WO2014094659A1

WO2014094659A1 - Process for preparation of meropenem trihydrate crystals

Info

Publication number: WO2014094659A1
Application number: PCT/CN2013/090169
Authority: WO
Inventors: 卫宏远; 党乐平; 魏颖
Original assignee: 浙江海正药业股份有限公司
Priority date: 2012-12-21
Filing date: 2013-12-20
Publication date: 2014-06-26
Also published as: CN102977102A

Abstract

Disclosed is a process for preparation of meropenem trihydrate crystals, comprising: 1) dissolving crude meropenem in an alkali solution, thus forming a saturated solution of meropenem; 2) adding activated carbon into the saturated solution for decolorizing and filtering to obtain a filtrate; 3) adding an acid solution to the filtrate to adjust the pH of the solution to pH<7, reducing the temperature and crystallizing, filtering to obtain meropenem trihydrate crystals. The process of the present preparation is simple and easy for industrialization. The process is safe and environmental due to avoiding the use of organic solvents. The meropenem trihydrate is obtained with higher yield, higher purity and stable quality.

Description

Method for preparing meropenem trihydrate crystal

Technical field

The invention belongs to the field of chemistry and relates to a method for preparing a drug crystal. Background technique

Meropenem trihydrate, chemical name (4R, 5S, 6S)-3-[[(3S,5S)-5- (dimethylcarbamoyl)-3-pyrrolidine]sulfonate-6 -[(lR)-l-hydroxyethyl]-4-indolyl-7-oxo-1-azanthene ring [3.2.0]hept-2-ene-2-carboxylic acid trihydrate, the molecular formula is C ₁₇ H ₂₅ N ₃ 0 ₅ S'3H ₂ 0. White to slightly yellow crystalline powder, odorless, CAS No. 119478-56-7.

3⁄4 mouth:

The drug was developed by Sumitomo Corporation of Japan. It was marketed outside of Japan by AstraZeneca under the trade names "Merrem" and "Memnem" in 1995. It belongs to the class of β-lactam antibiotics and carbapenems. The drug has a wide range of antibacterial properties and can be used to treat a variety of different infections, including meningitis and pneumonia. Its antibacterial spectrum and antibacterial activity are similar to those of imipenem, but due to the structure of hydrocarbons with methyl groups. Mycophenolate, which is more stable to dehydropeptidase in the kidneys, does not require an enzyme inhibitor, and can reduce the risk of epilepsy compared to imipenem.

Peinan antibiotics are a kind of drugs that are difficult to develop and have complicated production processes. They are mainly prepared by chemical synthesis. The synthesis process includes key side chain synthesis and skeleton core synthesis. Crystallization is the purification step necessary for the production process of meropenem, applied to the final stage of production and determines the final quality of the product.

In recent years, there have been some patents for the preparation of meropenem trihydrate crystals.

US2007197781, CN200610083362.7 discloses a method of adding a large amount of acetone to a crude aqueous solution of meropenem for elution crystallization. Since the solubility of meropenem in water is small, the amount of acetone added is relatively large, resulting in high operating costs, large solvent residues in the product, and safety hazards in the production process. Great question.

U.S. Patent No. 2,009,216,101 discloses a method of concentrating an aqueous solution in which melopenem is dissolved in a reverse osmosis membrane, and then adding a lysing agent such as tetrahydrofuran or acetone to obtain meropenem crystals.

US2009264643 provides a process for first adding ammonia water to a crude aqueous solution of meropenem, adjusting the pH with citric acid, and adding tetrahydrofuran for elution crystallization. It is cumbersome to understand the process, and tetrahydrofuran belongs to the second class of solvents and should be avoided in the final crystallization process.

CN201010232062.7 discloses a method for refining meropenem trihydrate crystal, dissolving crude meropenem in water at a temperature of 30-70 ° C, decolorizing with activated carbon, filtering at 5~3 (TC, cooling to 0~) After crystallization at 10 ° C, the meropenem trihydrate crystals and the filtrate were obtained by filtration, and meropenem was further recovered by adding an organic solvent such as a lower alcohol or a ketone to the filtrate.

CN201010232096.6 discloses the following crystallization method: Dissolving crude meropenem in water at a temperature of 30-70 ° C, decolorizing with activated carbon, filtering, adding organic solvent to the filtrate, and cooling to -20~0 °C to make the solution A crystal nucleus is formed, and the crystal nucleus is melted, and crystallized by adding an organic solvent, and filtered to obtain a meropenem trihydrate crystal.

CN201010275223.0 provides a method for crystallizing meropenem in sterol: after dissolving the crude product in decyl alcohol, performing decolorization, decarbonization, sterilization filtration, adding water and a precipitating agent (alcohol, ketone, ether, The mixture of tetrahydrofuran or a mixture is crystallized, washed with a mixed solvent of water and an alcohol or an ester, and dried to obtain a product.

