KR20060098110A - Process for preparing refined crystalline imipenem from thienamycin - Google Patents

Abstract

The present invention relates to a process for the preparation and purification of high purity crystalline imipenem from thienamycin in high yield.

Thienamycin, imipenem, crystalline imipenem, tablets

Description

Process for preparing crystalline imipenem purified from thienamycin {Process for Preparing Refined Crystalline Imipenem from Thienamycin}

The present invention relates to the preparation of crystalline imipenem and its purification method, and more particularly to a high-purity crystalline imipenem of high purity without a special purification process through the imidation reaction and hydrogenation reaction from thienamycin It relates to a method and a purification method thereof.

Imipenem is one of the beta lactam antibiotics with the carbapenem ring system and exhibits a broad spectrum activity against gram positive and gram negative aerobic and anaerobic species.

Methods for preparing imipenem can be prepared from 4-acetoxy azetidinone, which are known in the art.

US Pat. No. 4,194,047 describes for the first time a method for the preparation of imipenem, which is purified by column chromatography during the preparation and obtained through lyophilization, which is amorphous and thermodynamically unstable.

U.S. Patent No. 4,894,450 describes a method for preparing imipenem using derivatives of bis (2,4-dichlorophenyl) phosphorochlorate, a new protective agent during the manufacture of thienamycin, It is not suitable for commercial use because it is not commercially available and the imipenem has to be manufactured through cumbersome steps such as making and using it yourself.

Korean Patent Laid-Open Publication No. 10-2004-0010649 and International Patent 2002/94773 disclose a method for obtaining crystalline imipenem, but after several reactions, the separated aqueous layer is washed with an organic solvent to remove accumulated impurities. Special operation is required, such as a low overall yield is a disadvantage.

The present inventors have tried to solve the above-mentioned problems of the prior art, and at the same time, as a result of research on the development of a manufacturing process and crystallization method thereof, which have excellent economical efficiency, stability, and high yield, such as column chromatography or lyophilization, etc. The present invention has been accomplished by minimizing the accumulation of impurities without including non-industrial processes and completing a method for obtaining a desired product in maximum yield.

An object of the present invention is to minimize the accumulation of impurities through a relatively short manufacturing process without the use of column chromatography or lyophilization, which is difficult to economically use industrially difficult to use imipenem having a wide range of activities, crystalline imipenem in high yield By developing a method for preparing the present invention, it is intended to provide a novel method for preparing crystalline imipenem that can be directly applied to production.

In the present invention to achieve the above object,

The fienbi (para-nitrobenzyl) thienamycin of formula 1 is reacted with benzyl formimate hydrochloride of formula 2 (known in US Pat. No. 4,374,772) to prepare the penibi impenem of formula 3, without successive separation Hydrogenation of the Pienbi Imipenem under a palladium catalyst to obtain an aqueous solution of Imipenem of formula (4) to provide a method for producing a crystalline imipenem of formula (4) by adjusting the pH by inorganic base without special treatment and mixing with a water-soluble organic solvent do.

In the present invention, in the step of preparing a crystalline imipenem from pienbi Thienamycin, to prepare a penibi imipenem by reaction with benzyl formimidate hydrochloride in the presence of a base and proceeds the hydrogenation reaction under a palladium catalyst without special separation operation After that, crystalline imipenem is produced in high yield without complicated processing.

Pienbi (para-nitrobenzyl) thienamycin represented by the formula (1) which is the starting material of the present invention can be obtained by the method described in US Patent Publication 2002/0095034.

The process for preparing crystalline imipenem of the present invention consists of the following two steps and purification steps:

(1) reacting with benzyl formimidate hydrochloride of formula (2) in the presence of a base from step 1 of the pienbi thienamycin represented by the formula (1) to obtain the fienbi impenem of formula (3);

(2) In step 2, the pyenobi imipenem represented by the formula (3) is hydrogenated under a palladium catalyst to obtain an aqueous imipenem aqueous solution, and then a high purity crystalline imipenem is obtained by controlling pH by an inorganic base without complicated treatment. Obtained as

(3) In the purification step, the obtained imipenem is dissolved in water, and then reverse osmosis is used to concentrate and crystallize by adding an aqueous solvent to obtain pure imipenem crystals.

Schematic diagram of the preparation of crystalline imipenem according to the present invention as described above is shown in Scheme 1.

