KR20140147262A - A process for the preparation of crystalline Meropenem trihydrate - Google Patents

Abstract

The present invention provides a method for preparing crystalline meropenem trihydrate represented by chemical formula 1 by hydrogenating bis-meropenem represented by chemical formula 2 in a mixture of tetrahydrofuran and water only by adjusting pH using a base without using a buffer solution; and a method including an optimized reaction condition for manufacturing meropenem including the same. According to the method for preparing crystalline meropenem trihydrate of the present invention, meropenem hydrate with high purity and high yield can be prepared just by simple post-processes. Moreover, unlike meropenem trihydrate prepared by a prior method, the meropenem trihydrate of the present invention has a significantly reduced amount of residues of an organic solvent, especially acetone.

Description

[0001] The present invention relates to a process for preparing crystalline meropenem trihydrate,

More particularly, the present invention relates to a process for the industrial production of crystalline Meropenem trihydrate, and more particularly to a process for producing a crystalline meropenem represented by the following formula (1) containing an excellent antibacterial agent, namely (1R, 5S, 6S Pyrrolidinyl] thio] -6 - [(1R) -hydroxyethyl] -4-methyl-7-oxo- 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; (1R, 5S, 6S) -3 - [[(3S, 5S) -5- (Dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) -hydroxyethyl] -4-methyl- -azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid in the form of a pharmaceutically acceptable hydrate.

The compound represented by the above formula (1) is a compound named Meropenem, which is a generic name, and is an antibacterial agent exhibiting a wide range of activities in gram-positive and gram-negative bacteria.

Meropenem is sensitive to pH and temperature, resulting in impurities such as meropenemic acid (Meropenemic acid) and meropenem dimer (Merck, Pharm. Bull. 43 (4) 1995, Pharm. &Amp; Biomedical Analysis 41, 1363, 2006) In order to overcome the unstable characteristics of pH and temperature of meropenem in the prior art, a buffer solution was used as in the following example.

In U.S. Patent No. 5,122,604, a compound of the formula (2) is hydrogenated by adding 10% by weight of Pd / C of morpholinopropane sulfonic acid buffer to tetrahydrofuran, water and ethanol, A method of concentrating under reduced pressure and separating by column chromatography containing a column chromatography resin containing a resin to obtain a compound of formula (1) is described. However, in the concentration of carbapenem unstable in a solution, Resulting in lower yield and lower purity (Chem. Pharm. Bull. 4 (11), 1998-2002 (1993)). In addition, column chromatography involving a resin is required for separation of buffer, which makes economic and industrial use difficult.

A similar process is described in Korean Patent Laid-Open No. 10-2010-0103427, US Patent No. 4,888,344, US Patent No. 4,943,569, WO 2012/052978, and WO 2011/141847, but the bis-meropenem of Formula 2 In the process of reduction with meropenem, all buffers are used in order to prevent the generation of impurities. In order to remove them, column chromatography involving a resin must be carried out, so that the problem that efficient production is difficult has not been solved.

Korean Patent Laid-Open No. 10-2011-0062515 discloses a process for producing p-nitrobenzyl- (1R, 5R, 6S) -6- [(1R) -hydroxyethyl] -2 - [(diphenylphosphono) oxy] (1R, 5R, 6S) -6 - [(1R) -1-hydroxyethyl] -2 - [(diphenylphosphono) oxy] -1-methylcarbapen (2S, 4S) -2-dimethyl-aminocarbonyl-4-mercapto-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine -dimethylaminocarbonyl-4-mercapto-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine is reacted with a low polarity organic solvent selected from the group consisting of acetone, tetrahydrofuran and acetonitrile, and a polar organic solvent selected from the group consisting of N-methylpyrrolidinone, N, N-dimethylacetamide in the presence of a base to obtain the compound of Formula 2 (bis-methophenem);

(ii) deprotecting the compound of formula (2) in situ in the mixed solvent to form a p-nitrobenzyl group bonded to the? -lactam ring moiety and p-nitrobenzyloxycarbonyl moiety bonded to the pyrrolidine ring moiety Lt; / RTI > to obtain melopenem; And

(iii) adding an organic solvent selected from the group consisting of acetone, tetrahydrofuran, acetonitrile, ethanol, and propanol to the mixed solvent to crystallize the meropenem trihydrate represented by the following formula (I) A method of adding activated carbon without using column chromatography containing a separate resin is described.

