WO2014088315A1 - Crystalline doripenem monohydrate, and method for preparing same - Google Patents

Abstract

The present invention relates to a method for preparing doripenem monohydrate, and more particularly, to a method for preparing doripenem monohydrate produced through the steps of: conducting a deprotecting reaction by reacting doripenem-PNB with a zinc powder in a mixture solution including an organic solvent and an aqueous phosphate solution (step 1); removing phosphate from the product of step 1 (step 2); and crystallizing the product of step 2 using a solvent for crystallization to crystallize the doripenem monohydrate (step 3). According to the method for preparing the doripenem monohydrate, the method can be conducted at room temperature and at a moderate atmospheric pressure without using an expensive metal catalyst and special equipment. Thus, the method is economical and safe, and the doripenem monohydrate can be obtained at a high yield. Accordingly, the preparation method of the present invention can be usefully applied in an industrial field related to doripenem monohydrate.

Description

Crystalline doripenem monohydrate and preparation method thereof

The present invention relates to a method for preparing doripenem monohydrate, and more specifically, a step of deprotecting by reacting doripenem-PNB represented by the following Chemical Formula 2 with zinc powder in a mixed solvent composed of an organic solvent and an aqueous solution of phosphate (step One); Removing phosphate from the product of step 1 (step 2); And a method for preparing doripenem monohydrate, which is prepared through the step (step 3) of crystallizing doripenem monohydrate represented by Chemical Formula 1 using the product of step 2 as a solvent for crystallization.

[Formula 1]

[Formula 2]

First used as a modern antibiotic in the 1940s, penicillin has been known as a miracle medicine by saving the lives of many patients with infectious diseases. However, shortly after penicillin was used, staphylococcus resistant to this emerged, and in the 1960s, methicillin, a semisynthetic penicillin, was developed and used to treat penicillin-resistant staphylococcal infections. However, since methicillin-resistant staphylococcus aureus (MRSA) resistant to methicillin began to develop, various cephalosporin preparations and various antibiotics such as quinolone, carbapenem, monobactam, and glycoside were developed in the 1980s and clinically Used in

Carbapenem antibiotics have the strongest antibacterial effect among the beta-lactam antibiotics, and have been used to treat severe patients of children or elderly people with weak immunity due to its excellent safety and therapeutic effects. In addition, since it shows an excellent antibacterial effect to the resistant bacteria difficult to treat, it has been used as a treatment for this.

Carbapenem antibiotics are prepared by total synthesis and are generally stereoselectively synthesized using 4-acetoxyazetidinone as a key intermediate. Beta-methyl group is introduced from 4-acetoxyazetidinone through stereoselective reaction, and then a multi-step reaction is a key intermediate of various carbapenem antibiotics (meropenem, attafenim, viafenim, doripenem, etc.). Beta-methyl vinyl phosphate carbapenem is synthesized.

Doripenem monohydrate (DoripenemH ₂ O, chemical name: (4R, 5S, 6S) -6-((R) -1-hydroxyethyl) -4-methyl-7-oxo-3-((3S, 5S) ) -5-((sulfamoylamino) methyl) pyrrolidin-3-ylthio) -1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid hydrate) is a gram-positive bacterium And compounds having broad antibiotic efficacy against Gram-negative bacteria. In general, doripenem monohydrate is prepared by a deprotection reaction of doripenem-PNB in which a carboxyl group is protected by a p-nitrobenzyl group.

In EP 0528678 B1, as shown in Scheme 1, MAP is subjected to a coupling reaction with a side chain to prepare doripenem-PNB, in which a carboxyl group is protected with p-nitrobenzyl, and an appropriate amount thereof. After dissolving in a mixed solvent of tetrahydrofuran and water, hydrogenated at room temperature for 4 hours by adding 10% palladium-carbon, 0.1 M-MES (2- (N-morpholino) ethanesulfonic acid) buffer (pH 7.0), and the catalyst was After filtration and washing with ethyl acetate, the remaining aqueous solution is distilled under reduced pressure, separated by styrene-divinylbenzene copolymer resin column chromatography, and lyophilized to obtain doripenem monohydrate.

Scheme 1

International Patent Publication No. WO2006-117763 discloses doripenem-PNB in a mixed solvent of ethyl acetate and N-methylmorpholine / acetic acid buffer solution (pH 6.0-7.0), and 5% palladium-carbon was added at room temperature under hydrogen atmosphere. After reacting for 4 hours, the catalyst filtration and the aqueous layer are separated, added to methyl alcohol at room temperature, and crystallized to obtain a desired doripenem. Compared to the European Patent Registration No. EP 0528678 B1, the method performs catalytic hydrogenation in a solvent mixture of ethyl acetate and a buffer without using tetrahydrofuran, so that the process is directly performed from an aqueous solution without column chromatography, lyophilization, separation and recovery. There is an advantage that the desired compound can be obtained.

