WO2013029293A1 - Method for preparing ertapenem sodium - Google Patents

Abstract

Provided is a method for preparing ertapenem sodium. In the method provided by the invention, ertapenem sodium is prepared by directly catalytic hydrogenation of an undried ertapenem intermediate or by catalytic hydrogenation of the ertapenem intermediate being dried at 20~30℃ to a water content of 5~65%。The method provided by the invention is advantageous to getting ertapenem sodium with a high quality simply and efficiently.

Description

 Method for preparing ertapenem sodium

 The present invention relates to a process for the preparation of carbapenem antibiotics, and in particular to a process for the preparation of ertapenem sodium. Background technique

 Ertapenem (shown in Formula 1) is a carbapenem antibiotic with broad-spectrum antibacterial properties. It was jointly developed by Merck and AstraZeneca. Its chemical name is (4R, 5R, 6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)aminodecanoyl]pyrrolidin-3-yl]thio-6-[(lR)-l-hydroxyethyl]-4 - mercapto-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-indoleic acid, the specific structural formula is as follows:

 Ertapenem sodium (as shown in Formula 2) is an active ingredient of the ertapenem formulation, and its synthesis has received extensive attention.

 2

The synthesis of ertapenem sodium is usually carried out according to the following route:

 PE'

Specifically, a condensation reaction is carried out by the 1 β-mercapto carbapenem parent nucleus MAP and the side chain ES to obtain a protected ertapenem intermediate PE, which is then deprotected by a hydrogenation reduction reaction, and then Treatment resulted in ertapenem sodium (Formula 2). Wherein, it is allyl, substituted benzyl; R ₂ is allyloxycarbonyl, substituted benzyloxycarbonyl or H ₂ ⁺ C1_; is 11, allyl or substituted benzyl.

 The existing synthetic routes of ertapenem sodium include the following:

 1. Synthesis by ertapenem intermediate PE of three protective structure types

In U.S. Patent No. 5,478,820, the following two three-protection types of ertapenem intermediate PE, a technical scheme for synthesizing ertapenem sodium are disclosed: URR ₃ is an allyl group, and R ₂ is an allyloxycarbonyl group; RR ₂ is p-nitrobenzyl and R ₃ is allyloxycarbonyl.

 2. Synthesis of ertapenem intermediate by double protection structure type PE' synthesis

In PCT patent application WO9802439, a technical solution for the synthesis of ertapenem sodium of the ertapenem intermediate PE' of the double-protected structure type of p ₂ nitrobenzyl and R ₃ is H is disclosed.

 3. Synthesis by ertapenem intermediate PE of single-protection structure type

In U.S. Patent No. 6,504,027, it is disclosed that the ertapenem intermediate PE of the single-protected structure type is a p-nitrobenzyl group, R ₂ is H ₂ ⁺ Cr, and R ₃ is H, and ertapenem sodium is synthesized. Technical solutions.

 Obviously, the preparation process of ertapenem sodium has undergone a development process from three protection, double protection and single protection. From the "atomic economy" perspective of green chemistry, in the chemical synthesis process, the synthesis method and process should be designed to convert as much of the raw materials used in the reaction process as possible into the final product, single protection Undoubtedly the most reasonable.

However, the preparation method of ertapenem sodium disclosed in U.S. Patent No. 6,504,027 is to prepare ertapenem sodium from MAP by a one-pot method, although the ertapenem intermediate is not isolated. ΡΕ' , but the excess alkali, the resulting inorganic salt, the diphenoxyphosphonic acid and other impurities in the reaction are brought into the hydrogenation reaction, so that in order to remove excess alkali and diphenoxyphosphonic acid, it is necessary to increase the extraction. The treatment step increases the difficulty of post-treatment, and introduces inorganic salts into the crude product, which affects the purity and content of the product. Therefore, the impurities must be removed as much as possible before hydrogenation to ensure the efficiency of the subsequent hydrogenation reaction and the quality of the final product. The one-pot method is not conducive to the effective removal of impurities.