However, in the process of reducing the bis-meropenem of formula (2) to meropenem, the method also uses palladium carbon (Pd / C) as a hydrogenation catalyst and acetic acid buffer solution of pH 6-7, Activated carbon is added during the production and filtration is performed. Therefore, the Pd / C is filtered and then the filtration process is performed again to remove the activated carbon. Therefore, there is a limit in commercial use in terms of time and cost.

In WO 2006/035300, an ethyl acetate solution as an extractant during the preparation of bis-meropenem of formula (2) is concentrated and then a buffer solution (pH 7.0) of ethyl acetate, N-methylmorpholine and acid Hydrogenation reaction is carried out at the interface to prepare the meropenem of formula (1). However, since meropenem should be prepared without the separation process of formula (2), impurities generated during the preparation of the compound of formula (2) and impurities produced by the hydrogenation reaction are generated and the physical properties are similar to those of the target compound, .

All of the production methods described in the above-mentioned literatures require a buffer solution and a buffer washing step in order to reduce the bis-meropenem and to use the buffer solution in the reduction reaction to obtain meropenem. Therefore, the production process is complicated, and further purification and purification processes through silica gel chromatography separation of intermediates and resin chromatography of melopenem should be additionally applied, resulting in problems in economical and industrial applications.

US 5122604A Korean Patent Publication No. 10-2010-0103427 WO 2011/141847 Korean Patent Publication No. 10-2011-0062515 US 4888344 A US4943569A WO 2006/035300

Chem. Pharm. Bull. 4 (11), 1998-2002 (1993)

It is an object of the present invention to provide a method for efficiently producing highly pure crystalline meropenem trihydrate.

It is also an object of the present invention to provide an efficient production method of highly purified crystalline meropenem trihydrate in which the residual amount of organic solvent is remarkably reduced.

In order to achieve the object of the present invention,

(i) reacting a compound represented by the following formula (2) in a reaction solution comprising a hydrogenation catalyst, a reaction solvent and a base,

ii) after the step i), filtering the hydrogenation catalyst, and

iii) After the filtration in the step ii), an organic solvent which can be mixed with water is added to the filtered solution to effect crystallization, and a process for producing the tripeptide of meropenem according to the following formula 1 is provided.

Also, the present invention provides a method for preparing meropenem trihydrate, further comprising the step of sequentially adding isopropanol and acetone to the meropenem trihydrate obtained in step iii).

In addition, the present invention relates to a method for solubilizing the meropenem trihydrate obtained in the step iii), followed by solubilizing 5 to 20 vol%, preferably 5 to 10 vol.%, More preferably 5 vol.% Of the solution with isopropyl alcohol Reacting the resultant mixture with a solvent to crystallize the mixture, adding the remaining solution to the isopropyl alcohol to crystallize the mixture, and adding acetone to the reaction mixture to prepare a melepenem trihydrate.

The present invention is based on the discovery that high purity and high yield of meropenem can be obtained through the optimization of reaction conditions such as reaction solvent mixing ratio, base type, equivalence and temperature by using a base and water without using a buffer solution during a hydrogen reaction Thereby providing an efficient production method of hydrate. The method for preparing meropenem trihydrate according to the present invention excludes the step of column chromatography separation and purification, which includes a resin for removing the buffer, as compared with the conventional method using a buffer solution, and a high purity and a high yield The crystalline form of meropenem hydrate can be prepared.

The present invention is also advantageous in that it is possible to produce meropenem trihydrate, which is different from meropenem trihydrate prepared by the production method according to the prior art, and in which the residual amount of residual organic solvent, especially acetone, is remarkably reduced.

Hereinafter, the present invention will be described in detail.

The present invention

(i) reacting a compound represented by the following formula (2) in a reaction solution comprising a hydrogenation catalyst, a reaction solvent and a base,

ii) after the step i), filtering the hydrogenation catalyst, and

iii) adding the organic solvent which can be mixed with water to the filtered solution after the filtration of the step ii)

Wherein R < 1 > and R < 2 >

The above method is characterized in that the hydrogenation reaction is carried out under optimal conditions without using a buffer solution. In comparison with the conventional method using a buffer solution, separation and purification using a column chromatography including a resin for removing the buffer The refining process is excluded, and a high purity, high yield crystalline meropenem hydrate is produced by a simple post-treatment process.