CN201110218567.2 provides a method for crystallizing meropenem in aqueous sodium hydroxide solution: the crude product is dissolved in 10% aqueous sodium hydroxide solution, decolorized, filtered, crystallized at 0 ° C, and ethyl acetate is added to the filtrate to recover the beauty. Luo Peinan. However, with this method, meropenem is prone to ring-opening reactions. Under the process conditions described in this document, about 50% of the meropenem raw materials will undergo ring-opening reaction. Therefore, the product obtained by the method is extremely low in yield, high in impurity content, and difficult to implement industrialization. Guarantee the stability of product quality. Summary of the invention

The object of the present invention is to provide a preparation method of meropenem trihydrate, which has high yield, high purity, no organic solvent residue, and a preparation method.

The technical solution of the present invention is as follows:

A method for preparing meropenem trihydrate crystals, comprising the steps of:

1) Dissolving the crude meropenem in an alkali solution to form a saturated solution of meropenem;

2) adding decoloration to the saturated solution, filtering, and obtaining a filtrate; 3) An acid solution is added to the filtrate to adjust the pH to <7, and the crystal is cooled and crystallized, and the meropenem trihydrate crystal is obtained by filtration.

Preferably, the pH of the lye in step 1) is 7 to 12.

Preferably, the lye is a weak base solution, more preferably selected from the group consisting of ammonia water, sodium carbonate, and sodium hydrogencarbonate solution, and has a mass concentration of 5 to 15%.

Preferably, the lye is a potassium hydroxide or sodium hydroxide solution.

Preferably, the acid solution is selected from the group consisting of hydrochloric acid, 4 acid or acetic acid solution, and the concentration is 10-50%.

Preferably, step 3) adding an acid solution to the filtrate to bring the pH to 4-7.

Preferably, the temperature of the lye in step 1) is 10 to 30 ° C, more preferably 20 to 30 ° C.

Preferably, step 3) the temperature of the temperature-lowering crystallization is -5 to 10. C.

Preferably, step 1) the crude meropenem has a purity of 80 to 90%.

Preferably, the decolorization temperature of step 2) is 10 to 30 °C.

In step 3), you can choose to add or not add seed crystals.

Preferably, step 3) is: adding acid to the filtrate to pH 6.5~9, adding seed crystals, continuing to add acid to pH 5.5~6.0, cooling to -5~5 °C, stirring and crystallization, filtering Derived from meropenem trihydrate crystals.

Preferably, the preparation method further comprises the step of subjecting the meropenem trihydrate crystal obtained in the step 3) to a cold water rinsing.

Unlike the method described in the relatively similar patent document CN201110218567.2, the present invention strictly controls the pH of the lye used for dissolving the crude meropenem, and greatly reduces the solubility of meropenem in the lye. The probability of a ring-opening reaction with meropenem. In addition, after the alkali solution is dissolved and decolorized by the activated carbon, the method of the invention adjusts the pH of the solution to acidity, and then cools and crystallizes, thereby avoiding the long-term meropenem in an alkaline environment and reducing the occurrence of meropenem. The reaction plays an important role.

The method of the invention has simple process, is easy to be industrialized, avoids the use of organic solvent, and the process is safe and environmentally friendly; in the process, by preferably controlling the temperature in each step, the ring-opening degradation of meropenem is further reduced, and the obtained meropenem trihydrate is obtained. High yield, high purity and stable quality. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a 200x photomicrograph of the product obtained in Example 1.

Figure 2 is an XRD pattern of the product obtained in Example 1.

Figure 3 is an RD spectrum of the meropenem trihydrate standard. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further illustrated by the following examples. It should be understood that the preparation methods of the embodiments of the present invention are only for explaining the present invention, and are not intended to limit the present invention. The simple improvement of the preparation method of the present invention within the scope of the present invention is within the scope of the present invention. .

The reagents in the following examples are all commercially available products, and the crude product of meropenem is in accordance with the US patent.

The method described in US 4,943,569 is prepared.

Example 1:

12 g of crude meropenem with a purity of 80% was added to a 10% aqueous solution of 8% ammonia at a temperature of 10 Torr, stirred until completely dissolved, and 3 g of activated carbon was added to the obtained solution, which was decolorized at 20 ° C, filtered, and mass concentration was added to the filtrate. It was 10% hydrochloric acid solution to pH = 6.9, cooled to 10 ° C and stirred for 2 h, filtered, and the filter cake was rinsed with cold water and dried under vacuum to obtain 9.5 g of meropenem trihydrate crystal. Yield: 79.2%, purity (in terms of anhydrous meropenem) was 99.5%.

The resulting product was analyzed as meropenem trihydrate. The appearance of the product is white or off-white needle crystal, 200 times photomicrograph is shown in Figure 1, X D spectrum is shown in Figure 2, and the XRD pattern of meropenem trihydrate standard is shown in Figure 3.