 Therefore, the high-purity ertapenem intermediate is first isolated and then hydrogenated, which is convenient for the high-quality ertapenem sodium. Summary of the invention

 The present inventors have found in the research that in the process of preparing the ertapenem intermediate (the cartridge), since the reaction solution is poured into an aqueous acid solution, the obtained precipitate has a high water content, and generally, the preparation is obtained. After the compound, drying and dehydration is beneficial to the preservation of the compound, but the ertapenem intermediate is sensitive to heat. If the drying condition is not good and the drying time is long during heating and drying, the ertapenem intermediate is seriously decomposed, resulting in serious decomposition. The product impurities of the further reaction increase and the purity decreases. In addition, large-scale materials used in industrial production, even after long-term drying, are difficult to completely dry inside (up to <5% water content).

 Accordingly, it is an object of the present invention to provide a novel process for the preparation of ertapenem sodium in order to overcome the disadvantages of high impurity content and low purity of the prepared product.

 The object of the present invention is achieved by the following technical solutions.

 A process for the preparation of ertapenem sodium, which comprises subjecting ertapenem intermediate represented by the following formula 经过 to catalytically hydrogenation to obtain ertapenem sodium:

 ΡΕ wherein it is a carboxy protecting group selected from the group consisting of p-nitrobenzyl, o-nitrobenzyl, p-nonyloxybenzyl, allyl or trimethylsilyl, preferably ^p-nitrobenzyl;

Wherein the ertapenem intermediate is an undetrant ertapenem intermediate, or dried at 20-30 ° C to a water content of 5-65% by weight, preferably a water content of 40-65% by weight. Er He is an intermediate in Pein.

 Preferably, the reaction system of the catalytic hydrogenation reaction comprises: 1) a mixed solvent of an organic solvent and water, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-didecyl One or more of an amide and a fluorenyl-pyridylpyrrolidone, preferably tetrahydrofuran; and a volume ratio of the organic solvent to water of from 1.05 to 1.5:1, preferably from 1.05 to 1.2:1; 2) a catalyst selected from the group consisting of One or more of palladium carbon, rhodium, tetrakis(triphenylphosphine)palladium, preferably palladium carbon, more preferably 7.5 wt% palladium carbon; and 3) alkalizing agent, preferably hydrogencarbonate, such as sodium hydrogencarbonate .

 Preferably, in the reaction system, the volume/molar ratio of the mixed solvent to the ertapenem intermediate is 10 to 30:1, preferably 16:1; and/or the alkalizing agent and the ertapenem intermediate The molar ratio is from 3 to 4:1; and/or the mass ratio of the ertapenem intermediate to the catalyst is from 1.7 to 3:1, preferably 2.4:1. The mole number of the ertapenem intermediate oxime is the same as the number of moles of the carbapenem parent MAP, that is, it is regarded as 100% conversion of the carbapenem parent MAP to the ertapenem intermediate PE; The quality of the Peinan intermediate is the quality without water.

 Preferably, the catalytic hydrogenation reaction conditions include: a pressure of 10-17 atmospheres; a temperature of 15-20 ° C; a time of 30 mii! ~ 120min, preferably 60~90min.

 In a preferred embodiment, the process provided by the present invention comprises the steps of: 1) preparing an ertapenem intermediate of the formula PE; 2) catalytically hydrogenating the ertapenem intermediate prepared in step 1).

 Preferably, the method of the ertapenem intermediate prepared in the step 1) comprises the carbapenem mother core represented by the following formula MAP and the ertapenem side chain represented by the following formula ES in the base. React in the presence:

 MAP ES

 Wherein it represents a carboxy protecting group selected from the group consisting of p-nitrobenzyl, o-nitrobenzyl, p-nonyloxybenzyl, allyl or trimethylsilyl; preferably ^ is p-nitrobenzyl.

Preferably, the base in the step 1) is selected from the group consisting of diisopropylethylamine, diisopropylamine, tetradecylguanidine, triethylamine, diethylamine, 4-anthracene, fluorene-diaminopyridine. One or more, preferably a mixture of tetradecyl fluorene and 4-anthracene-quinone-diaminopyridine, the molar ratio of the base to MAP is preferably 3-4:1, more preferably 3·3~3· 5:1. Preferably, a reducing agent is added to the reaction of the step 1), the reducing agent is selected from an organophosphorus reagent such as tri-n-butylphosphorus, triphenylphosphine, triisobutylphosphine, preferably tri-n-butylphosphorus. .