In the step i), the bis-meropenem represented by the general formula (2) is reacted in a reaction solution composed of a hydrogenation catalyst, a reaction solvent and a base.

Means that the reaction solution in step i) is composed of the bis-meropenem represented by the formula (2), the hydrogenation catalyst, the reaction solvent and the base, does not contain the buffer solution in addition to the above components.

The buffer solution means a solution, that is, a buffer solution, in which the hydrogen ion concentration (pH) of the solution does not largely change due to the common ion effect even when an acid or base is added. The buffer solution may be prepared by a person skilled in the art in a known / common method.

The base in step i) is preferably at least one selected from the group consisting of sodium hydrogencarbonate (NaHCO ₃ ), triethylamine (TEA), imidazole and N-methylmorpholine (NMM).

When the base is sodium hydrogencarbonate (NaHCO ₃ ), it is preferable to use 0.4 to 0.5 equivalents, preferably 0.44 to 0.45 equivalents, relative to the compound of formula (2).

When the base is triethylamine (TEA) or imidazole, the amount thereof is preferably 0.2 to 0.5 equivalent, preferably 0.35 to 0.40 equivalent based on the compound of formula (2). When the base is N-methylmorpholine (NMM), the amount thereof is preferably 0.2 to 0.5 equivalents, preferably 0.27 to 0.35 equivalents relative to the compound of formula (2).

The pH of the compound of formula (2) and the reaction solution of step (i) is preferably 6 to 8, more preferably 6.0 to 7.0. When the pH of the mixture of the compound of formula (2) and the reaction solution of step (i) is lower than 6, the yield of the melopenem obtained after the hydrogenation reaction is increased to decrease the yield. When the pH is higher than 8, C may be deactivated and the progress of the hydrogenation reaction may be delayed.

The pH is measured by mixing the compound of Formula 2 of Step i) and the reaction solution, and after completion of the reaction, Pd / C is filtered and then measured using a pH meter generally used in the art can do.

The above results are summarized in Table 1 below.

In the step i), the reaction solvent is preferably a mixture of tetrahydrofuran (THF) and water.

The volume ratio of the mixture of tetrahydrofuran and water is preferably in the range of 3: 7 to 7: 3, more preferably 4: 6 to 6: 4. When the mixing ratio of tetrahydrofuran to water is lower than 3: 7, the reaction may be difficult because the bis-meropenem of Formula 2 is not completely dissolved. When the mixing ratio is higher than 7: 3, the meropenem produced after the reaction is precipitated as a solid And is likely to be lost during Pd / C filtration.

The above results are summarized in Table 2 below.

The hydrogenation catalyst of step i) is preferably a palladium carbon catalyst (Pd / C), but is not limited thereto.

The palladium carbon catalyst is preferably 15 to 30% by weight based on the compound of formula (2). When the palladium carbon catalyst is used in an amount of 15 wt% or less, the hydrogenation reaction may not be performed well, and when the palladium carbon catalyst is used in an amount of 30 wt% or more, the economical efficiency may decrease.

The temperature of the hydrogenation reaction in step i) is preferably 20 to 35 ° C. If the reaction temperature is lower than 20 ° C, the hydrogenation reaction may not be performed well. If the reaction temperature exceeds 35 ° C, if the temperature is excessively high, impurities may be formed.

The reaction time of the hydrogenation reaction in step i) is preferably from 1.5 hours to 5 hours. If the reaction time is short, the hydrogenation reaction may not be performed well, and if the reaction time is prolonged, impurities may be formed and the economical efficiency may decrease.

The above results are summarized in Table 3 below.

The pH of the reaction solution after step i) is preferably 5 to 7, more preferably 6.2 to 6.5. If the pH is lower than 5 or higher than 7 after the completion of the step i), the yield of the meropenem trihydrate may be lowered or the purity may be lowered.

When the reaction of step i) is completed, the reaction solution is filtered (step ii)). The filtration is preferably performed on a cellite, but is not limited thereto.