In addition, doripenem-PNB was dissolved in a mixed solvent of tetrahydrofuran and purified water, and 10% palladium / carbon catalyst and magnesium chloride were added to react for 2 hours at room temperature under a hydrogen atmosphere, and then the catalyst was filtered and the aqueous layer was separated. It is known to obtain the desired doripenem through the crystallization process using (Yutaka Nishino et al., Org.Process Research Dev. 2003, 7, p 846-50).

As described above, conventional doripenem monohydrate manufacturing methods have a disadvantage of low economic efficiency because expensive palladium / carbon is used for the deprotection reaction. In addition, there is a safety problem because the use of hydrogen gas with a very high risk of explosion as a reducing agent, there is a disadvantage that a special facility is required to invest in a separate facility. Therefore, there is a need for a technique for producing doripenem monohydrate, which is economically and secured.

Under the above background, the inventors of the present invention are studying a method for preparing doripenem monohydrate through a safe process without requiring special equipment and expensive catalysts, and zinc powder instead of expensive metal catalysts and hydrogen gas in a deprotection reaction. The present invention was completed by confirming that a high yield of doripenem monohydrate can be obtained using an aqueous solution of phosphate.

It is an object of the present invention to provide a process for the preparation of high yield crystalline doripenem monohydrate through mild reaction conditions at room temperature and atmospheric pressure without special equipment.

In order to solve the above problems, the present invention comprises the step of reacting the doripenem-PNB represented by the formula (2) with zinc powder in a mixed solvent consisting of an organic solvent and an aqueous solution of phosphate (step 1); Removing phosphate from the product of step 1 (step 2); And crystallizing doripenem monohydrate represented by the following Chemical Formula 1 using the product of step 2 as a crystallization solvent (step 3).

[Formula 1]

[Formula 2]

The step 1 is, in order to deprotect the carboxyl protecting group PNB (4-nitrobenzyl) and the amine protecting group PNZ (4-nitrobenzyl oxy carbonyl) from the doripenem-PNB represented by the formula (2), the zinc powder is It is a step of performing deprotection reaction into a mixed solvent of an organic solvent and phosphate aqueous solution in which doripenem-PNB is represented. The zinc powder is preferably used four to twelve times the weight of doripenem-PNB, and in order to prevent decomposition of the target compound due to rapid exotherm, it is preferable to gradually divide and maintain the appropriate temperature.

The phosphate is preferably any one or more selected from the group consisting of KH ₂ PO ₄ , K ₂ HPO ₄ , H ₃ PO ₄ , NaH ₂ PO _4, and Na ₂ HPO ₄ . The organic solvent is preferably any one or more selected from the group consisting of tetrahydrofuran, acetonitrile, acetone, ethyl acetate, methylene chloride and chloroform. In addition, the pH of the mixed solvent is preferably 4 to 7, and the concentration of the phosphate in the mixed solvent is preferably 0.5 M to 2 M. If the reaction proceeds out of the pH range or the phosphate concentration range, only the nitro portion of the protecting group stays in the intermediate which is reduced to the amine, so that the target compound cannot be obtained to the maximum, which may cause a problem in yield reduction.

Step 1 is preferably carried out at 20 ℃ to 40 ℃ for 0.5 hours to 3 hours. If the temperature is less than 20 ° C., the reaction may proceed only to the primary reduced amine intermediate, thereby preventing a complete reaction. When the temperature exceeds 40 ° C., the reaction rate and the degree of completion may be increased, whereas a large amount of the target compound may be decomposed to reduce yield and purity.

In addition, the step 1, after the deprotection reaction is completed, it is preferable to further include the step of removing the organic solvent after removing the zinc powder by filtration and washing. The washing is preferably performed using a mixture of an organic solvent and water used in the reaction, the organic solvent is methyl acetate, butyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, isopropyl ether, methyl ethyl ketone Or dichloromethane can be removed via extraction. If the concentration is performed to remove the organic solvent, a problem may occur in that the target compound is gradually decomposed in the weakly acidic reaction solution to lower the yield and content.

Step 2 is a step of removing the phosphate from the product of step 1, it can be carried out using the adsorption resin slurry extraction method or co-precipitation method.