 Preferably, after the reaction of the step 1) is completed, the pH of the reaction solution is gradually added to the reaction solution to a pH of 6.5 to 7.5, and the reaction is dropped into an aqueous acid solution to make the pH of the solution 5.5 to 5.9; The acid is preferably selected from the group consisting of glacial acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, citric acid, p-toluenesulfonic acid, sulfonic acid, benzoic acid, succinic acid, oxalic acid, and trifluoroacetic acid. One or more of them are more preferably glacial acetic acid and/or potassium dihydrogen phosphate.

 Preferably, the step 1) further comprises separating the obtained reaction precipitate by suction filtration or centrifugation to obtain an ertapenem intermediate represented by the formula PE; further, drying the obtained erecta at 20-30 ° C The perennial intermediate has a water content of 5 to 65% by weight, preferably 40 to 65% by weight.

 Preferably, the method further comprises the following step 3): after the reaction of the step 2) is completed, the acid is added dropwise to the reaction solution to adjust the pH to 5.5-6.0, suction filtration, and the filtrate is extracted with dichloromethane. After the aqueous phase was filtered, it was filtered with activated carbon, and crystallized at a constant volume ratio of decyl alcohol and isopropanol at -20 to 10 °C. In the above-mentioned post-treatment, the acid was first added dropwise to adjust the pH in order to remove the black oil complexed with palladium, and then most of the palladium complex was removed by suction filtration.

 It can be seen that the method for preparing ertapenem sodium provided by the invention can directly treat a single-protected ertapenem intermediate having a water content of 85% or less, especially 5-65% (ie, undexified ertapenem). The hydrogenation reaction of the intermediate, or the ertapenem intermediate which is dried to such a water content range at room temperature, not only can greatly reduce the operation, but also facilitates the improvement of the purity and the cost, that is, it is advantageous for the cartridge to be efficiently obtained. High quality product ertapenem sodium. The present inventors have found through research that the intermediate product PE is directly hydrogenated without drying, and the product ertapenem sodium has the lowest impurity content, and thus the product has the highest purity. The vacuum drying of the intermediate PE at room temperature 20~30 °C and then hydrogenation will increase the impurity content of the obtained product, but the increase of the impurity content is not large, so the purity of the product does not change much. However, as the drying temperature increases, the intermediate PE is vacuum dried and then hydrogenated at a temperature higher than 35 ° C, and the resulting product impurities are significantly increased, and the purity is less than 90%. It can be seen that the intermediate PE is directly hydrogenated without drying, or dried at 20 to 30 ° C, and then hydrogenated, which can significantly reduce the impurities of the hydrogenated product ertapenem sodium and increase the purity of the product. The best way to implement the invention

 The invention is described below with reference to specific embodiments. Those skilled in the art can understand that the examples are only intended to illustrate the invention, and are not intended to limit the scope of the invention in any way.

The raw material 1 β-mercaptocarbamethylene bicyclonuclear MAP used in the following examples can be purchased from 邯 Bengbu Kangrui Biotechnology Co., Ltd., or the method disclosed in the reference US4933333 or CN100347175; ertapenem side chain ES can be purchased from Tianjin Jingye Fine Chemical Co., Ltd., or reference Karel MJ Brands et al. J.Org The method disclosed in .Chem. 2002, 67, 4771-4776 is synthesized.

 The method for determining moisture in the following examples is a Karl Fischer reagent assay, and the purity assay method is described in the method disclosed in Karel MJ Brands et al., J. Org. Chem. 2002, 67, 4771-4776, the purity is HPLC area % purity against standard.

 The other experimental methods in the following examples are conventional methods unless otherwise specified. Other chemical materials, reagent materials, and the like used in the following examples are commercially available products unless otherwise specified. Example 1

 The ertapenem intermediate of the single-protection structure was prepared by reacting 1 β-mercapto carbapenem bicyclic nucleus MAP with ertapenem side chain ES. The specific steps are as follows:

A. First pass N ₂ in a 500ml four-necked flask, add 100ml of dimercaptoamide (DMF), cool down to 0 °C, add 11.6g MAP, then add 6.48g side chain ES, add 0.3g three positive Butylphosphine, after stirring and completely dissolved, reduce the temperature to -50 ° C, add 8.1 g of tetramethyl hydrazine (TMG), add 0.35 g of 4-indole, hydrazine-diaminopyridine (DMAP), keep the system temperature -50 °C~-40°C, reaction for 3h.

