KR100781821B1 - Process for preparing carbapenem compound - Google Patents

Abstract

The present invention is a carbapenem-based advanced antibiotic, meropenem.3H2O [(1R, 5S, 6S) -2-[((2'S, 4'S)-(2'-dimethylaminocarbonyl) pyrrolidin-4'-yl. Thio] -6-[(R) -1-hydroxyethyl] -1-methyl carbafen-2-m-3-carboxylic acid, trihydrate], which is a starting material M-2- Process to remove PNB (paranitrobenzyl) group, which is a carboxyl protecting group of meropenem precursor obtained by synthesizing phosphate and proline derivatives, in an industrially simple and high yield, and to prepare meropenem trihydrate after preparing meropenem precursor By using the precipitation method using a simple mixed solvent instead of the freeze-drying method or the column chromatography purification method, the yield of meropenem trihydrate, the target substance, is greatly improved, and the production cost is very simple and industrially. New manufacturing methods that can greatly reduce The ball.

Carbapenem, Meropenem

Description

Process for preparing carbapenem compound

The present invention relates to a method of preparing meropenem having excellent efficacy and stability as a carbapenem-based antibiotic, and more particularly, to the carboxyl of the meropenem precursor, which is a key intermediate of the final substance. Easy removal of p-nitrobenzyl groups protecting carboxyl groups in high yield and purification of merpenem trihydrate, a target substance, by industrially high cost and low efficiency freeze drying or column chromatography By inventing a crystallization method by a simple solvent precipitation method without using a purification method by the present invention, a new production method that can industrially produce the target material in high yield, high purity at low cost.

As the carboxyl group protecting group, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl or allyl are commonly used as protecting groups of substance molecules in the penicillin or cephalosporin antibiotics.

Looking at the conventional manufacturing technology for the meropenem synthesis technology, the manufacturing process of the meropenem generally published is the trans-4-hydroxy-L-proline (trans-4-hydroxy-L) p-nitrobenzyloxy carbonylchloride is reacted with methoxy-benzyl chloride, starting with -proline as a starting material, and trans-1- (p-nitrobenzyloxycarbonyl) is reacted with methoxy-benzyl chloride. ) -4-hydroxy-L-proline, p-methoxybenzyl ester (trans-1- (p-nitrobenzyloxy carbonyl) -4-hydroxy-L-proline, p-methoxy benzyl ester) to obtain thiourea (thiourea) is reacted with diethoxy carbonyl diazide, triphenylphosphine, trifluoroacetic acid and DCC, and then hydrolyzed with 1N caustic soda to form the core of meropenem. Cis-4-mercap, one of the side chains -N, N-dimethyl-1- (p-nitrobenzyloxycarbonyl) -L-prolineamide [cis-4-mercapto-N, N-dimethyl-1- (p-nitrobenzyloxycarbonyl-L-prolin amide or (2s -cis) -2-[(dimethylamino) carbonyl] -4-mercapto-1-pyrrolidine carboxylic acid (4-nitrophenyl) methyl ester, molecular weight: 353.39, MP: 118-120 ° C.].

This compound was converted to M-2-phosphate [4R--3-[(diphenyloxy-phosphinl) oxy] -6- (1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3,2,0] hept 2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester, molecular weight: 594.52] to react the meropenem precursor [4-nitrobenzyl (5S, 6S) -3-[((3S, 5S) -5- [ (dimethylamino) carbonyl] -1-{[(4-nitro benzyl) oxy] carbonyl} pyrrolidinyl) sulfanyl] -6-[(1R) -1-hydroxyethyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate, molecular weight: 697.73], and if the p-nitrobenzyl group, the protecting group of the carboxyl group, is catalytically reduced with hydrogen in the presence of 10% palladium carbon as a catalyst, the crude Meropenem is obtained, which is crystallized in a suitable water and solvent in a sterile process to obtain sterile crystalline meropenem trihydrate (molecular weight: 437.47) as the final target.