The method for preparing crystalline imipenem shown in Scheme 1 will be described in more detail below for each step.

First, in step 1, dienpropylethylamine is dissolved in a mixed solvent of ethyl acetate and methanol, and then the benzyl formimidate hydrochloride represented by the formula (2) is added to -40 ° C. After reacting at -60 ° C. for 2 hours, a Pienbi-Imiphenem solution represented by Chemical Formula 3 is obtained.

As a solvent that can be used in step 1, an aprotic solvent, ethyl acetate, tetrahydrofuran, methylenedichloride, 1,2-dichloroethane, toluene, benzene, and the like can be used. Used. In addition, a lower alcohol which is a protic solvent may be used as a polar solvent used as a mixed solvent, and methanol, ethanol, normal-propanol, normal-butanol, iso-propanol, iso-butanol, and the like may be used. Preferably methanol is used.

In addition, the reaction temperature in step 1 can be freely reacted from -40 ℃ to -60 ℃, preferably from -45 ℃ to -50 ℃. Benzyl formimidate hydrochloride to be used is prepared by a known method (US Patent No. 4,374,772), the amount to be used may be used from 1 equivalent to 3 equivalents, but preferably from 1 equivalent to 1.5 equivalents.

In step 2, the pH of the solution containing Pienbi impenem represented by Formula 3 is adjusted to a pH of 6.80 to 7.30 by adding 0.5 mol 4-methylmorpholine aqueous solution without any treatment. The contents are transferred to a hydrogenation reactor, a palladium catalyst is added, hydrogen is injected (4-5 atm) and stirred for 2 hours. The contents are filtered and the aqueous layer is separated and the pH of the aqueous layer is adjusted between 6.50 and 7.00 using inorganic bases. The temperature is then maintained at 5 to 20 degrees Celsius. Activated carbon was added thereto, decolorized for 1 hour, filtered, cooled to 0 ° C to 5 ° C, and water-soluble organic solvent was added to precipitate crystals of imipenem. After stirring for about 2 hours, the product was filtered and dried in vacuo to obtain crystalline imipenem, the target compound represented by Formula 4, in high purity (> 99% by HPLC) and high yield (60%).

As the buffer solution that can be used in Step 2, most inorganic and organic buffer solutions can be used, but 4-methylmorpholine / acetic acid buffer solution is preferably used as in the present embodiment. The pH to be adjusted can be freely selected between 6.80 and 7.30 but is preferably adjusted to 7.00.

In addition, as a catalyst used in the hydrogenation reaction, 10% to 20% of palladium hydroxide or palladium carbon is used in a ratio of 5% to 20% by weight, and preferably 10% (weight ratio) of 10% palladium carbon is used. . The pressure of the reacted hydrogen may proceed freely between 3 and 7 atm, but preferably at 5 atm. The temperature of the hydrogenation reaction may be carried out between 0 ° C and 25 ° C, but preferably between 10 ° C and 20 ° C.

In particular, the feature of this patent is characterized by adjusting the pH between 6.50 and 7.00 before decolorization and crystallization, not only because it facilitates decolorization but also because the crystalline imipenem precipitates smoothly in high yield only when the pH is adjusted. In this case, as the base for adjusting pH, general inorganic and organic bases may be used. Preferably, inorganic bases are sodium bicarbonate (NaHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), sodium hydroxide (NaOH), and potassium. Carbonate (K ₂ CO ₃ ), potassium bicarbonate (KHCO ₃ ), potassium hydroxide (KOH), lithium hydroxide (LiOH).

In the purification step, the unpurified imipenem represented by Formula 4 is dissolved in water adjusted to pH 8.00 to 8.50 with an inorganic base at a concentration of 1%, and then concentrated to 40% using reverse osmosis. Activated carbon is added and the temperature is maintained between 5 ° C. and 20 ° C. and stirred for about 1 hour. Cool by filtration, add excess water soluble solvent, stir for 2 hours and filter. High purity (more than 99%) pure imipenem white crystals are obtained.

