (290 mL) and heated under inert atmosphere at 90-100°C until 45 complete conversion of starting ester to corresponding acid (controlled by HPLC). Methanol (150 ml), thereafter dimethyl carbonate (843 mL, 10 mol) was added to the reaction mixture. Reaction mixture was heated at 90°C wherein R represents CH3, C2H5, C3H7, i-C3H7, 50 in a reactor until the reaction was complete (controlled C4H9, i-C4H9 and C6H5CH2, and from the 3-(2,2- by HPLC). Methanol, dimethyl carbonate and water were dimethylhydrazino)propionic acid (R represents H), removed by distillation at a reduced pressure. The distil- by reaction with dimethyl carbonate in a solvent, se- lation residue was dissolved in hot isopropyl alcohol (500 lected from the group, comprising water and water- ml), and evaporated again. Obtained 3-(2,2,2-trimethyl- containing solvents, e. g. lower alcohols, acetone, hydrazinium)propionate dihydrate was dried under re- 55 ethyl acetate, acetonitrile, dioxane, dimethylforma- duced pressure. The yield was 172 g (94.4%). mide, dimethylsulphoxide, alkylketones and mix- tures thereof and at a temperature in the range from 70-100°C.

3 5 EP 2 247 572 B1 6

2. Aprocess according to the claim 1, wherein the dime- carbonat der Reaktionsmischung gemäß Formel (I) thyl carbonate is added to the reaction mixture after zugegeben wird. the hydrolysis of the compound of formula (I) in a solvent is completed. 3. Verfahren nach Anspruch 1, worin das Dimethylcar- 5 bonat der Reaktionsmischung zusammen mit dem 3. Aprocess according to the claim 1, wherein the dime- Lösungsmittel zugegeben wird. thyl carbonate is added to the reaction mixture to- gether with the solvent. 4. Verfahren nach Anspruch 1-3, worin Wasser das Lö- sungsmittel ist. 4. A process according to the claims 1-3, wherein the 10 solvent is water. 5. Verfahren nach Anspruch 1-3, worin eine Mischung aus Wasser und Methanol das Lösungsmittel ist. 5. A process according to the claims 1-3, wherein the solvent is a mixture of water and methanol. 6. Verfahren nach Anspruch 1-3, worin Methyl-3-(2,2- 15 dimethylhydrazin)Propionat der 3-(2,2-dimethylhy- 6. A process according to claims 1-3, wherein 3-(2,2- drazin)Propionatester gemäß Formel (I) ist. dimethylhydrazino)propionate ester of formula (I) is methyl-3-(2,2-dimethylhydrazino)propionate. 7. Verfahren nach Anspruch 1-3, worin die 3-(2,2-di- methylhydrazin)Propionsäure die Verbindung ge- 7. A process according to claims 1-3, wherein the com- 20 mäß Formel (I) ist. pound of formula (I) is 3-(2,2- dimethylhydrazino)pro- pionic acid. 8. Verfahren nach Anspruch 7, worin die Reaktion bei Temperaturen zwischen 90 und 95 °C durchgeführt 8. A process according to claim 7, wherein the reaction wird. is carried out at the temperatures in the range from 25 90-95°C. Revendications

Patentansprüche 1. Le processus doit être faits dans un récipient pour 30 préparer le 3-(2,2,2-triméthyl hydrazine) propionate 1. In einem Gefäß durchzuführendes Verfahren zur dihydrate des esters propionate 3-(2,2-dimethylhy- Gewinnung von 3-(2,2,2-trimethylhydrazin)Propio- drazino) si la formule générale est (I) nat-Dihydrat aus 3-(2,2- dimethylhydrazin)Propiona- tester, wenn die allgemeine Formel (I) 35

40

où R représente CH3, C2H5, C3H7, i-C3H7, C4H9, i- C4H9 et C6H5CH2, et de 3-(2,2-dimethylhydrazino) zugänglich ist, worin R sich auf CH 3, C2H5, C3H7, i- acide-propionique (R représente H), 45 C3H7, C4H9, i-C4H9 und C6H5CH2 bezieht, und aus en utilisant la réaction avec le dimethylcarbonate 3-(2,2-dimethylhydrazin)Propionsäure (R bezieht dans le solvant, choisi dans le groupe qui embrasse sich auf H), l’eau et les solvants aqueux, par ex., alcools infé- unter Anwendung der Reaktion mit Dimethylcarbo- rieurs, acétone, acétate d’éthyle, acétonitrile, dioxa- nat in einem Lösungsmittel, das aus einer Gruppe ne, dimethylformamide, diméthylsulfoxyde, alkylke- gewählt wird, in die auch Wasser und lösungsmittel- 50 tones et leurs mélanges, et à la température dans haltiges Wasser fallen, das zum Beispiel niedere Al- les limites entre 70 et 100 °C. kohole, Aceton, Ethylacetat, Acetonitril, Dioxan, Di- methylformamid, Dimethylsulfoxid, Alkylketone und 2. Le processus conforme à la première revendication Mischungen aus diesen enthält, und bei Tempera- où le carbonate de diméthyle est ajouté au mélange turen zwischen 70 und 100°C. 55 de réaction après l’hydrolyse, selon la formule (I).

2. Verfahren nach Anspruch 1, worin nach der Hydro- 3. Le processus conforme à la première revendication lyse der Verbindung zu Lösungsmittel das Dimethyl- où le dimethylcarbonate est ajouté au mélange de

4 7 EP 2 247 572 B1 8

reaction ensemble avec le solvant.

4. Le processus conforme aux revendications 1 - 3, où le solvant est l’eau. 5 5. Le processus conforme aux revendications 1 - 3 , où le solvant est le mélange de l’eau et de méthanol.

6. Le processus conforme aux revendications 1 - 3 , où l’ester propionate de la formule (I) 3-(2,2-dimetilhi- 10 drazino)est le méthyl-3-(2,2- diméthylhydrazine)pro- pionate.

7. Le processus conforme aux revendications 1 - 3 , où le composé de formule (I) est 3-(2,2- dimethylhydra- 15 zino) acide-propionique.

8. Le processus conforme à la 7 ième revendication, où la réaction est faite à la température dans les limites entre 90 et 95 °C. 20

25

30

35

40

45

50

55

5 EP 2 247 572 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• SU 849724 [0004] • US 4481218 A [0006] • WO 2008028514 A, SILVA JORGE [0005] [0011]

6