CN104151191A - A new method for synthesizing meldonium drug raw material - Google Patents

Abstract

A new method for synthesizing mildronate medicine raw material, which is a medicine used for cardiovascular diseases, mildronate C₆H₁₄N₂O₂.2H₂O is methyl 3- (2, 2, 2-trimethylhydrazinium) propionate (CH) as intermediate₃)₃N⁺NHCH₂CH₂COOCH₃X^-(wherein X represents Cl)^-、Br^-、I^-、CH₃SO₄ ^-) The products after alkaline hydrolysis and acidification have a complex acidification purification process after hydrolysis, so that the process is not better solved so far, and therefore, industrial production brings about a lot of difficulties. The technical scheme of changing the desalting technology after acidification or synthesizing mildronate by using a novel acidification compound for the first time is adopted to obtain a high-purity product, the problem that emulsion generated by acidification of acid gas is difficult to remove salt is solved, and the advantages of commercial scale production, cost reduction, simple equipment and the like are realized.

Description

A new method for synthesizing meldonium drug raw material

technical field

The invention relates to the field of organic synthesis research, in particular to a synthesis route and compound separation technology for synthesizing 3-(2,2,2-trimethylhydrazine) dihydrate "meldonium" drug raw material.

Background technique

3-(2,2,2-Trimethylhydrazine) propionate dihydrate with the International Nonproprietary Name Meldonium is known for its cardioprotective effects. Typically the methods include:

1,1-Dimethylhydrazine reacts with methyl acrylate to form 3-(2,2-dimethylhydrazino)propionic acid methyl ester, further generates the appropriate 3-(2, 2,2-trimethylhydrazine) propionate methyl halide or methyl sulfate, which is then hydrolyzed and deionized, and separated with a saturated solution of carbon dioxide or sulfur dioxide. Although this method can avoid the use of electrodialysis in the preparation of 3(2,2,2-trimethylhydrazine)propionate dihydrate, this method simultaneously forms double salts and must undergo a double salt separation step. The separation of inorganic salts caused by this acidification brings some difficulties. Since the acidification uses acid gas, the acidity and alkalinity during industrial production are not easy to control, and the milk produced is difficult to desalt. So far, no other inorganic salts have been successfully used. The compound is acidified, so it brings many difficulties in industrial production.

Contents of the invention

The inventor unexpectedly found that if the solution was acidified with CO ₂ (or SO ₂ ) and filtered, a small amount of related inorganic salts was added to the milk produced, or the emulsion was broken through the filter layer filled with related inorganic salts, or directly added to the reactant Related ammonium salts are used as acidifying reagents, and the corresponding methyl 3-(2,2,2-trimethylhydrazine) propionate salt (CH ₃ ) ₃ N ⁺ NHCH ₂ CH ₂ COOCH ₃ X ^- (where X represents Cl ^- , Br ^- , I ^- , CH ₃ SO ₄ ^- ) acidification of the hydrolyzate to produce 3-(2,2,2-trimethylhydrazine) propionate dihydrate. The main advantage of the present invention is that all the milk is deposited to obtain a clear solution or acidified quantitatively, and no acidity meter is needed to test the complex process of controlling the pH during production. Quantitative acidification is easy to control the acidity and alkalinity of hydrolysis reactants, and completely solves the problem of complex processes such as milky inorganic salts produced by acid gas saturation or refractory double salts formed. The advantages of commercial large-scale production, cost reduction, simple and easy operation of equipment are realized.

In order to solve the above-mentioned technical problems, the technical scheme adopted by the present invention is to obtain the rice by acidifying and filtering the hydrolyzed product of the pharmaceutical intermediate with acid gas CO ₂ (SO ₂ ) after emulsion breaking or using related ammonium salts to directly acidify. Methods and reactivity properties of Dronazine drug substance, including:

reaction route

1. Composition: Meldonium molecular structure formula: C ₆ H ₁₄ N ₂ O ₂ .2H ₂ O; drug intermediate 3 (2,2,2-trimethylhydrazine) propionate methyl ester salt (CH ₃ ) ₃ N ⁺ NHCH ₂ CH ₂ COOCH ₃ X ^- , where X stands for Cl ^- , Br ^- , I ^- , CH ₃ SO ₄ ^- ; the acidifying agent is an ammonium salt (NH ₄ ) _n Y, where n stands for 1, 2 or 3; Y represents OH, NO ₃ ^- , CO ₃ ^2- , HCO ₃ ^- , HSO ₄ ^- , PO ₄ ^3- or halide ion.