If more detailed prior art related to the present invention (Korean Patent Publication No. 1986-4062 (Sumitomo) and US Patent No. 4,943,569 (Sumitomo Pharmaceutical, etc.) is described, M-2-phosphate is reacted with a proline derivative during the above process. After preparing a meropenem precursor in which a carboxyl group is protected with a p-methoxybenzyl group or a p-nitrobenzyl group, it is dissolved in an appropriate amount of a mixed solvent of THF (tetrahydrofuran) and ethanol, followed by morpholic in the presence of 10% palladium-carbon. After hydrogenating with morpholinopropanesulfonic acid buffer solution at room temperature for 3 hours, the catalyst was filtered, THF and ethanol were distilled under reduced pressure, the remaining solution was washed with ethyl acetate (EA), and the solvent in the aqueous solution was distilled under reduced pressure. After lyophilization, the desired amorphous meropenem is obtained in a yield of about 65%, and this is again subjected to crystallization to obtain meropenem as a target product. Get trihydrate.

However, the method is not only limited to industrial use because of the complicated process and the high cost of equipment, and the use of expensive palladium-carbon and the high risk of explosion. It is relatively low, such as 50 to 65%.

Or a meropenem precursor in which the carboxyl group of the crude meropenem is protected with p-methoxybenzyl group or p-nitrobenzyl group at room temperature with trifluoroacetic acid and anisole to react with p-methoxybenzyl group or p Techniques for removing nitrobenzyl groups and using solvents such as methylene chloride, m-dimethoxybenzene, and trifluoroacetic acid have been introduced, but yields are very low and column chromatography is performed at the final stage. There are many problems in terms of equipment cost and efficiency in mass production, such as purification.

In addition, according to Korean Patent Publication No. 1999-32285 and Korean Patent Registration No. 215551, the protecting group of the carboxyl group in the C-3 position of the carbapenem type imine compound is acetic acid, formic acid, metacresol, trifluoroacetic acid or aluminum chloride. A method of effectively removing the p-nitrobenzyl group, which is a protecting group, by reacting at -20 to 100 ° C for 1 to 20 hours using Lewis acid such as is introduced.

Looking at this preparation method in detail, the reactant was dissolved in methacresol, heated to 50-60 ° C. and reacted for 2 to 10 hours, then ethyl acetate and water were added, the pH was adjusted to about 10 with sodium bicarbonate, and the water layer was separated. The pH was adjusted to 2 again with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, distilled under reduced pressure to remove the solvent, and the residue was dissolved in an aqueous sodium bicarbonate solution to freeze-dried to obtain a target product. Although it is evaluated as an advanced manufacturing process rather than a direct contact reduction method, the yield is 9.73%, 21%, 42%, 68%, 85%, 94%, etc., very irregular depending on the reactants, and there is a problem in that a lyophilization method should be used.

In addition, in the method invented by the Korea Research Institute of Chemical Technology, the imine compound is dissolved in dioxane or THF and 0.1 mol of morpholinopropanesulfonic acid buffer solution (pH 7.0) and 10% palladium carbon or platinum oxide (platinum oxide) at room temperature. ) And reacted under hydrogen atmosphere (10 psi) for 2 to 6.5 hours, the catalyst was filtered through Celite, the volatile solvent was removed under reduced pressure, the residue was washed with ethyl acetate and diethyl ether, and then the aqueous layer. After distilling under reduced pressure to obtain an appropriate amount of the organic solvent remaining in the column, it was separated by column chromatography using Dilion CHP-20P, lyophilized to obtain white crystals, and then recrystallized to obtain the target product (46% to 55.3%). Although this process is introduced, the process is very complicated and it is expected to cost a lot for mass production. Uh seems.

An object of the present invention is to easily remove the p-nitrobenzyl group protecting the carboxyl group of the meropenem precursor in the preparation method of the carbapenem antibiotic meropenem trihydrate, and do not use a freeze-drying method or a column chromatography purification step. By using a simple precipitation method using an insoluble mixed solvent of meropenem, it is to provide a new manufacturing method that can produce meropenem trihydrate commercially in high yield and high purity.

In order to achieve the above object, the meropenem precursor represented by the formula (1) is reacted with a deprotection mixed solvent composed of cresol and an aromatic solvent to remove p-nitrobenzyl group, which is a carboxyl group protecting group of merofenem precursor, and then merope Provided is a dropwise addition of a mixed solvent for crystallization comprising a nem insoluble solvent and a soluble solvent to provide a method for producing meropenem, characterized by obtaining a trihydrate crystal of meropenem represented by the formula (2).

The cresol used in the present invention is preferably metacresol, and the aromatic solvent is at least one selected from toluene, benzene, and xylene, by using a deprotective mixed solvent composed of 5 to 30% by volume of such an aromatic solvent and cresol. The p-nitrobenzyl group could be removed in a high yield of 90% or more, and the composition ratio of the preferred aromatic solvent is 10 to 25% by volume based on the total volume of the mixed solvent.