B. Add 20 ml of saturated KH ₂ P0 ₄ aqueous solution dropwise, pH 6.5-7.5, stir at -40 °C for 30 min, and warm to 10 °C.

 C. The solution obtained in step B is slowly added dropwise to 1000 ml of 1% hydrochloric acid solution, so that the pH of the solution is 5.5-5.9, stirred for 30 min, filtered by suction, and washed twice with ice water to obtain 34 g of PE wet product. The purity is 98.6% and the water content is 65%. Example 2

 Ertapenem sodium is prepared by catalytic hydrogenation of a single-protected ertapenem intermediate PE. The specific steps are as follows:

 A. Add 7g of palladium on carbon (7.5%) to 80ml of pure water and mix well.

B. The undried PE wet product obtained in Example 1 (65% aqueous) was dissolved in 210 ml of tetrahydrofuran (THF), and after total dissolution, it was added to 60 ml of water (containing 5 g of NaHC0 ₃ , and the molar ratio to MAP was 3 equivalents). ).

C. Add the solution obtained in step B to the solution obtained in step A, 15~20 °C, Hydrogenation at 1.7 MPa for 90 min.

D. Post-treatment: Pour out the hydrogenation solution, adjust the pH to 5.8 with 20% hydrochloric acid, suction filtration, extract the filtrate once with 300 ml cold CH ₂ C1 ₂ , separate the organic phase, filter the water layer, add 3 g of activated carbon, stir lOmin, pump filter.

 E. To the solution obtained in step D, add 250ml of sterol, then add 250ml of isopropanol, drop to -10 ° C, stir for 30min, then cool to -15 °C, add sterol / isopropyl 500 ml of alcohol (1:1) mixture, stirring for 30 min, suction filtration, acetone filter cake, vacuum drying, 4.88 g of ertapenem sodium white solid, yield 50.3% (by MAP), purity: 97.1%. Example 3

 The ertapenem intermediate of the single-protection structure was prepared by reacting 1 β-mercapto carbapenem bicyclic nucleus MAP with ertapenem side chain ES. The specific steps are as follows:

A. First pass N ₂ in a 500ml four-necked flask, add 100ml of dimercaptoamide (DMF), cool down to 0 ° C, add 11.6g MAP, then add 6.48g side chain ES, add 0.3g of tri-n-butyl After the phosphine was stirred and dissolved, the temperature was lowered to -50 ° C, and 7.9 g of 4-N,N-diaminopyridine (DMAP) was added to maintain the temperature of the system at -50 ° C to -40 ° C for 3 h.

 B. Add 1.2 g of glacial acetic acid dropwise, add 20 ml of water, pH 6.5-7.5, stir at -40 °C for 30 min, and raise the temperature to 10 °C.

C. The solution obtained in step B is slowly added dropwise to 1000 ml of 3% KH ₂ P0 ₄ aqueous solution to make the solution pH 5.5-5.9, stirred for 30 min, suction filtered, and washed twice with ice water to obtain PE wet product 30 g. The purity was determined to be 98% and the moisture was 60%. Example 4

 Ertapenem sodium is prepared by catalytic hydrogenation of a single-protected ertapenem intermediate PE. The specific steps are as follows:

 A. Add 7g of palladium on carbon (7.5%) to 80ml of pure water and mix well.

B. The undried PE wet product obtained in Example 3 (60% aqueous) was dissolved in 160 ml of N-decylpyrrolidone (NMP), and after total dissolution, it was added to 60 ml of water (containing 5 g of NaHC0 ₃ , with MAP moles). The ratio is 3 equivalents).

 C. Add the solution obtained in step B to the solution obtained in step A, hydrogenation at 15-20 ° C, l.OMPa, for 120 min.

D. Post-treatment: Pour out the hydrogenation solution, adjust the pH to 6.0 with 20% hydrochloric acid, suction filtration, use the filtrate 300 ml of cold ethyl acetate was extracted once, the organic phase was separated, and the aqueous phase was added with 3 g of activated carbon, stirred for 10 min, and suction filtered.