The filtrate obtained by filtering the catalyst after the hydrogenation reaction is crystallized with an organic solvent which can be mixed with water, such as acetone, acetonitrile, isopropyl alcohol, ethyl alcohol, methyl alcohol, tetrahydrofuran, preferably tetrahydrofuran, Can be obtained.

According to the process for preparing the tripeptide of meropenem according to the present invention, the production of impurities such as meropenemic acid compound and meropenem dimer, which are by-products of hydrolysis of meropenem, is suppressed and only the crystallization in the solvent A desired purity of the desired meropenem compound can be obtained without a separate purification step. In particular, since the reaction is completed stably through the pH control of the reaction solution using a base without a buffer solution, a purification process such as preparation and separation of a buffer solution is unnecessary, and the production cost of the target compound is lowered.

Also, the present invention provides a method for preparing meropenem trihydrate, further comprising the step of sequentially adding isopropanol and acetone to the meropenem trihydrate obtained in step iii).

The meaning of adding isopropyl alcohol and acetone sequentially means that the isopropyl alcohol is added first and the acetone is added later.

As described above, crystallized meropenem trihydrate after adding isopropyl alcohol and acetone can be used for injection, and the amount of acetone remaining in the crystals is remarkably reduced.

In addition,

After solubilizing the meropenem trihydrate obtained in the step iii), 5 to 20%, more preferably 5 to 10 vol%, and even more preferably 5 vol% of the solution is reacted with isopropyl alcohol to preferentially Crystallizing the solution, adding the remaining solution to the isopropyl alcohol after the crystallization, and further crystallizing the solution, and adding acetone. The present invention also provides a method for producing melopenem trihydrate.

The meropenem trihydrate obtained by solubilization of the meropenem trihydrate obtained in the step iii) and then partially crystallized by reacting with isopropyl alcohol and further crystallized by adding acetone can be used for the main use, Lt; RTI ID = 0.0 > of organic < / RTI >

Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood, however, that the scope of the present invention is not limited to these embodiments.

Example 1: Synthesis of (lR, 5S, 6S) -3 - [[(3S, 5S) -5- (dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

(4R, 5S, 6S) - (p-nitrobenzyl) -3 - [[(3S, 5S) -1- (p- nitrobenzyloxycarbonyl) -5- (dimethylaminocarbonyl) Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (bis- Meropenem) in 300 ml of tetrahydrofuran (THF), dissolving at 28 ° C, adding 325 ml of purified water and 0.98 g of N-methylmorpholine. 2.5 g of Pd / C is added to this reactor and bubbled with nitrogen gas for 10 minutes. The mixed solution was stirred vigorously at 30 DEG C under hydrogen pressure of 4.0 kgf / cm < 2 > for 3 hours. The reaction solution is filtered, washed with 25 mL of purified water, and the filtrate is cooled to 12 째 C. To this was added 325 mL of THF, cooled to 3 [deg.] C, and then added with 1.3 L of THF to crystallize. The crystals are stirred at 3 DEG C for 1.5 hours, and the resulting crystals are filtered and washed with 200 mL of acetone. The obtained crystals were dried under reduced pressure at 30 DEG C or lower to obtain 14.3 g of the target compound as a white crystalline solid. (Yield: 91.0%).

Purity: 99.60% (HPLC)

Content: 99.40% (HPLC)

(S, 3H), 2.97 (ddd, IH), 2.99 (s, 3H), 1.91 (d, IH) ), 3.34 (dd, IH), 3.39 (dd, IH), 3.62 (dd,

Examples 2 to 5: Preparation of (1R, 5S, 6S) -3 - [[(3S, 5S) -5- (dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

The target compound was obtained in the same manner as in Example 2, except that the mixing ratio of tetrahydrofuran to water in the reaction solvent used in Examples 2 to 5 was as shown in Table 4 below.

Examples 6 and 7: 1R, 5S, 6S) -3 - [[(3S, 5S) -5- (Dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) Ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

Except that 0.37 equivalents and 0.27 equivalents of N-methylmorpholine in Examples 6 and 7 were used as shown in the following Table 4, the target compound was obtained.