The adsorption resin slurry extraction method means that the product of step 1 is added to the adsorption resin, stirred and slurried, and then filtered with water to remove phosphate. The adsorption resin may be SP-207, Amberlite XAD-4, Amberlite XAD-7, Diaion HP-20 or HP-40, but is not limited thereto.

 The water may be used 50 to 200 times the weight of the doripenem-PNB, preferably 50 to 100 times. After removing the phosphate, recovering doripenem from the resin with a mixed solution of an organic solvent of methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, isopropyl ether or methyl ethyl ketone and water desirable. The mixed solution is preferably used 10 to 100 times the weight of the doripenem-PNB.

The phosphate removal method using the conventional adsorption resin was carried out by filling the adsorption resin in a special facility, adsorbing doripenem, washing with excess water, removing phosphate, and concentrating for a long time at 50 ° C. or lower using an eluent. Therefore, a special facility is required, and a large amount of impurities are generated by heat and concentration time, so that there is a problem in that yield and purity are lowered.

On the other hand, the adsorption resin slurry extraction method of the present invention can be carried out in a general reactor without a special resin column installation, a polar organic having greater affinity with the adsorption resin than doripenem adsorbed on the adsorption resin without mixing with water as eluent By using a mixture of solvent and water, doripenem can be recovered by simple layer separation.

The coprecipitation method means that the phosphate salt is crystallized by mixing the product of step 1 with an organic solvent of methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile and a mixed solvent of water to remove phosphate. The mixed solvent is preferably used 10 times to 40 times the weight of the doripenem-PNB, and the mixed solution is preferably cooled to 0 ℃ to 10 ℃ to prevent the generation of impurities by heat generation. Do.

Since the coprecipitation method of the present invention excludes the resin process conventionally used conventionally, the target compound can be recovered without concentrating the eluate. Therefore, the generation of impurities by heat and concentration time can be minimized, and doripenem of high purity and high yield can be obtained.

In step 2, doripenem recovered after phosphate removal is added dropwise to methanol, ethanol, isopropyl alcohol, acetone or tetrahydrofuran, followed by filtration and drying in vacuo at room temperature to produce amorphous doripenem monohydrate. It is preferable to include as.

Step 3 is a step of crystallizing the product of step 2 with a solvent for crystallization in order to obtain crystalline doripenem monohydrate. The solvent for crystallization is preferably water or a mixed solvent of water and methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.

The method for producing doripenem monohydrate according to the present invention can be carried out under mild conditions of room temperature and atmospheric pressure without expensive metal catalysts and special facilities, and economical and safe as well as high yield of doripenem monohydrate can be obtained. .

In addition, in the doripenem recovery step after the removal of phosphate, it is possible to recover by simple layer separation without concentration, thereby minimizing impurities generated during the concentration process, thereby producing high purity doripenem monohydrate.

Therefore, the manufacturing method of this invention can be usefully applied to the industrial field related to doripenem monohydrate.

1 is a graph showing a powder X-ray diffraction analysis of doripenem monohydrate according to an embodiment of the present invention.

Figure 2 shows the thermogravimetric analysis (TGA) of doripenem monohydrate according to an embodiment of the present invention.

Figure 3 shows the results of differential scanning calorimetry (DSC) analysis of doripenem monohydrate according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following Examples and Experimental Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Preparation Example: Preparation of Doripenem-PNB

Doripenem-PNB was prepared according to Scheme 2 below. 98 g of the compound represented by the formula (3) was added to 490 ml of methanol, and 25 ml of sulfuric acid was slowly added thereto, followed by reaction for 3 hours while maintaining the internal temperature of 60 ° C to 65 ° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol, and extracted with 100 ml of water and 100 ml of ethyl acetate. The organic layer was recovered and washed with water and 5% brine. Anhydrous magnesium sulfate was used to remove the water remaining in the organic layer and concentrated under reduced pressure. 100 g of the compound represented by Chemical Formula 4 and 100 ml of dimethylformamide were added and dissolved in the concentrated solution. After cooling to 0 ° C.-5 ° C., 47 ml of diisopropylethylamine was added dropwise. After stirring for 10 hours or more at the same temperature, 100 ml of ethyl acetate and 100 ml of water were added to the reaction mixture, the reaction mixture was stirred and the layers were separated. 100 mL of 1N HCl was added to the ethyl acetate layer to remove the remaining base and washed with 100 mL of saturated brine. Anhydrous magnesium sulfate was used to remove the remaining water and the filtrate was concentrated under reduced pressure. The concentrated solution was slowly added to toluene, stirred at room temperature for 1 hour, and filtered to give 132.51 g of doripenem-PNB represented by Formula 2 (yield 98%).