 E. To the solution obtained in step D, add 250ml of sterol, then add 250ml of isopropanol, drop to -10 ° C, stir for 30min, then cool to -20 ° C, add sterol / isopropyl Alcohol (1:1) mixture 500ml, after stirring for 30min, suction filtration, acetone filter cake, vacuum drying, to obtain 4.83g ertapenem sodium white solid, yield 49.8% (in MAP), purity 97.3 %. Example 5

 The ertapenem intermediate of the single-protection structure was prepared by reacting 1 β-mercapto carbapenem bicyclic nucleus MAP with ertapenem side chain ES. The specific steps are as follows:

A. First pass N ₂ in a 500ml four-necked flask, add 100ml of dimercaptoamide (DMF), cool down to 0 ° C, add 11.6g MAP, then add 6.15g side chain ES, add 0.3g of tri-n-butyl Base phosphine, after stirring and completely dissolved, cool to -50 ° C, add 7.6 g of tetramethyl hydrazine ( TMG ), add 0.35 g of 4-Ν, Ν-diaminopyridine (DMAP), keep the system temperature -50 ° C~-40 ° C, reaction for 3 h.

 B. Add 1.2 g of glacial acetic acid dropwise, add 20 ml of water, pH 6.5-7.5, stir at -40 °C for 30 min, and raise the temperature to 10 °C.

C. The solution obtained in step B is slowly added dropwise to 1000 ml of 3% KH ₂ P0 ₄ aqueous solution to make the pH of the solution 5.5-5.9, stirred for 30 min, centrifuged, and washed twice with ice water to obtain PE wet product 19.8 g, the purity was determined to be 98%, and the moisture was 40%. Example 6

 Ertapenem sodium is prepared by catalytic hydrogenation of a single-protected ertapenem intermediate PE. The specific steps are as follows:

 A. Add 5 g of palladium on carbon (7.5%) to 80 ml of pure water and mix well.

B. The undried PE wet product obtained in Example 5 (40% aqueous) was dissolved in 160 ml of tetrahydrofuran (THF), and after total dissolution, it was added to 60 ml of water (containing 5 g of NaHC0 ₃ and a molar ratio of 3 equivalents to MAP). ).

 C. The solution obtained in the step B is added to the solution obtained in the step A, and hydrogenated at 15 to 20 ° C and 1.5 MPa for 90 minutes.

D. Post-treatment: Pour out the hydrogenation solution, adjust the pH to 5.5 with 20% hydrochloric acid, suction filtration, extract the filtrate once with 300 ml of cold dichloromethane, separate the organic phase, filter the aqueous layer, add 3 g of activated carbon, stir for 10 min, pump filter. E. To the solution obtained in step D, add 250ml of sterol, then add 250ml of isopropanol, drop to -10 ° C, stir for 30min, then cool to -15 ° C, add sterol / isopropyl 500 ml of alcohol (1:1) mixture, stirring for 30 min, suction filtration, acetone filter cake, vacuum drying, 4.90 g of ertapenem sodium white solid, yield 50.5% (by MAP), purity : 97.2%. Example 7

 The ertapenem intermediate of the single-protection structure was prepared by reacting 1 β-mercapto carbapenem bicyclic nucleus MAP with ertapenem side chain ES. The specific steps are as follows:

A. First pass N ₂ in a 500 ml four-necked flask, add 100 ml of dimercaptoamide (DMF), cool to 0 ° C, add 11.6 g of MAP, then add 6.25 g of side chain ES, add 0.3 g of triphenylphosphine After stirring and completely dissolved, the temperature was lowered to -50 ° C, 7.6 g of tetramethyl hydrazine (TMG) was added dropwise, and 0.35 g of 4-indole, hydrazine-diaminopyridine (DMAP) was added to maintain the system temperature of -50 ° C. -40 ° C, reaction for 3 h.

 B. Add 1.2 g of glacial acetic acid dropwise, add 20 ml of water, pH 6.5-7.5, stir at -40 °C for 30 min, and raise the temperature to 10 °C.

 C. The solution obtained in step B is slowly added dropwise to 1000 ml of 1.3% aqueous solution of HOAc, so that the pH of the solution is 5.5-5.9, stirred for 30 min, filtered by suction, and washed twice with ice water to obtain 42.5 g of PE wet product. Its purity is 98.2% and its moisture is 72%. Example 8

 Ertapenem sodium is prepared by catalytic hydrogenation of a single-protected ertapenem intermediate PE. The specific steps are as follows:

 A. Add 7 g of palladium on carbon (7.5%) to 130 ml of pure water and mix well.

B. The undried PE wet product obtained in Example ( (72% aqueous) was dissolved in 320 ml of tetrahydrofuran (THF), and after total dissolution, it was added to 136 ml of water (containing 5 g of NaHC0 ₃ , and the molar ratio to MAP was 3 equivalents).