Example 8: Preparation of 1R, 5S, 6S) -3 - [[(3S, 5S) -5- (dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

3 g (4.3 mmol) of bis-methophenem was dissolved in a tetrahydrofuran / purified water = 2/1 mixture. After charging with nitrogen, 0.17 g (1.9 mmol) of sodium hydrogencarbonate and 0.75 g of Pd / C were added thereto and stirred for 10 minutes . The mixture was stirred vigorously under a hydrogen pressure of 3.9 kgf / cm < 2 > for 3 hours. The reaction solution was filtered on celite, washed with ethyl acetate, and acetone was gradually added to obtain 0.92 g (yield: 48.9%) of the title compound as a crystalline solid.

Purity: 91.9% (HPLC)

The < 1 > H-NMR data of the compound prepared was the same as in Example 1 above.

Examples 9 and 10: 1R, 5S, 6S) -3 - [[(3S, 5S) -5- (dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) Ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

The procedure of Example 8 was repeated except that triethylamine and imidazole were used as the base in Examples 9 and 10 as shown in Table 4 to obtain the target compound.

The < 1 > H-NMR data of the compound prepared was the same as in Example 1 above.

Comparative Example 1: Synthesis of (1R, 5S, 6S) -3 - [[(3S, 5S) -5- (dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

35 mg of bis-methophenem is dissolved in tetrahydrofuran / ethanol / mol / mol propan sulfonic acid buffer solution (pH 7.0) = 1.9 / 0.3 / 1.9. Add 10% Pd / C to the reaction mixture, react for 1 hour, concentrate, remove ethanol, and extract with ethyl acetate. The extracted aqueous layer was further concentrated under reduced pressure to remove the organic solvent, and the product was separated by chromatography (CHP-20P) filled with resin to prepare the desired compound. (Yield: 25.7%).

Purity: 69.5% (HPLC)

The < 1 > H-NMR data of the compound prepared was the same as in Example 1 above.

Comparative Examples 2 to 4: Preparation of (1R, 5S, 6S) -3 - [[(3S, 5S) -5- (dimethylaminocarbonyl) -3-pyrrolidinyl] thio] -6 - [(1R) Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid trihydrate (meropenem trihydrate)

The target compounds were obtained in the same manner as in Example 2 except that the tetrahydrofuran and the buffer solution were used in the same manner as in Comparative Examples 2 to 4,

The < 1 > H-NMR data of the compound prepared was the same as in Example 1 above.

Experimental Example 1: Optimization of Aseptic Purification Process

For the aseptic purification of the meropenem compounds prepared in Example 1, the amount of residual solvent was measured by applying a crystallization solvent under various conditions.

12 g of the meropenem compound prepared in Example 1 was dissolved in 360 mL of warm water heated to 50 DEG C, cooled to 10 DEG C or lower, 0.66 g of activated carbon was added thereto, and the mixture was sterilized and filtered. 5 vol% of the obtained filtrate was added to a sterilization filtration reactor together with 54 mL of isopropyl alcohol and then cooled to 3 ° C to precipitate crystals. The remaining filtrate was added to precipitate crystals. 3 Lt; / RTI > After the stirring, the temperature of the reaction solution was raised to 29 占 폚. To the reaction solution, 850 mL of sterilized acetone (Acetone) was added, and the mixture was stirred for 1 hour. Thereafter, the reaction solution was cooled to 3 캜 and stirred for 1 hour to crystallize, and then the reaction solution containing crystals was transferred to a filter drier and filtered. The filtered crystals were washed with 500 mL of sterile filtered acetone and vacuum dried at 35 ° C or below to obtain sterile meropenem trihydrate.

Experimental Example 2 and Experimental Example 3

Experimental Example 2 and Experimental Example 3 were carried out in the same manner as Experimental Example 1, except that 10 vol% and 20 vol% of filtrate were respectively applied to precipitate crystals.

Experimental Example 4 and Experimental Example 5

Experimental example 4 was carried out in the same manner as in Experimental example 1 except that 52 mL of isopropyl alcohol was added to crystallize all of the filtrate of Experimental Example 1, and then 52 mL of acetone was added.

Experimental Example 5 was carried out in the same manner as in Experimental Example 4, except that the amount of acetone was increased to 104 mL.