Scheme 2

Example 1: Preparation of amorphous doripenem monohydrate-adsorption resin slurry extraction method

To confirm yield, two doses of amorphous doripenem monohydrate were prepared.

1) 20 g doripenem-PNB

20 g of doripenem-PNB of the above preparation was dissolved in 100 ml of tetrahydrofuran. To this was added 200 ml of water in which 40 g of potassium phosphate monobasic (KH ₂ PO ₄ ) was dissolved and warmed to 30 ° C. Then, 160 g of zinc powder was divided and added slowly, followed by stirring for 2 hours between 30 ° C and 35 ° C. After the reaction was completed, the zinc powder was removed by filtration. The filtrate was washed three times with 200 ml of methylene chloride to remove tetrahydrofuran and impurities present in the aqueous layer. Adsorption resin SP-207 was added and stirred to adsorb doripenem. The resin was filtered and washed with 1 L of water to remove the potassium phosphate salt and impurities used in the reaction. A mixed solution of 200 ml of ethyl acetate and 100 ml of water was added to the reactor, followed by stirring, followed by filtration to elute doripenem. The eluate was separated and the aqueous layer containing doripenem was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C. to 5 ° C. for 1 hour. Filtration and drying under reduced pressure at room temperature yielded 10.26 g of amorphous doripenem monohydrate (yield 90%).

2) 1 kg doripenem-PNB

1 kg of doripenem-PNB of the above preparation was dissolved in 10 L of tetrahydrofuran. To this was added 20 L of water in which 3 kg of potassium phosphate monobasic (KH ₂ PO ₄ ) was dissolved and warmed to 30 ° C. Thereafter, 8 kg of zinc powder was divided and added slowly, followed by stirring for 2 hours between 30 ° C and 35 ° C. After the reaction was completed, the zinc powder was removed by filtration. The filtrate was washed three times with 10 liters of methylene chloride to completely remove the tetrahydrofuran present in the aqueous layer. 30 L of adsorption resin SP-207 was added and stirred to adsorb doripenem. The resin was filtered and washed with 1 L of water to remove the potassium phosphate salt and impurities used in the reaction. 10 L of ethyl acetate and 5 L of water were added to the reactor, followed by stirring, followed by filtration and washing to elute doripenem. The eluate was separated and the aqueous layer containing doripenem was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C. to 5 ° C. for 1 hour. Filtration and drying under reduced pressure at room temperature gave 0.51 kg of amorphous doripenem monohydrate (yield 90%).

Example 2 Preparation of Amorphous Dorifene Monohydrate-Coprecipitation Method

For yield confirmation, amorphous doripenem monohydrate was prepared using two doses.

1) 20g doripenem-PNB

20 g of doripenem-PNB of the above preparation was dissolved in 200 ml of tetrahydrofuran. To this was added 400 ml of water in which 60 g of potassium phosphate monobasic (KH ₂ PO ₄ ) was dissolved and warmed to 30 ° C. Thereafter, 160 g of zinc powder was divided and added slowly, followed by stirring for 2 hours between 30 ° C and 35 ° C. After the reaction was completed, the zinc powder was removed by filtration. The filtrate was washed three times with 200 ml of methylene chloride to remove tetrahydrofuran and impurities present in the aqueous layer. Isopropyl alcohol was added dropwise to the aqueous layer and stirred for 30 minutes to crystallize the phosphate. The crystals were filtered to remove potassium phosphate salts and impurities. The filtrate was added dropwise to isopropyl alcohol to precipitate crystals, stirred at 0 ° C to 5 ° C for 1 hour, filtered and dried under reduced pressure at room temperature to give 10.81 g of amorphous doripenem monohydrate (yield 95%).

2) 1 kg doripenem-PNB

1 kg of doripenem-PNB of the above preparation was dissolved in 10 L of tetrahydrofuran. To this was added 20 L of water in which 3 kg of potassium phosphate monobasic (KH ₂ PO ₄ ) was dissolved and warmed to 30 ° C. Thereafter, 8 kg of zinc powder was divided and added slowly, followed by stirring for 2 hours between 30 ° C and 35 ° C. After the reaction was completed, the zinc powder was removed by filtration. The filtrate was washed three times with 10 liters of methylene chloride to remove tetrahydrofuran and impurities present in the aqueous layer. Isopropyl alcohol was added dropwise to the aqueous layer and stirred for 30 minutes to crystallize the phosphate. The crystals were filtered to remove potassium phosphate salts and impurities. The filtrate was added dropwise to isopropyl alcohol to precipitate crystals, stirred for 1 hour at 0 ° C to 5 ° C, filtered and dried under reduced pressure at room temperature to give 0.54 kg of amorphous doripenem monohydrate (yield 95%).