Example 2:

40 g of crude meropenem with a purity of 83% was added to 100 ml of a 10% sodium carbonate solution at a temperature of 20 ° C, stirred until completely dissolved, and 8 g of activated carbon was added to the obtained solution, which was decolorized at 20 ° C, filtered, and filtered into the filtrate. Add 50% acetic acid solution to pH = 6.1, cool to 0 ° C, stir for 2 h, filter, filter cake was rinsed with cold water, and dried under vacuum to obtain 31.8 g of meropenem trihydrate crystal. Yield: 79.5%, purity (in terms of anhydrous meropenem) was 99.6%.

The obtained product was analyzed to be meropenem trihydrate, and its appearance, microscopic morphology and XRD pattern were similar to those in Example 1.

Example 3:

30 g of crude meropenem with a purity of 90% was added to 100 ml of a 15% sodium hydrogen carbonate solution at a temperature of 30 ° C, stirred until completely dissolved, and 6 g of activated carbon was added to the obtained solution, and the mixture was decolorized at 30 ° C, and then filtered. Add 30% sulfuric acid solution to pH=9, add seed crystals and continue adding acid to pH=5.8, cool down to -5 °C, stir for 2h, filter, filter cake with cold water, vacuum dry, get meropenem Water The crystal of the compound was 24.2 g. Yield: 80.7%, purity (calculated as anhydrous meropenem) was 99.6%.

Example 4:

30 g of crude meropenem with a purity of 85% was added to 100 ml of a 5% sodium carbonate solution at a temperature of 30 ° C, stirred until completely dissolved, and 6 g of activated carbon was added to the obtained solution, which was decolorized at 10 ° C, filtered, and filtered into the filtrate. Add 20% hydrochloric acid solution to pH = 8, add seed crystals, continue to add acid to pH = 5.6, cool to 0 ° C, stir for 2 h, filter, filter cake rinsed with cold water, vacuum dried to obtain meropenem trihydrate The crystal was 23.8 g. Yield: 79.3%, purity (calculated as anhydrous meropenem) was 99.5%.

Example 5:

30 g of crude meropenem with a purity of 85% was added to 100 ml of a 5% sodium carbonate solution at a temperature of 30 ° C, stirred until completely dissolved, and 6 g of activated carbon was added to the obtained solution, which was decolorized at 10 ° C, filtered, and filtered into the filtrate. Add 20% hydrochloric acid solution to pH = 6.5, add seed crystals, continue to add acid to pH = 5.6, cool to 0 ° C, stir for 2 h, filter, filter cake rinsed with cold water, vacuum dried to obtain meropenem trihydrate The crystal was 23.8 g. Yield: 79.3%, purity (calculated as anhydrous meropenem) was 99.5%.

Claims

Rights request

A method for preparing meropenem trihydrate crystals, comprising the steps of:

2) adding decolorization to the saturated solution, filtering, and obtaining a filtrate;

3) An acid solution is added to the filtrate to adjust the pH to <7, and the meropenem trihydrate crystal is filtered.

The method according to claim 1, wherein the pH of the liquid reduction step is from 7 to 12.

The method according to claim 1 or 1, wherein the alkali liquid is selected from the group consisting of ammonia water, sodium carbonate or sodium hydrogencarbonate solution, and the concentration is 5 to 15%.

The method according to claim 1 or 2, wherein the alkali solution is a potassium hydroxide or sodium hydroxide solution.

The method according to claim 3, wherein the acid solution is selected from the group consisting of hydrochloric acid, sulfuric acid or acetic acid solution at a concentration of 10 to 50%.

The method according to claim 5, wherein step 3) adding an acid solution to the filtrate to bring the pH to 4 to 7.

The method according to claim 5, wherein the temperature of the lye is 10 to 30 ° C, more preferably 20 to 30 ° C.

The method according to claim 7, wherein the step 3) the temperature of the cooling and crystallization is -5 to 10. C.

The method according to claim 1, 2 or 8, wherein the step 1) the crude meropenem has a purity of 80 to 90%.

10. A method according to claim 1, 2 or 8, characterized in that the decolorization temperature of step 2) is from 10 to 30. C.

11. The method according to claim 8, wherein: step 3) adding or not seeding the filtrate; and adding the seed crystal, the pH of the solution is 8 to 9 when added.

The method according to claim 3, wherein the step 3) is: adding acid to the filtrate to pH 6.5 to 9, adding seed crystals, continuing to add acid to pH 5.5 to 6.0, and cooling to -5~5 °C, stirring and crystallization, The meropenem trihydrate crystals were filtered.

The method according to claim 1, 2 or 8, characterized in that the method further comprises the step of subjecting the meropenem trihydrate crystal obtained in the step 3) to a cold water rinsing step.