Inorganic bases that can be used in the purification step include sodium bicarbonate (NaHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), sodium hydroxide (NaOH), potassium carbonate (K ₂ CO ₃ ), potassium bicarbonate (KHCO ₃ ), Potassium hydroxide (KOH), lithium hydroxide (LiOH) and other common inorganic bases may be used, preferably sodium carbonate (Na ₂ CO ₃ ) is used. Moreover, it is preferable to advance the temperature which concentrates between 0 degreeC-15 degreeC. Concentration may be selected by a distillation under reduced pressure, but is preferably concentrated using a reverse osmosis system.

Hereinafter, the manufacturing method of the present invention will be described in more detail with reference to the following examples. However, these examples are only illustrative of the present invention, and the scope of the present invention is not limited thereto.

Example 1. 3- (2-formimidoylamino-ethylsulfanyl) -6- (1-hydroxy-ethyl) -7-oxo-1-aza-bicyclo [3.2.0] hept-2-ene Preparation of 2-Carboxylic Acid 4-nitro-benzyl ester (P & B Imipenem).

100 grams of P & B thienamycin was suspended in 2000 ml of ethyl acetate cooled to 0 ° C to 5 ° C, and gradually 60 ml of diisopropylethylamine were added. Further 300 ml of methanol is added and the temperature is slowly lowered to -45 ° C to -50 ° C. After confirming that the starting material is completely dissolved, 46 grams of benzyl formimidate hydrochloride is slowly added for 30 minutes and then stirred for 2 hours. After confirming disappearance of starting material by HPLC, proceed to the next step.

Example 2. 3- (2-formimidoylamino-ethylsulfanyl) -6- (1-hydroxy-ethyl) -7-oxo-1-aza-bicyclo [3.2.0] hept-2-ene Preparation of 2-Carboxylic Acid (Imipenem).

2300 ml of a 0.5 mole 4-methylmorpholine aqueous solution prepared in advance was added to the cooled solution of Example 1, and then the pH was adjusted to 7.00 with acetic acid. At this time, the temperature is maintained at 5 ℃ to 10 ℃. The whole solution was added to a hydrogenation reactor, 10 grams of 10% palladium carbon catalyst was added, and the pressure of hydrogen was brought to 5 atm, followed by stirring for 2 hours while maintaining the temperature at 10 ° C to 20 ° C. Once the reaction is complete proceed to the next step.

Example 3. Crystallization of Imipenem.

The reaction solution is filtered through Celite and the aqueous layer is separated. The pH of the aqueous solution is adjusted between 6.50 and 7.00 with sodium hydroxide (NaOH), then activated carbon is added and the temperature is stirred at 5 ° C. and 20 ° C. for 1 hour. The aqueous solution obtained by filtration is cooled to 0 degreeC-5 degreeC, 7000 ml of acetone is added, and it stirred vigorously for 2 hours. The resulting yellow crystalline imipenem is filtered off and dried in vacuo. 42.9 grams (60%) of yellow crystalline imipenem having a purity of 99% or more (content = 93%) is obtained.

Example 4 Purification of Imipenem

150 mg of sodium carbonate is added to 1000 ml of distilled water, dissolved, and warmed to a temperature of 27 ° C to 30 ° C. After adding 10 grams of imipenem (content = 93%) to confirm complete dissolution, the mixture is filtered and cooled to 0 ° C to 10 ° C. Concentrate to 400 ml, maintaining the temperature in a reverse osmosis concentrator, add 3 grams of activated carbon and stir for 40 minutes. Filter and add 1200 ml of acetone and stir for 2 hours. Filtration and vacuum drying yielded 7 grams of 7 grams of pure white imipenem crystals (content = 99.5%, purity = 99.3%).

UV (pH 7.0 0.1 N phosphate buffer) λ _max 297 nm, IR (KBr) 1767 cm ^-1 , ¹ H NMR (300 MHz, D ₂ O) δ 1.37 (d, 3H, CH ₃ CH), 3.0-3.75 (m , 6H, -CH _2- ), 4.2-4.8 (m, 4H), 7.87 (s, 1H, -CH = NH)

As described above, the present invention relates to a method for obtaining a target compound in high purity and high yield from the intermediate complex purification process from PENB Tienamycin in the preparation of crystalline imipenem, and a short reaction step thereof. In addition to minimizing the cumulative impurities, it has proved that it can be used for industrialization by presenting a method that can be obtained in large quantities at low cost by directly depositing imipenem crystals without using column chromatography or lyophilization. The features and the superiority of the present invention will be described in detail as follows:

First, the production process of imipenem so far has been manufacturing imipenem by a method such as column chromatography or lyophilization, which is uneconomical and industrially unavailable. In the present invention, such expensive equipment is not required, and it is complicated and It was succeeded in obtaining crystalline imipenem of high purity by increasing the ease of crystallization by adjusting the pH without treatment after unnecessary reaction.