Example 3: Preparation of Crystalline Doripenem Monohydrate

20 g of the amorphous doripenem monohydrate of Example 2 was dissolved in 100 ml of water, cooled to 0 ° C to 5 ° C, and stirred to precipitate a crystal. After stirring for 2 hours at the same temperature, filtration and drying under reduced pressure at 50 ℃ to give 16 g of crystalline doripenem monohydrate (yield 80%, content 99%).

Comparative Example 1: Amorphous Doripenem-Palladium / Carbon

For yield comparison, amorphous doripenem was prepared.

1) 20 g doripenem-PNB

20 g of doripenem-PNB of the above preparation was dissolved in 400 ml of tetrahydrofuran. To this was added 200 ml of 0.1 M MES buffer (pH 7.0) and 13.5 g of palladium / carbon (10% w / w) as a catalyst to this solution. The mixture was then stirred for 4 hours under hydrogen stream. After the reaction was completed, the catalyst was removed by filtration, washed with ethyl acetate to remove the organic layer, and the aqueous layer was concentrated. The concentrated aqueous solution was adsorbed by chromatography on HP-20 resin column. Doripenem was recovered from the adsorptive resin by developing on a resin column with a 5-10% ethanol solution. The recovered mother liquor was lyophilized to give 9.1 g of amorphous doripenem (yield 80%).

Comparative Example 2: Amorphous Doripenem Monohydrate Preparation-Adsorption Resin Column

For yield comparison, two doses of amorphous doripenem monohydrate were prepared.

1) 20 g doripenem-PNB

20 g of doripenem-PNB of the above preparation was dissolved in 200 ml of tetrahydrofuran. To this was added 400 ml of water in which 60 g of potassium phosphate monobasic (KH ₂ PO ₄ ) was dissolved and warmed to 30 ° C. Then, 160 g of zinc powder was divided and added slowly, followed by stirring for 2 hours between 30 ° C and 35 ° C. After the reaction was completed, the zinc powder was removed by filtration. The filtrate was washed three times with 200 ml of methylene chloride to remove tetrahydrofuran and impurities present in the aqueous layer to prepare a doripenem mother liquor. 600 ml of adsorptive resin SP-207 was packed into a resin column and the doripenem mother liquor was passed through to adsorb doripenem. One liter of water was run on a resin column to remove the potassium phosphate salt and impurities used in the reaction. 2 L of 70% isopropyl alcohol (IPA) was then developed on the resin column to recover doripenem from the adsorption resin. Fractions containing doripenem were collected and concentrated to 5 times volume by weight of doripenem-PNB. The concentrated solution was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C to 5 ° C for 1 hour. Filtration and drying gave 8.0 g of amorphous doripenem monohydrate (yield 70%).

2) 1 kg doripenem-PNB

1 kg of doripenem-PNB of the above preparation was dissolved in 10 L of tetrahydrofuran. To this was added 20 L of water in which 3 kg of potassium phosphate monobasic (KH ₂ PO ₄ ) was dissolved and warmed to 27 ° C. Thereafter, 8 kg of zinc powder was divided and added slowly, followed by stirring for 2 hours between 30 ° C and 35 ° C. After the reaction was completed, the zinc powder was removed by filtration. The filtrate was washed three times with 10 L of methylene chloride to remove tetrahydrofuran and impurities present in the aqueous layer to prepare a doripenem mother liquor. 30 L of adsorption resin SP-207 was charged to the resin column and the doripenem mother liquor was passed through to adsorb the doripenem. 50 liters of water was run on a resin column to remove the potassium phosphate salt and impurities used in the reaction. 100 L of 70% isopropyl alcohol (IPA) was then developed on the resin column to recover doripenem from the adsorption resin. Fractions containing doripenem were collected and concentrated to 5 times volume by weight of doripenem-PNB. The concentrated solution was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C to 5 ° C for 1 hour. Filtration and drying gave 0.68 kg of amorphous doripenem monohydrate (yield 60%).