In the present invention, the deprotection group reaction of the meropenem precursor is preferably performed at 70 to 80 ° C. for 1 to 3 hours. The yield of the deprotection reaction is lowered when the reaction is lower than 70 ° C., and when the reaction time is less than 1 hour, the unreacted substance remains.

The mixed solvent for crystallization used in the present invention is composed of meropenem insoluble solvent, meropenem soluble solvent and distilled water, the composition ratio is preferably 50: 45: 5 as the volume ratio.

The meropenem insoluble solvent used in the present invention is at least one chloromethane solvent selected from methylene chloride, chloroform and carbon tetrachloride, and the meropenem soluble solvent is preferably acetone or isopropyl alcohol.

As such, when a solvent in which a target substance is not dissolved and a solvent in which a target is dissolved in a mixture is used in the crystallization process, an unreacted substance, that is, impurities are removed during the precipitation of the target substance during synthesis, where chloromethane, an insoluble solvent, is removed. If the ratio is high, the yield is improved, but the quality is deteriorated. On the contrary, if the ratio of the soluble solvent (acetone, isopropyl alcohol, etc.) is high, the quality is good but the yield tends to be lowered. Therefore, the mixing ratio of the mixed solvent for crystallization is preferably 50: 45: 5 as the volume ratio of meropenem insoluble solvent: meropenem soluble solvent: distilled water.

In the present invention, the crystallization process using the mixed solvent for crystallization is preferably carried out at 0 to 5 ℃. If the temperature is below 0 ° C., the production of hydrates is hindered. If the temperature is above 5 ° C., the product may be dissolved in the solvent again.

The present invention provides a carbapenem-based advanced antibiotic, meropenem.3H2O ((1R, 5S, 6S) -2-[(2'S, 4'S)-(2'-dimethylaminocarbonyl) pyrrolidine-4'-ylthio] -6-[(R ) -1-hydroxy ethyl] -1-methyl-carbapen-2-em-3-apen-2-em-3-carboxylic acid, molecular weight = 437.47).

The present invention synthesizes M-2-phosphate, which is a key step in the preparation of meropenem trihydrate, with a proline derivative, as shown in Scheme 2, and the meropenem precursor represented by Chemical Formula 1 [4-nitrobenzyl (5S, 6S)- 3-[((3S, 5S) -5-[(dimethylamino) carbonyl] -1-{[(4-nitrobenzyl) oxy] carbonyl} pyrrolidinyl) sulfanyl] -6-[(1R) -1-hydroxyethyl-7- carboxyl protecting group at C-3 position of oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate, molecular weight = 697.73] and p-nitrobenzyl group protecting carboxyl group of pyrrolidine Removal provides a method for mass production of meropenem trihydrate at low cost with high yield and high purity.

To describe the core technology of the present invention in more detail, after dissolving the meropenem precursor, which is the core intermediate of meropenem, in a mixed solvent in which an aromatic solvent such as cresol and toluene is formed in an appropriate ratio, and raising the temperature to 70 to 80 ℃ 1 To 3 hours.

Next, the mixture was stirred with ethyl acetate and water, an aqueous alkali solution such as an aqueous sodium bicarbonate solution was added to adjust the pH to 9-12, and the water layer was separated. Then, an organic solvent such as cresol remaining in the aqueous layer was mixed with ethyl acetate. After washing 2-3 times with the same organic solvent to remove the remaining cresol, etc. If impurities are present in the celite (Celite) filtration to remove the foreign matter.

Next, the pH was adjusted to 1 to 4 by adding a weakly acidic aqueous solution such as dilute hydrochloric acid to the aqueous layer, and then extracted with a solvent such as ethyl acetate and ethanol, and then the extracted organic solution was washed 1 to 2 times with saturated brine. After 2/3 to 3/4 of the solution by distillation under reduced pressure to remove the organic solvent.

Next, if the residual solution is slowly added dropwise with strong stirring in a solvent in which a solvent of chloromethane, such as methylene chloride and chloroform, which has been cooled to about 0 to 5 ° C. in advance, and acetone, isopropyl alcohol, and distilled water is mixed appropriately, Meropenem trihydrate is obtained as white crystals.