Comparative Experimental Examples 1 to 3

12 g of the meropenem compound prepared in Example 1 was dissolved in 360 ml of warmed water for injection, cooled to 10 캜 or lower, 0.66 g of activated carbon was added thereto, stirred, and sterilized by filtration. The filtrate was mixed with 27.5 mL of isopropyl alcohol and 27 mL of acetone (Comparative Experimental Example 1), 13.5 mL of isopropyl alcohol and 40.5 mL of acetone (Comparative Experimental Example 2), 13.5 mL of methyl alcohol, (Comparative Experimental Example 3) mixed with 40.5 mL of water and then introduced into the reactor. Then, the mixed solution was cooled (3 캜) to precipitate crystals, which were stirred for 3 hours. After stirring, the mixture was heated to 29 deg. To the reaction solution, 850 mL of sterilized acetone was added, and the mixture was stirred for 1 hour. Thereafter, the reaction solution was cooled to 3 캜 and stirred for 1 hour to crystallize, and then the reaction solution containing crystals was transferred to a filter drier and filtered. Thereafter, the cells were washed with 500 mL of sterilized acetone and vacuum-dried at 35 DEG C or less to obtain sterile meropenem trihydrate.

The results of Comparative Experimental Examples 1 to 3 and Experimental Examples 1 to 5 are summarized as follows.

According to the Experimental Examples and Comparative Experimental Examples, it can be seen that when the crystals are formed in the order of isopropyl alcohol and acetone, the residual amount of acetone can be lowered.

Further, when 5 to 20 vol%, more preferably 5 to 10 vol% of the filtrate is reacted with isopropyl alcohol to form crystals in advance, and further crystals are obtained by adding the remaining filtrate, The amount of residual solvent can be remarkably lowered.

Claims (14)

i) reacting a compound of formula 2
Hydrogenation catalyst,
Reaction solvent, and
Reacting in a reaction solution composed of a base,
ii) after the step i), filtering the hydrogenation catalyst, and
iii) adding the organic solvent which can be mixed with water to the filtered solution after the filtration of the step ii)
(I), wherein R < 1 > and R < 2 >

The method according to claim 1, wherein the base is at least one selected from the group consisting of sodium hydrogencarbonate, triethylamine, imidazole and N-methylmorpholine. [3] The method of claim 2, wherein the base comprises sodium hydrogen carbonate in an amount of 0.4 to 0.5 equivalents based on the compound of Formula 2, and 0.2 to 0.5 equivalents of the compound of Formula 2 when triethylamine is used. Methylmorpholine in an amount of 0.2 to 0.5 equivalent based on the compound of Formula 2 and 0.2 to 0.5 equivalent of the compound of Formula 2 in the case of N-methylmorpholine. The method according to claim 1, wherein the reaction solvent is a mixture of tetrahydrofuran and water. The method according to claim 4, wherein the mixing ratio of tetrahydrofuran to water is 3: 7 to 7: 3. The process according to claim 1, wherein the hydrogenation catalyst is palladium carbon catalyst (Pd / C). [6] The method according to claim 6, wherein the palladium carbon catalyst is 15 to 30% by weight based on the compound of formula (2). The method according to claim 6, wherein the reaction temperature of the hydrogenation reaction is 20 to 35 ° C. [Claim 7] The method according to claim 6, wherein the hydrogenation reaction has a reaction time of 1.5 to 5 hours. The method according to claim 1, wherein the mixture of the compound of Formula 2 and the reaction solution has a pH of 6 to 8. The method of claim 1, wherein the pH of the reaction solution is 5 to 7 after completion of the step i). The method according to claim 1, wherein the organic solvent that can be mixed with the water of step iii) is at least one selected from the group consisting of acetone, acetonitrile, isopropyl alcohol, ethyl alcohol, methyl alcohol, and tetrahydrofuran, ≪ / RTI > The method according to claim 1,
iv) a step of sequentially adding isopropyl alcohol and acetone to the meropenem trihydrate obtained in the step iii) The method according to claim 1,
iv) solubilizing the meropenem trihydrate obtained in the step iii), 5 to 10 vol% of the solution is reacted with isopropyl alcohol to crystallize preferentially, and after the crystallization, the remaining solution is added to the isopropyl alcohol Further crystallizing, and
v) After step iv), adding acetone
≪ / RTI >