 C. Add the solution obtained in step B to the solution obtained in step A, and hydrogenate at 15~20 ° C, 1.7 MPa for 90 min.

 D. Post-treatment: Pour out the hydride solution, adjust the pH to 5.9 with 20% hydrochloric acid, suction filtration, extract the filtrate once with 300 ml of cold dichloromethane, separate the organic phase, filter the aqueous layer, add 3 g of activated carbon, stir for 10 min, pump filter.

E. To the solution obtained in step D, add 500 ml of isopropanol dropwise, cool to -10 ° C, add 500 ml of isopropanol, add stirring for 30 min, filter by suction, rinse the filter cake with acetone, and dry in vacuum. 5.1 g of ertapenem sodium white solid were obtained in a yield of 52.6% (based on MAP) with a purity of 96.8%. Example 9

 The ertapenem intermediate of the single-protection structure was prepared by reacting 1 β-mercapto carbapenem bicyclic nucleus MAP with ertapenem side chain ES. The specific steps are as follows:

A. First pass N ₂ in a 500ml four-necked flask, add 100ml of dimercaptoamide (DMF), cool down to 0 ° C, add 11.6g MAP, then add 6.15g side chain ES, add 0.3g of tri-n-butyl Phosphine, after stirring, completely cooled to -50 ° C, add 8.3 g of diisopropylethylamine (DIPEA), add 0.35 g of 4-N,N-diaminopyridine (DMAP), keep the temperature of the system -50 ° C ~ -40 ° C, reaction for 3 h.

 B. Add 1.2 g of glacial acetic acid dropwise, add 20 ml of water, pH 6.5-7.5, stir at -40 °C for 30 min, and raise the temperature to 10 °C.

C. The solution obtained in step B is slowly added dropwise to 1000 ml of 3% Na3⁄4P0 ₄ aqueous solution, so that the pH of the solution is 5.5-5.9, stirred for 30 min, filtered, and washed twice with ice water to obtain 36 g of PE wet product. The purity was 97.8%, and the water content was 67%. After vacuum drying of the intermediate PE at room temperature of 20 to 30 ° C, 27.7 g of PE wet product was obtained, and the purity was determined to be 96.6%, and the water content was 57%. Example 10

 Ertapenem sodium is prepared by catalytic hydrogenation of a single-protected ertapenem intermediate PE. The specific steps are as follows:

 A. Add 4 g of palladium on carbon (10%) to 45 ml of pure water and mix well.

B. 27.7 g (containing 57%) of PE wet product which was vacuum-dried at room temperature 20 to 30 ° C obtained in Example 9 was dissolved in 100 ml of tetrahydrofuran (THF), and after total dissolution, it was added to 50 ml of water (containing 6.6 g of NaHC0). ₃ , the molar ratio to MAP is 4 equivalents).

 C. The solution obtained in the step B is added to the solution obtained in the step A, and hydrogenated at 15 to 20 ° C and 1.7 MPa for 90 minutes.

 D. Post-treatment: The hydrogenation solution was poured out, the pH was adjusted to 5.8 with glacial acetic acid, suction filtration, and the filtrate was extracted once with 300 ml of cold isoamyl alcohol. The organic phase was separated, the aqueous layer was filtered, and 3 g of activated carbon was added thereto, stirred for 10 min, and suction filtered.

E. To the solution obtained in step D, add 250ml of sterol, then add 250ml of isopropanol, cool down to -10 ° C, stir for 30min, then cool to -15 ° C, add sterol / isopropyl Alcohol (1:1) mixture 500ml, after stirring for 30min, suction filtration, acetone filter cake, vacuum drying, 4.8g ertapenem sodium white solid, yield 49.5% (in MAP), purity 90.2 %. Example 11

 The ertapenem intermediate of the single-protection structure was prepared by reacting 1 β-mercapto carbapenem bicyclic nucleus MAP with ertapenem side chain ES. The specific steps are as follows:

A. First pass N ₂ in a 500ml four-necked flask, add 100ml of dimercaptoamide (DMF), cool down to 0 ° C, add 23.2g MAP, then add 12.3g side chain ES, add 0.6g of tri-n-butyl Phosphine, after stirring, completely cooled to -50 ° C, add 17 g of tetramethyl hydrazine ( TMG ), add 0.7 g of 4-indole, hydrazine-diaminopyridine (DMAP), keep the system temperature -50 ° C ~-40 ° C, reaction for 3 h.