Next, the resulting crystals were further stirred at 0 to 5 ° C., filtered, washed with methylene chloride and acetone, and then dried under reduced pressure at 30 to 40 ° C. to obtain pure meropenem trihydrate of white crystals.

The present invention is a novel high value-added technology that solves the problems of the prior art, and can effectively remove the p-nitrobenzyl group, which is a carboxyl protecting group of a carbapenem-based imine compound, and obtains a crystalline meropenem trihydrate from a meropenem precursor. It is a very useful invention for industrialization as it can be produced in high yield by shortening the process from 2 to 1 step.

Example 1

20 g of meropenem precursor (0.29 mmol) was dissolved in 50 ml of metacresol and 10 ml of toluene and the temperature was heated to 75 ° C. After stirring for 1.5 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous sodium bicarbonate solution was added to raise the pH to about 10. The aqueous layer was separated, and then the aqueous layer was washed 2-3 times with 20 ml of ethyl acetate. Residual metacresol was removed.

6 N hydrochloric acid was added to the solution to lower the pH to 2, and then the reaction product was extracted two to three times with 50 ml of ethyl acetate. The organic solvent was removed by distillation under reduced pressure. The remaining solution was added dropwise to 50 ml of a mixed solvent of methylene chloride, acetone, and distilled water (50: 45: 5) that had been cooled to about 0 to 5 ° C in advance to obtain a white precipitate.

The mixture was stirred for about 30 minutes more, filtered, washed twice with 10 ml of a mixed solvent of methylene chloride and acetone (50:50), and dried under reduced pressure at 30 to 40 ° C. to give 11.99 g (yield: 94.5%) of crystalline merope. Nem trihydrate was obtained.

'H-NMR (D ₃ O ₄ ): 1.22 (3H, d, J = 6.7 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.91 (1H, m), 3.01 (3H, s), 3.07 (3H, s), 3.30-3.49 (3H, m), 3.66 (1H, m), 4.05 (1H, m), 4.21-4.29 (2H, m)

UVλ nm 295

IR (KBr) Cm ^- 3400, 1750, 1650

Example 2

20 g of meropenem precursor (0.29 mmol) was dissolved in 50 ml of metacresol and 10 ml of xylene and the temperature was heated to 75 ° C. After stirring for 2 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous sodium bicarbonate solution was added to raise the pH to about 10. The aqueous layer was separated, and then the aqueous layer was washed 2-3 times with 20 ml of ethyl acetate. Residual metacresol was removed.

6 N hydrochloric acid was added to the solution to lower the pH to 2, and then the reaction product was extracted two to three times with 50 ml of ethyl acetate. The extracted organic solution was washed one to two times with saturated brine, and then about 3/4 of the solution was added. The organic solvent was removed by distillation under reduced pressure. The remaining solution was dispersed dropwise into 50 ml of a mixture of methylene chloride, acetone, and distilled water (50: 45: 5) that had been cooled to about 5 ° C in advance to obtain a white precipitate.

After stirring for about 30 minutes more, it was filtered, washed sequentially with 10 ml of methylene chloride and 10 ml of 10 ml of acetone, and then dried under reduced pressure at 30 to 40 ° C to give 11.84 g (yield: 93.3%) of crystalline meropenem trihydrate. Got it.

Example 3

20 g of meropenem precursor (0.29 mmol) was dissolved in 50 ml of metacresol and 10 ml of benzene and the temperature was heated to 70 ° C. After stirring for 2.5 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous sodium bicarbonate solution was added to raise the pH to about 10. The aqueous layer was separated, and the aqueous layer was washed 2-3 times with 20 ml of ethyl acetate. Residual metacresol was removed.

6 N hydrochloric acid was added to the solution to lower the pH to about 2, and then the reaction product was extracted twice with 50 ml of ethyl acetate. The extracted organic solution was washed twice with saturated brine, and the solution was distilled under reduced pressure. Solvent was removed. The remaining solution was dispersed dropwise into 50 ml of a mixture of methylene chloride, acetone, and distilled water (50: 45: 5) that had been cooled to about 5 ° C in advance to obtain a white precipitate.

The mixture was stirred for about 30 minutes more, filtered, washed sequentially with 10 ml of methylene chloride and 10 ml of acetone, and dried under reduced pressure at 30 to 40 ° C. to obtain 11.29 g (yield: 89.1%) of crystalline meropenem trihydrate.