Second, in the present invention, by preparing the target compound represented by the formula (4) without separating the intermediate product from only a two steps from the piebithienamycin represented by the formula (1) due to the simplified reaction step compared to the conventional known method The accumulation of impurities that can occur when proceeding without separating the steps is minimized.

Third, as a result, no additional manipulation is needed to remove impurities after the hydrogenation reaction is progressed, and the pH is adjusted from 6.50 to 7.00 using an inorganic base to compensate for the disadvantage that crystallization is difficult in the absence of pH adjustment. By doing so, there is an advantage that a high-purity crystalline imipenem can be produced in the best yield.

Fourth, by using aprotic solvents and protic solvents in combination, it not only contributes to increasing solubility of starting materials and products, but also plays a useful role in removing impurities that may be generated during the hydrogenation reaction in the future.

Fifth, since the purification of imipenem, which has poor solubility in water, requires a large amount of solvents, the concentration of the imipenem aqueous solution by reverse osmosis greatly reduces the required amount of solvent and removes a certain amount of impurities, thereby purifying pureer imipenem. Can be obtained. In addition, by increasing the solubility by the addition of an inorganic base it can contribute to the increase in productivity and the stability of the product.

As mentioned above, the method for preparing and purifying the crystalline imipenem according to the present invention is a more advanced technology than the conventional method, and can be economically effective because of the simple manufacturing process and excellent productivity.

Claims (9)

Reaction of the pyenbi thienamycin of formula 1 with benzyl formimate hydrochloride of formula 2 in the presence of a base to prepare the pyenbi impenem of formula 3: Hydrogenation under palladium catalyst without separation to determine from solution Step 2, obtaining a sex imipenem; And Method for producing a purified crystalline imipenem comprising the purification step of dissolving the obtained crystalline imipenem in water and then concentrated and crystallized using a reverse osmosis method. [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

The process of claim 1, wherein steps 1 and 2 are carried out in a series of reactions without special separation operations. The solvent according to claim 1, wherein the solvent used in step 1 is aprotic solvent selected from ethyl acetate, tetrahydrofuran, acetonitrile, methylenedichloride, 1,2-dichloroethane, toluene, benzene, methanol, A process for producing purified crystalline imipenem, characterized in that it is used singly or in combination with a protic solvent selected from ethanol, normal-propanol, normal-butanol, iso propanol, and isobutanol. The method for preparing purified crystalline imipenem according to claim 1, wherein the crystals are precipitated from the solution after the hydrogenation reaction in step 2 through pH adjustment. The method of claim 4, wherein the pH range is 6.50 to 7.00. The method of claim 5, wherein the inorganic base used for pH adjustment is sodium bicarbonate (NaHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), sodium hydroxide (NaOH), potassium carbonate (K ₂ CO ₃ ), potassium bi Process for preparing purified crystalline imipenem, characterized in that it is selected from carbonate (KHCO ₃ ), potassium hydroxide (KOH), lithium hydroxide (LiOH). The method for preparing purified crystalline imipenem according to claim 1, wherein in the purification step of the crystalline imipenem, the aqueous solution of imipenem is concentrated by reverse osmosis and crystallized by an aqueous solvent. According to claim 1 or 7, wherein the inorganic base used for pH adjustment in the purification step sodium bicarbonate (NaHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), sodium hydroxide (NaOH), potassium carbonate ( K ₂ CO ₃ ), potassium bicarbonate (KHCO ₃ ), potassium hydroxide (KOH), lithium hydroxide (LiOH) method for producing a purified crystalline imipenem. The water-soluble solvent according to claim 1 or 7, wherein the water-soluble solvent used in the purification step is a lower alcohol selected from ethanol, normal-propanol, normal-butanol, iso-propanol, iso-butanol, methoxyethanol, ethoxyethanol and Acetone, methyl ethyl ketone, tetrahydrofuran and 1,4-dioxane are used alone or in combination to produce a purified crystalline imipenem.