 B. Add 2.4 g of glacial acetic acid dropwise, add 40 ml of water, pH 6.5-7.5, stir at -40 °C for 30 min, and warm to 10 °C.

C. The solution obtained in step B is slowly added dropwise to 2000 ml of 3% KH ₂ P0 ₄ aqueous solution to make the solution pH 5.5-5.9, stirred for 30 min, centrifuged, and washed twice with ice water to obtain PE wet product 34 g. The purity was determined to be 98% and the moisture was 30%. Example 12

 Ertapenem sodium is prepared by catalytic hydrogenation of a single-protected ertapenem intermediate PE. The specific steps are as follows:

 A. Add 7 g of palladium on carbon (5%) to 320 ml of pure water and mix well.

B. The undried (30% aqueous) PE wet product obtained in Example 11 was dissolved in 640 ml of tetrahydrofuran (THF), and after total dissolution, it was added to 240 ml of water (containing 10 g of NaHCO ₃ and a molar ratio of 3 equivalents to MAP). ).

 C. The solution obtained in the step B is added to the solution obtained in the step A, and hydrogenated at 15 to 20 ° C and 1.7 MPa for 60 minutes.

 D. Post-treatment: The hydrogenation solution was poured out, the pH was adjusted to 5.8 with glacial acetic acid, suction filtration, and the filtrate was extracted once with 900 ml of cold ethyl acetate. The organic phase was separated, and 6 g of activated carbon was added to the aqueous phase, stirred for 10 min, and filtered.

E. To the solution obtained in step D, add 1000ml of sterol, then add 1000ml of isopropanol dropwise, cool down to -10 ° C, stir for 30min, then cool to -20 ° C, add sterol / isopropyl Alcohol (1:1) mixture 2000ml, after stirring for 30min, suction filtration, acetone filter cake, vacuum drying, 9.1g ertapenem sodium white solid, yield 47% (in MAP), purity 97.2 %. Example 13 The drying temperature and time of the intermediate PE prepared in Example 1 were investigated. Table 1 below shows the purity and water content of the intermediate PE prepared by drying at 20~30 °C for different time.

 The above results show that the purity of the intermediate PE is reduced after vacuum drying of the intermediate PE at room temperature of 20 to 30 ° C, but the purity is not reduced. Example 14

 This example provides the preparation of ertapenem sodium by catalytic hydrogenation of the ertapenem intermediate PE of a single-protected structure having different water contents obtained by drying at different temperatures under different temperature conditions, which are prepared by the method of the above-described embodiment. Table 2 below gives partial representative result data.

From the results of Table 2, it is known that the prepared intermediate PE is directly hydrogenated without drying, and the product ertapenem sodium has the lowest impurity content, so the product has the highest purity, and the water content has little effect on the purity and yield of the product. High quality products of ertapenem sodium are available. The vacuum drying of the intermediate PE at room temperature 20~30 ° C and then hydrogenation will increase the impurity content of the obtained product, but the increase of the impurity content is not large, so the purity of the product does not change much. However, as the drying temperature increases, such as vacuum drying of the intermediate PE at a temperature higher than 35 ° C and then hydrogenation, the resulting product impurities are significantly increased, and the purity is less than 90%. It can be seen that the intermediate PE is directly hydrogenated without drying, or is further dried after being dried at 20 to 30 ° C, and the impurities of the hydrogenated product ertapenem sodium can be significantly reduced and the purity of the product can be improved. Table 2

Intermediate PE Intermediate PE After hydrogenation, crude hydrogenation, dihydrogenation, crude product, dry temperature, water content, purity, impurity ratio (in MAP), undried 85%, 96.9%, 1.1%, 51.8%, undried, 65%, 97.1%, 1.2%, 50.3 % not dried 40% 97.2% 1.3% 50.5%

20-30 °C 60% 96.6% 1.7% 48.4%

 40% 95.8% 2.3% 51.6%

5% 94% 3.4% 45%

35~40 °C 40% 88.5% 5.3% 43.2%

 5% 89.4% 6.6% 39.8%

40-45 °C 40% 79.2% 8.8% 35.4%

 5% 78.9% 9.1% 30.6%

Claims

Rights request A method for preparing ertapenem sodium, which comprises subjecting ertapenem intermediate represented by the following general formula PE to ertapenem sodium by catalytic hydrogenation reaction:

 Wherein PE is a carboxy protecting group selected from the group consisting of p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl, allyl or trimethylsilyl, preferably ^p-nitrobenzyl;  Wherein the ertapenem intermediate is an undetrant ertapenem intermediate or is dried at 20-30 ° C to an ertapenem intermediate having a water content of 5-65% by weight. 2. The method according to claim 1, wherein the reaction system of the catalytic hydrogenation reaction comprises:  1) a mixed solvent of an organic solvent and water; wherein the organic solvent is one or more selected from the group consisting of tetrahydrofuran, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide, and fluorenyl-pyridylpyrrolidone , preferably tetrahydrofuran; and the volume ratio of the organic solvent to water is 1.05 to 1.5:1, preferably 1.05-1.2:1;  2) a catalyst selected from the group consisting of palladium on carbon, ruthenium powder, tetrakis(triphenylphosphine)palladium, preferably palladium on carbon, more preferably 7.5 wt% palladium on carbon;  3) An alkalizing agent, preferably a hydrogencarbonate such as sodium hydrogencarbonate. The method according to claim 2, wherein the volume/molar ratio of the mixed solvent to the ertapenem intermediate is 10 to 30:1, preferably 16:1; Or the molar ratio of the alkalizing agent to the ertapenem intermediate is from 3 to 4:1; and/or the mass ratio of the ertapenem intermediate to the catalyst is from 1.7 to 3:1, preferably 2.4:1. The method according to claim 2, wherein the catalytic hydrogenation reaction conditions comprise: a pressure of 10-17 atmospheres; a temperature of 15-20 ° C; a time of 30 min to 120 min, Preferably 60~90min _c The method according to any one of claims 1 to 4, characterized in that the method comprises the following steps:  1) preparing an ertapenem intermediate represented by the formula PE;  2) Catalytic hydrogenation step 1) Preparation of ertapenem intermediate. The method according to claim 5, wherein the method of the ertapenem intermediate prepared in the step 1) comprises the carbapenem core represented by the following formula MAP and the following formula The ertapenem side chain shown by ES reacts in the presence of a base:

 MAP ES  Wherein it represents a carboxy protecting group selected from the group consisting of p-nitrobenzyl, o-nitrobenzyl, p-nonyloxybenzyl, allyl or trimethylsilyl; preferably ^ is p-nitrobenzyl. The method according to claim 6, wherein the base in the step 1) is selected from the group consisting of diisopropylethylamine, diisopropylamine, tetradecylguanidine, triethylamine, diethylamine, One or more of 4-anthracene, anthracene-diaminopyridine, preferably a mixture of tetradecylguanidine and 4-anthracene-quinone-diaminopyridine, the molar ratio of the base to MAP is preferably from 3 to 4. More preferably, it is 3.3 to 3.5: 1; preferably, a reducing agent is added to the reaction of the step 1), and the reducing agent is selected from an organophosphorus reagent such as tri-n-butylphosphorus, triphenylphosphine, Triisobutylphosphine, preferably tri-n-butylphosphorus. The method according to claim 6 or 7, wherein after the reaction of the step 1) is completed, the pH of the reaction solution is 6.5-7.5, and the reaction liquid is dropped into the reaction solution. In the aqueous solution of the acid, the pH of the solution is 5.5-5.9; the acid is selected from the group consisting of glacial acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, citric acid, p-toluenesulfonic acid, sulfonic acid, One or more of benzoic acid, succinic acid, oxalic acid and trifluoroacetic acid, preferably glacial acetic acid and/or potassium dihydrogen hydride. The method according to any one of claims 6 to 8, wherein the step 1) further comprises separating the obtained reaction precipitate by suction filtration or centrifugation to obtain an intermediate of ertapenem represented by the formula PE. Alternatively, the obtained ertapenem intermediate is dried at 20 to 30 ° C to have a water content of 5 to 65% by weight. The method according to claim 5, wherein the method further comprises: 3) After the reaction of the step 2) is completed, the acid is added dropwise to the reaction solution to adjust the pH to 5.5-6.0, suction filtration, and the filtrate is extracted with dichlorosilane. The obtained aqueous phase is filtered, and activated carbon is added for filtration. , crystallization at -20~ - 10 °C in an equal volume ratio of a mixture of decyl alcohol and isopropanol.