'H-NMR (D ₃ O ₄ ): 1.22 (3H, d, J = 6.7 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.91 (1H, m), 3.01 (3H, s), 3.07 (3H, s), 3.30-3.49 (3H, m), 3.66 (1H, m), 4.05 (1H, m), 4.21-4.29 (2H, m)

UVλ nm 295

IR (KBr) Cm ^- 3400, 1750, 1650

Example 4

20 g of meropenem precursor (0.29 mmol) was dissolved in 60 ml of metacresol and 20 ml of toluene and the temperature was heated to 70 ° C. After stirring for 2.5 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous solution of sodium bicarbonate was added to raise the pH to about 10. The aqueous layer was separated, and the aqueous layer was washed three times with 25 ml of ethyl acetate. Metacresol was removed and impurities were removed by celite filtration.

6 N hydrochloric acid was added to the solution to lower the pH to 2, and then the reaction product was extracted two or three times with 50 ml of ethyl acetate. The extracted organic solution was washed twice with saturated brine, and about 4/5 of the solution was removed. The organic solvent was removed by distillation under reduced pressure. The remaining solution was added dropwise to a mixed solvent composed of 30 ml of methylene chloride, 3 ml of distilled water, and 15 ml of acetone, which had been cooled to about 5 ° C. in advance, to form white crystals. After stirring, the mixture was filtered, washed twice with 10 ml of methylene chloride and 10 ml of acetone, and then dried under reduced pressure at 40 ° C. to obtain 12.18 g (yield: 96%) of crystalline meropenem trihydrate.

Example 5

20 g of meropenem precursor (0.29 mmol) was dissolved in 50 ml of metacresol and 10 ml of toluene and the temperature was heated to 75 ° C. After stirring for 2 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous solution of sodium bicarbonate was added to raise the pH to about 10. The aqueous layer was separated, and the aqueous layer was washed twice with ethyl acetate. The impurities were removed by celite filtration.

6 N hydrochloric acid was added to the solution to reduce the pH to 2, and then the reaction product was extracted two to three times with 50 ml of ethyl acetate. The extracted organic solution was washed twice with saturated brine, and the solution was distilled under reduced pressure about 3/4 of the solution. To remove the organic solvent. The remaining solution was added dropwise to a mixed solvent composed of 30 ml of methylene chloride, 5 ml of distilled water, and 10 ml of isopropyl alcohol, which had been cooled to about 5 ° C in advance, to obtain white crystals.

The mixture was further stirred at 5 ° C. for about 30 minutes, filtered, washed sequentially with 10 ml of methylene chloride and 10 ml of acetone, and dried under reduced pressure at 40 ° C. to give 11.74 g (yield: 92.5%) of crystalline meropenem trihydrate. Got.

Example 6

20 g of meropenem precursor (0.29 mmol) was dissolved in 50 ml of metacresol and 10 ml of xylene, heated at 75 ° C. for 2 hours, and stirred with addition of 30 ml of ethyl acetate and 30 ml of water, followed by carbonic acid. Aqueous solution of sodium hydrogen was added to raise the pH to about 10, and the aqueous layer was separated. The aqueous layer was washed three times with ethyl acetate to remove residual metacresol, and impurities were removed by Celite filtration.

6 N hydrochloric acid was added to the solution to lower the pH to 2, and then the reaction product was extracted three times with 50 ml of ethyl acetate. The extracted organic solution was washed twice with saturated brine, and then distilled under reduced pressure to about 4/5 of the solution. Solvent was removed. The remaining solution was dispersed dropwise into a mixed solvent composed of 40 ml of chloroform, 5 ml of distilled water, and 10 ml of acetone, which had been cooled to about 5 ° C in advance, to obtain white crystals.

After further stirring at about 5 ° C. for about 30 minutes, the mixture was filtered, washed twice with 10 ml of a mixture of methylene chloride and acetone (50:50), and dried under reduced pressure at 35 ° C. to obtain 11.99 g (yield: 94.5%) of crystalline form. Meropenem trihydrate was obtained.

'H-NMR (D ₃ O ₄ ): 1.22 (3H, d, J = 6.7 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.91 (1H, m), 3.01 (3H, s), 3.07 (3H, s), 3.30-3.49 (3H, m), 3.66 (1H, m), 4.05 (1H, m), 4.21-4.29 (2H, m)

UVλ nm 295

IR (KBr) Cm ^- 3400, 1750, 1650

Example 7

20 g of meropenem precursor (0.29 mmol) was dissolved in a mixed solvent composed of 50 ml of metacresol and 5 ml of toluene and benzene, respectively, and the temperature was heated to 75 ° C. After stirring for 2 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous solution of sodium bicarbonate was added to raise the pH to about 10. The aqueous layer was separated, and the aqueous layer was washed three times with ethyl acetate. The impurities were removed by celite filtration.