2. Ingredient ratio: the main content of the meldonium pharmaceutical raw material is 99.0-101%.

3. Process:

1) Hydrolysis: Slowly add a certain concentration of alkaline solution into the emulsion of 3-(2,2,2-trimethylhydrazine) propionate methyl ester salt and keep stirring to control the temperature between 18-20°C between;

2) Spot analysis During the hydrolysis process, take samples every 1 hour for spot analysis to determine whether the hydrolysis reaction is terminated;

3) vacuum concentration;

4) Separation of solid and liquid by suction filtration;

5) Acidification:

a) SO ₂ or CO ₂ gas acidification:

(1) _SO2 or _CO2 gas is fed into the mother liquor until the pH value is 8.2-8.5 (acidity meter test), stirring, and precipitation occurs;

(2) Separation of solid and liquid by suction filtration (to obtain emulsion);

(3) After adding a small amount of relevant inorganic salts to the obtained emulsion and vigorously stirring, the emulsion is immediately deposited to obtain a clear solution or emulsion by filling the relevant inorganic salt filter layer;

(4) Vacuum distillation: the mother liquor is evaporated to dryness at a temperature of 20-70° C. in a vacuum state to obtain a white solid;

b) Acidification with ammonium hydrochloride:

(1) A certain amount of ammonium salt solution is added to the mother liquor, stirred, and precipitation occurs;

(2) suction filtration: solid and liquid separation (mother liquor is clear) with suction filtration;

(3) Vacuum distillation: after suction filtration, the mother liquor was evaporated to dryness at a temperature of 20-40° C. under a vacuum state to obtain a white solid;

6) Recrystallization:

a) dissolving, suction filtration: the two kinds of crude products obtained in 5) are dissolved with ethanol respectively, and suction filtration;

b) cooling and suction filtration: the filtered mother liquor is crystallized by cooling, suction filtration and washing;

c) Vacuum drying: the crystalline powder is vacuum dried at 20-65°C;

7) Packaging: The dried product packaging should be placed in a cool place;

The technological process a) is: alkaline hydrolysis—suction filtration—acidification (a)—suction filtration—mother liquor emulsion deposition—suction filtration—vacuum distillation—recrystallization—drying—packaging.

Process flow b) is: alkaline hydrolysis—suction filtration—acidification (b)—suction filtration—vacuum distillation—recrystallization—drying—packaging.

The product content of the drug raw material obtained according to the above process is 99.0-101%, the melting point range of the compound is 85-90 DEG C, and it is a colorless crystalline powder.

technical effect

The technical effect of the present invention is to add a small amount of related inorganic salts to the milk produced by the above-mentioned a) acidification and then vigorously stir the milk to immediately deposit a clear solution or emulsion to pass through the filter layer of the relevant inorganic salts; or b) the chlorination Ammonium replaces carbon dioxide or sulfuric acid dioxide as the basis, and does not need to involve the strong basic anion exchange resin extraction method to directly realize a pharmaceutical raw material meldonium product with simple process, high yield and high purity.

Detailed ways

Example 1

Get 67g potassium hydroxide (90%) and add in 470ml ethanol and dissolve, add 121g 3-(2,2,2 trimethylhydrazine) methyl propionate bromide temperature control 18-20 ℃ hydrolysis when temperature drops to 1820 ℃ (use TLC detects whether the reaction is terminated), and when the temperature drops to 2 to 4°C, the precipitate is suction-filtered to remove the inorganic precipitate, washed with 2*20ml ethanol, and the washing liquid and the mother liquor are combined and acidified with _CO gas until the pH is 8.28.5 (PH acidity meter test), filter off the formed precipitate, wash with 2*20ml ethanol, combine the mother liquor of the lotion (it cannot be clarified by milk filtration method), add a small amount of K ₂ SO ₄ to the mother liquor, stir and let it stand for about 15 minutes, the milk will become clear and produce particles Then, the remaining inorganic salts were filtered out, and the obtained clear solution was concentrated under reduced pressure, cooled and crystallized to dry to obtain 91g of meldonium crude drug raw material with about 94%, which was recrystallized with isopropanol or ethanol, with a melting point of 86-88°C , content >99.5%.