As a result of comparing the amorphous doripenem monohydrate of Example 1, Example 2, Comparative Example 1, and Comparative Example 2, Example 1 and Example 2 were more remarkable than the preparation methods of Comparative Example 1 and Comparative Example 2. It was found that amorphous doripenem monohydrate can be obtained with improved yields.

Experimental Example 1: Powder X-ray Diffraction (XRD)

X-ray diffraction pattern results of the doripenem monohydrate prepared in Examples 1 and 2 are shown below and in FIG. 1.

Diffraction Angle (2θ) = 10.91 °, 13.07 °, 15.0 °, 15.90 °, 16.64 °, 18.10 °, 20.63 °, 21.09 °, 23.47 °, 23.89 °, 24.19 °, 24.47 °, 26.06 °, 26.96 °, 27.53 ° , 28.23 °, 28.91 ° and 34.15 °.

Experimental Example 2: Thermogravimetric Analysis (TGA)

Thermogravimetric analysis of the doripenem monohydrate prepared in Examples 1 and 2 was performed. Data obtained from thermogravimetric analysis (TGA) is affected by several factors, such as heating rate, sample purity, crystal size and sample size. For analysis, thermogravimetric analysis (TGA) was performed at 35 ° C. to 250 ° C. and 10 ° C./min rate, and the results are shown in FIG. 2.

As shown in FIG. 2, doripenem monohydrate showed a weight loss of 5.19% monohydrate at 125.24 ° C. to 132.74 ° C., and a weight loss due to decomposition of doripenem at 17.25% at 168.38 ° C. to 187.61 ° C. .

Experimental Example 3: Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry of doripenem monohydrate prepared in Examples 1 and 2 was performed. The temperature of the melting endothermic peak was recorded as the melting point. Data obtained from differential scanning calorimetry (DSC) is influenced by several factors such as heating rate, sample purity, crystal size and sample size. Thus, the following melting points are representative of the samples produced by the above examples. For analysis, differential scanning calorimetry (DSC) was performed using 3.30 mg of doripenem monohydrate prepared in Examples 1 and 2, and the results are shown in FIG. 3.

As shown in Figure 3, the doripenem monohydrate of Examples 1 and 2 exhibited an endothermic peak at 180.02 ℃.

Claims (14)

1) a deprotection reaction by reacting doripenem-PNB represented by Formula 2 with zinc powder in a mixed solvent consisting of an organic solvent and an aqueous solution of phosphate;

2) removing phosphate from the product of step 1; And

3) crystallizing the doripenem monohydrate represented by the following Formula 1 as a solvent for crystallization of the product of step 2;

Process for preparing doripenem monohydrate:

[Formula 1]

[Formula 2]

.

According to claim 1, wherein the zinc powder of step 1, characterized in that 4 to 12 times the weight of the doripenem-PNB is used.

The method of claim 1, wherein the phosphate of step 1 is any one or more selected from the group consisting of KH ₂ PO ₄ , K ₂ HPO ₄ , H ₃ PO ₄ , NaH ₂ PO ₄ and Na ₂ HPO ₄ . Manufacturing method.

The method of claim 1, wherein the organic solvent of step 1 is at least one selected from the group consisting of tetrahydrofuran, acetonitrile, acetone, ethyl acetate, methylene chloride and chloroform.

The method according to claim 1, wherein the pH of the mixed solvent of step 1 is 4 to 7.

The method according to claim 1, wherein the concentration of phosphate in the mixed solvent of step 1 is 0.5 M to 2 M.

The method of claim 1, wherein step 1 is performed at 20 ° C to 40 ° C for 0.5 hours to 3 hours.

The method according to claim 1, wherein the step 2 is characterized in that the product of step 1 is added to the adsorption resin, stirred and slurried, followed by filtration with water to remove phosphate.

The method of claim 8, wherein the water is used 50 to 200 times the weight of doripenem-PNB.

The method of claim 8, wherein the phosphate is removed, and then a mixed solution of an organic solvent of methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, isopropyl ether or methyl ethyl ketone and water is removed from the resin. A manufacturing method characterized by recovering doripenem.

The method of claim 10, wherein the mixed solution uses 10 to 100 times the weight of doripenem-PNB.

The method of claim 1, wherein step 2 is characterized in that the phosphate salt is removed by crystallizing the product of step 1 with a mixed solvent of water and an organic solvent of methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile. Manufacturing method.

The method of claim 12, wherein the mixed solvent uses 10 to 40 times the weight of doripenem-PNB.

The method of claim 1, wherein the solvent for crystallization of step 3 is water or a mixed solvent of water and methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.

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