6 N hydrochloric acid was added to the solution to lower the pH to 2, and then the reaction product was extracted three times with 50 ml of ethyl acetate. The extracted organic solution was washed twice with saturated brine, and the solution was distilled under reduced pressure to about 3/4 of the organic solvent. Solvent was removed. The residual solution was dispersed dropwise into a mixed solvent composed of 40 ml of carbon tetrachloride, 5 ml of distilled water, and 10 ml of acetone, which had been cooled to about 5 ° C. in advance, to obtain white crystals.

After stirring for about 30 minutes at 5 ℃, filtered and washed sequentially with 10 ml of methylene chloride and 10 ml of acetone, and dried under reduced pressure at 40 ℃ to obtain 11.79 g (yield: 93%) of crystalline meropenem trihydrate. .

Example 8

20 g of meropenem precursor (0.29 mmol) was dissolved in 60 ml of metacresol and 5 ml of xylene and the temperature was heated to 75 ° C. After stirring for 3 hours, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, followed by stirring. Then, an aqueous sodium bicarbonate solution was added to raise the pH to about 10. The aqueous layer was separated, and the aqueous layer was washed three times with 30 ml of ethyl acetate. Metacresol was removed and impurities were removed by celite filtration.

6 N hydrochloric acid was added to the solution to lower the pH to 2, and then the reaction product was extracted three times with 50 ml of ethyl acetate. The extracted organic solution was washed twice with saturated brine, and the solution was distilled under reduced pressure to about 3/4 of the organic solvent. Solvent was removed. The remaining solution was dispersed dropwise into a mixed solvent composed of 20 ml of methylene chloride, 5 ml of distilled water, and 20 ml of acetone, which had been cooled to about 5 ° C in advance, to obtain white crystals.

The mixture was further stirred at 5 ° C. for about 30 minutes, filtered, washed sequentially with 10 ml of methylene chloride and 10 ml of acetone, and dried under reduced pressure at 40 ° C. to obtain 11.84 g (yield: 93.3%) of crystalline meropenem trihydrate. Got it.

'H-NMR (D ₃ O ₄ ): 1.22 (3H, d, J = 6.7 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.91 (1H, m), 3.01 (3H, s), 3.07 (3H, s), 3.30-3.49 (3H, m), 3.66 (1H, m), 4.05 (1H, m), 4.21-4.29 (2H, m)

UVλ nm 295

IR (KBr) Cm ^- 3400, 1750, 1650

The present invention provides a method for industrially and simply and economically removing p-nitrobenzyl, p-methoxybenzyl, and the like, which are commonly used to protect carboxyl groups or amino groups in the synthesis of meropenem precursor compounds, and meropenem trihydrate. In the manufacturing process, the freeze-drying method or the purification method by column chromatography is used instead of the precipitation method using a simple mixed solvent, which greatly improves the yield of the target substance meropenem trihydrate, and is very simple in industry. It provides a new manufacturing method that can greatly reduce the production cost.

Claims (6)

After reacting the meropenem precursor represented by the formula (1) with a deprotected mixed solvent composed of cresol and an aromatic solvent to remove the p-nitrobenzyl group, which is a carboxyl protecting group of the meropenem precursor , at least one meropenem selected from methylene chloride and chloroform A method for producing meropenem, characterized by obtaining a trihydrate crystal of meropenem represented by the formula (2) by dropwise addition to a mixed solvent for crystallization comprising an insoluble solvent and a meropenem soluble solvent of acetone or isopropyl alcohol . [Formula 1]

[Formula 2]

The method of claim 1, wherein the cresol is metacresol, and the aromatic solvent is one or more selected from toluene, benzene, and xylene. The method of claim 1, wherein the deprotection group reaction of the meropenem precursor is performed at 70 to 80 ° C. for 1 to 3 hours. delete The method of claim 1, wherein the mixed solvent for crystallization is meropenem insoluble solvent: meropenem soluble solvent: distilled water 50: 45: 5. The method of claim 1, wherein the crystallization process by the mixed solvent for crystallization is carried out at 0 to 5 ℃.