Example 2

Take 67g of potassium hydroxide (90%) and add it into 470ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 145g of 3-(2,2,2-trimethylhydrazine) methyl propionate sulfate and control the temperature at 18-20°C Hydrolyze (use TLC to detect whether the reaction is terminated), and when the temperature drops to 2 to 4°C, precipitate by filtration to remove inorganic precipitates, wash with 2*20ml ethanol, combine the washing liquid and mother liquor and pass SO ₂ gas to acidify to pH 8.2-8.5 (PH acidity meter test), filter out the formed precipitate, wash with 2*20ml ethanol, combine the mother liquor of the washing liquid (the clear solution cannot be obtained by milk filtration method), add a small amount of K ₂ SO ₄ to the mother liquor, stir and let it stand for about 15 minutes The milky state becomes clear to produce granular precipitates, and then the remaining inorganic salts are filtered out. The obtained clear solution is concentrated under reduced pressure, cooled and crystallized to dry to obtain 88g of meldonium crude drug raw material with about 95%, recrystallized with isopropanol or ethanol, melting point At 86-88°C, the content is >99.5%.

Example 3

Take 71.5g of potassium hydroxide (90%) and add it into 480ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 129g of 3-(2,2,2-trimethylhydrazine) methyl propionate bromide. Temperature control 18-20 ℃ hydrolysis (use TLC to detect whether the reaction is terminated), when the temperature drops to 2 to 4 ℃, suction filter the precipitate, remove the inorganic precipitate, wash with 2*20ml ethanol, combine the washing liquid and mother liquor, add 19g NH ₄ NO ₃ aqueous solution, and suction filter In addition to inorganic precipitates, wash with 2*20ml ethanol, combine the lotion and mother liquor, pressurize, concentrate, cool and crystallize and dry to obtain 96g of crude drug raw material Meldonium with about 94%, recrystallized with isopropanol or ethanol, melting point is 85-87°C , content >99.5%.

Example 4

Take 33g of potassium hydroxide (90%) and add it into 480ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 145g of 3-(2,2,2-trimethylhydrazine) methyl propionate bromide and control the temperature at 18-20°C Hydrolyze (use TLC to check whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4°C, remove the inorganic precipitate, wash with 2*20ml ethanol, combine the washing liquid and mother liquor, add 33g NH ₄ NO ₃ aqueous solution, and filter off Inorganic precipitates were washed with 2*20ml of ethanol, combined with the mother liquor of the lotion, concentrated under pressure, cooled and crystallized, and dried to obtain 97.4g of the crude drug material of Meldonium, about 93%, recrystallized with isopropanol or ethanol, with a melting point of 85-87°C , content >99.5%.

Example 5

Take 33g of potassium hydroxide (90%) and add it into 480ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 145g of 3-(2,2,2-trimethylhydrazine) methyl propionate sulfate and control the temperature at 18-20°C Hydrolyze (use TLC to detect whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4°C, remove the inorganic precipitate, wash with 2*20ml ethanol, combine the washing liquid and the mother liquor and add 18g (NH ₄ ) ₃ PO ₄ to acidify, Remove the inorganic precipitate by suction filtration, wash with 2*20ml ethanol, combine the lotion mother liquor, pressurize, concentrate, cool and crystallize and dry to obtain 90g of crude drug material of Meldonium with about 94%, recrystallized with isopropanol or ethanol, melting point is 86- 88°C, content >99.5%.

Example 6

Take 28g of sodium hydroxide and add it to 480ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 96g of 3-(2,2,2-trimethylhydrazine) methyl propionate chloride and hydrolyze at 18-20°C under temperature control (use TLC Check whether the reaction is terminated), when the temperature drops to 2 to 4°C, suction filter the precipitate to remove the inorganic precipitate, wash the solid with 2*20ml ethanol, add 31g NH ₄ I to the washing liquid and the mother liquor to acidify, and suction filter to remove the inorganic precipitate. The solid was washed with 2*20ml of ethanol, combined with the mother liquor of the lotion, concentrated under pressure, cooled and crystallized, and dried to obtain 99g of crude drug material Meldonium, about 95%, recrystallized with isopropanol or ethanol, with a melting point of 87-88°C and a content of >99.5 %.

Example 7

Take 67g of potassium hydroxide (90%) and add it into 470ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 145g of 3-(2,2,2-trimethylhydrazine) methyl propionate sulfate and control the temperature at 18-20°C Hydrolyze (use TLC to detect whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4°C, remove the inorganic precipitate, wash with 2*20ml ethanol, combine the washing liquid and the mother liquor and pass CO ₂ gas to acidify to pH 8.2-8.5 (PH acidity meter test), filter off the formed precipitate, wash with 2*20ml ethanol, combine the washing liquid mother liquor (it is the emulsion filtration method that cannot obtain the clear solution), the emulsion is filled with CaCl ₂ filter layer, and the clear solution obtained is decompressed Concentrate, cool and crystallize and dry to obtain about 95% of 88g crude drug material of Meldonium, which is recrystallized with isopropanol or ethanol, with a melting point of 86-88°C and a content of >99.5%.

Example 8

Take 67g of potassium hydroxide (90%) and add it into 470ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 12lg of 3-(2,2,2-trimethylhydrazine) methyl propionate bromide and control the temperature at 18-20°C Hydrolyze (use TLC to detect whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4°C, remove the inorganic precipitate by suction, wash with 2*20ml ethanol, combine the washing liquid and the mother liquor and pass CO ₂ gas to acidify to pH 8.2 -8.5, remove the inorganic precipitate by suction filtration, wash with 2*20ml ethanol, combine the lotion mother liquor, pressurize, concentrate, cool and crystallize and dry to obtain 90g of meldonium crude drug raw material about 94%, recrystallized with isopropanol or ethanol, melting point At 85-88°C, the content is >99.5%.

Claims (3)

1. A new method for synthesizing meldonium drug raw materials, characterized in that: the molecular structural formula of meldonium is: C ₆ H ₁₄ N ₂ O ₂ .2H ₂ O; drug intermediate 3-(2,2,2- Trimethylhydrazine) propionate methyl ester salt (CH ₃ ) ₃ N ⁺ NHCH ₂ CH ₂ COOCH ₃ X ^- , where X represents Cl ^- , Br ^- , I ^- , CH ₃ SO ₄ ^- ; the acidifying reagent is a A kind of ammonium salt (NH ₄ ) _n Y, wherein, n represents 1, 2 or 3; Y represents OH ^- , NO ₃ ^- , CO ₃ ^2- , HCO ₃ ^- , HSO ₄ ^- , PO ₄ ^3- or halide ion. 2. The new method for synthesizing meldonium drug raw material according to claim 1, characterized in that: we change the desalination technology after sulfation of carbon dioxide or carbon dioxide, or use relevant ammonium hydrochloride for the first time to obtain the synthesis of meldonium raw material drug Technical solutions. the 3. a kind of new method of synthetic Meldonium pharmaceutical raw material according to claim 1, is characterized in that a) SO ₂ or CO ₂ gas acidification: The method comprises the use of inorganic salt demulsification sedimentation or desalination through the inorganic salt filter layer to add a small amount of related inorganic salt to the emulsion and then vigorously stir it to obtain a clear solution or emulsion immediately after filling the relevant inorganic salt filter layer A clear solution was obtained. the b) Acidification with ammonium hydrochloride: The method comprises acidifying methyl 3-(2,2,2-trimethylhydrazine)propionate (CH ₃ ) ₃ N ⁺ NHCH ₂ CH ₂ COOCH ₃ X ⁻ (where X represents Cl ⁻ , Br ^- , I ^- , CH ₃ SO ₄ ^- ) alkaline hydrolyzate; include: