WO2007104221A1

WO2007104221A1 - A process for the preparation of meropenem

Info

Publication number: WO2007104221A1
Application number: PCT/CN2007/000399
Authority: WO
Inventors: Hengli Zhang
Original assignee: Shenzhen Haibin Pharmaceutical Co., Ltd.
Priority date: 2006-03-14
Filing date: 2007-02-06
Publication date: 2007-09-20

Abstract

The invention relates to a process for the preparation of meropenem, a β-methylcarbopenem. The said process comprises the following steps: preparing the compound of Formula (XI) from the compound of Formula (IV) through three steps 'one-pot process'; then condensing the compound of Formula (XI) with the compound of Formula (XX) to form the compound of Formula (XXIV); finally preparing meropenam of Formula (I) from the compound of Formula (XXIV) by deprotection reaction by means of catalyst. The process of the invention is easily to carry out, the product is isolated in high content and yield, and the cost is reduced, thereby overcoming the shortage of the prior art.

Description

A PROCESS FOR THE PREPARATION OF MEROPENEM

Field of the invention

The invention relates to a process for the preparation of β -methylcarbapenem antibiotic, particularly to the process for the preparation of meropenem.

Background of the invention

So far, β -lactamase inhibitors have been extensively reported. Base on their chemical structure, those inhibitors may be divided into several classes such as oxapenams (or clavams), penems, carbapenems and monocyclic β -lactam clavams, wherein carbapenems, especially β -methylcarbapenem such as Imipenen, Meropenem, and Biapenem have shown excellent antibacterial action against a variety of resistant bacteria, especially against enzymes of type B , and are specific inhibitors against β -lactamase. The study on the synthesis of carbapenem or penem derivates which are similar to thienamycin has been extensively developed since the fact that thienamycin has potential antibacterial activity against Gram-negative and Gram-positive bacteria was discovered.

Currently, there are several commercially available carbapenems and β -methylcarbapenem, such as (4R,5S,6S,8R2'S,4'S)-3-[2-dimethylaminocarbonyl] pyrrolidinylthio]-4-methyl-6-(l-hydroxyethyl)-l-azabicyclye[3,2,0]hept-2-ene-7-one-2-carboxyli c acid (Meropenem) (I) of Sumitomo Pharmaceuticals Co., Ltd.;

( I) N-iminomethylthiomycin (Imipenen) (II) of Merck & Co., Inc.;

( II)

(1 R,5S,6S)-2-[(6,7-dihydroxyl-5H-pyrazolo [1 ,2-a] [1 ,2,4]triazolium-6~yl)]thio-6-[R- 1 -hydr oxyethyl]-l-methyl-carbapen-2-em-3-carboxylate (III) (biapenem) of Lederle Ltd., and the like.

N

( III) There are a variety of synthetic routes of β -methylcarbapenems, and the reaction route A of Sumitomo Pharmaceuticals Co., Ltd. (USP4933333) is depicted as follow:

( XI)

the reaction route B of Lederle Ltd. (USP4990613) is depicted as follow:

(XI)

As for the route of Sumitomo Pharmaceuticals Co., Ltd. as described above, the raw material is easily obtained, but there are substantive amount of optical isomers of Compound (V) required to be isolated, and thereby influencing the yield. As for the route of Lederle Ltd., the reaction steps are relatively simple, but the raw material is difficult to obtain, and the cost is more expensive.

In the synthesis of 4-thiolpyrrolidine derivates (the side chain of meropenem), Sumitomo Pharmaceuticals Co., Ltd. employed the reaction route C (USP4933333):

The route need more steps and is difficult to obtain targeted product with high purity.

In view of the step of condensation between core and side chain of carbapenem and deprotection, the condensation product has a purity of about 75% in most processes, or needs to be purified by column chromatography on silica gel to give purer product. In the step of deprotection by hydrogenation, the buffer solution of morpholine propanesulfonic acid (MOPS) is generally required, and also the macromolecular resin is required for purification. However, such steps would affect the final yield.

Summary of the invention

The purpose of the present invention is to provide a process for preparing of meropenem. The process is easily to carry out, the product is isolated in high content and yield, and the cost is reduced, thereby overcoming the shortage of the prior art.

The process for preparing of meropenem in the invention comprises the following steps: a) Reacting the compound of Formula (IV) with the compound of Formula (XV) to obtain the compound of Formula (VI); b) Preparing the compound of Formula (IX) from the compound of Formula (VI); c) Preparing the compound of Formula (XI) from the compound of Formula (IX); d) Reacting the compound of Formula (IX) with the compound of Formula (XX) to form the compound of Formula (XXTV); e) Converting the compound of Formula (XXIV) to meropenem of Formula (I) in the presence of catalyst.

In the process of the present invention, three steps of "one-pot process" are employed to obtain the compound of Formula (XI), and the particular steps are: a) reacting the compound of Formula (IV) with the compound of Formula (XV) to obtain the compound of Formula (XVI); using either reactant solution or condensate thereof in the next step without further separation to allow the compound of Formula (XIV) to be hydrolyzed into the compound of Formula (VI).

The reaction equation as follows:

in the above reaction, the raw 4-acetyl azetidinone (IV) initially reacts with α -bromopropionamide(XV). The reaction has good stereoselectivity, and mainly give targeted compound with β -configuration, thereby improving the prior process and increasing the yield.

The first step can be carried out by means of a variety of known methods (e.g., Tanabe Seiyaku Co., Ltd, USP: 5,847,115), and the separation methods are varying depending on different type of reaction after the reaction is completed. Toluene, which has relatively weak polarity, is added to the reaction solution. The organic phase is washed with 4N of hydrochloric acid to be acidic, then with brine. The organic phase is used directly for the next step.

The second step can be carried out by means of a variety of known methods, or by the following process: hydrogen peroxide and lithium hydroxide are added to the organic solution in above step and it is subjected to hydrolysis; after the hydrolysis, the reactant is adjusted to be acidic and the aqueous layer containing much hydrogen peroxide is separated; then the aqueous layer is adjusted to basic again, and sodium sulfite is added to reduce the remaining hydrogen peroxide; after filtration to remove spiro-cyclic compound, the filtrate is washed with organic solvent to remove the organic material, then hydrochloric acid is added to precipitate the crystals of compound (VI). The process combined such two steps increases the yield remarkably. b) preparing the compound of Formula (VII) from the compound of Formula (VI), preparing the compound of Formula (VIII) from the reaction solution with the compound of Formula (VII) or concentrate thereof which is not further separated, and preparing the compound of Formula (IX) from the reaction solution with the compound of Formula (VIII) or concentrate thereof which is not further separated The reaction equation as follows:

In the above synthetic reaction, the first step can be carried out by means of a variety of known methods (e.g., authentic reagents and methods). After completion of the reaction, the solution of ethyl acetate is used in the next step without further separation. The second step can be carried out by means of a variety of known methods, with the improvement in reacting directly in the above solution. After completion of the reaction, the solution is condensed and the concentrate is used in the next step without further separation. The third step can be carried out by means of a variety of known methods. After completion of the reaction, the solution is condensed and purified column chromatography on silica gel. The process combined such three steps increases the yield remarkably. c) preparing the compound of Formula(X) from the compound of Formula (IX), and preparing the core (XI) of β -methyl carbapenem from the reaction solution with the compound of Formula (VII) or concentrate thereof;

The reaction equation as follows:

(XI)

In the above synthetic reaction, the solvent in the first step is one or more than one kind of solvents selected from a group consisting of ethyl acetate, tetrahydrofunan, and methylene chloride. The amount of the solvent is from 1 to 10 times of the amount of compound (IX) by volume, preferably from 3 to 5 times. Rhodium acetate or rhodium caprylate is used as catalyst, and its amount is from 0.1% to 1% of compound (IX) by molar, preferably from 0.25% to 0.5%. The temperature of the reaction is from 25 ^°C to 100^°C.

The inert solvent employed in the second reaction is one or more than one kind of solvents selected from a group consisting of dioxane, tetrahydrofunan, dimethyl formamide, dimethyl sulfoxide, acetonitrile and hexamethyl phosphoramide, preferably acetonitrile and dimethyl formamide.

The bases used in the reaction are those ionic compounds that generate negative ions, which are all hydroxide radicals, when ionizing, and may include various organic and inorganic bases, for example inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, and the like; organic base such as potassium tert-butoxide, pyrimidine, various dimethyl pyridine, 4-dimethyl aminopyridine, triethylamine, diisopropylethylamine, and the like. Among which, organic bases such as diisopropyl amine, triethylamine and diisopropylethylamine are preferred. In one preferred embodiment of the present invention, diisopropylethylamine is selected as the base used in the reaction. The amount of base employed in the reaction should be sufficient to complete the reaction, and generally is from 1 to 2 equivalents per molar thiol derivate (IX), preferably from 1 to 1.5 equivalents per molar.

The inducing reactant of enol ester is diphenyl chlorophosphate, which amount employed in the reaction should be sufficient to complete the reaction and generally is from 1 to 2 equivalents per molar Compound (IX)₅ preferably from 1 to 1.2 equivalents per molar.

The reaction temperature is from -20 °C to 50 °C, preferably from -10^°C to O⁰C .

In the process of the present invention, step d) is a condensation reaction of β -methyl carbapenem with 4-thiolpyrrolidine derivate (XX). Its reaction product (XXTV) can produce targeted compound (meropenem) through deprotection by hydrogenation.

In Step d), the inert solvent employed in the reaction can be selected from one or more the following solvent: dioxane, tetrahydrofunan, dimethyl formamide, dimethyl sulfoxide, acetonitrile, hexamethyl phosphoramide, preferably acetonitrile and dimethyl formamide. The bases used in the reaction are those ionic compounds that generate negative ions, which are all hydroxide radicals, when ionizing, and generally may include various organic and inorganic bases, for example inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, and the like; organic bases such as potassium tert-butoxide, pyrimidine, various dimethyl pyridine, 4-dimethyl aminopyridine, triethylamine, diisopropylethylamine, and the like. Among which, organic bases such as diisopropyl amine, triethylamine and diisopropylethylamine are preferred. In one preferred embodiment of the present invention, diisopropylethylamine is selected as the base used in the reaction.

The amount of base employed in the reaction should be sufficient to complete the reaction, and generally is from 1 to 2 equivalents per molar thiol derivate (XX). The amount of thiol derivate (XX) employed in the reaction should be sufficient to complete the reaction, can be excessive, but generally is from 1 to 2 equivalents on the base of Compound (XI).

The reaction is carried out at a temperature of -78 °C to 60⁰C, and preferably -40 ^°C to 40.

After the reaction is completed, the reaction product can be obtained by conventional organic chemistry method.

In Step e), the reaction of removal protecting group is a catalytic reduction reaction in which catalyst is employed, the said catalyst may be platinum or palladium on carbon.

The solvent used in the reaction is organic solvent or aqueous organic solvent. The said organic solvent is selected from alcohols, ethers, organic acids, etc., and may be a single solvent or a mixture thereof. Among which, alcohols may be selected from methanol, ethanol and other lower alcohols, ethers may be selected from tetrahydrofunan, dioxane, etc., and organic acids may be selected from acetic acid, etc..

The bases used in the reaction are those ionic compounds that generate negative ions, which are all hydroxide radicals, when ionizing, And generally may include various organic and inorganic bases, for example organic bases such as N-dimethylaniline, 2,6-dimethylpyridine, etc.; for example inorganic bases such as sodium bicarbonate, potassium bicarbonate, etc. The base added in the reaction can adjust pH and its amount is from 1 to 10 equivalents of the compound (XXIV), preferably from 1 to 4 equivalents.

The reaction is carried out in the hydrogen atmosphere at atmospheric pressure or elevated pressure at a temperature of 0 "C to 100 ^°C , preferably 0⁰C to 40 ^°C .

According to another aspect of the present invention, there is provided a process for preparing of meropenem, wherein the compound (XXIV) is directly prepared from compound (IX) by one-pot synthetic method, and the synthetic route as follow:

( XXIV) each step in the above synthetic route uses the essentially same reaction condition as that in the same reaction above. For example, preparing the compound of Formula (XI) from the compound of Formula (IX) and preparing the compound of Formula (XXIV) directly from the reaction solution or concentrate thereof without further separation. After the completion of whole three reaction, the reaction product (XXIV) is isolated by.

1. The reactant is diluted with hydrophobic organic solvent, and the solvent may be one or more than one kinds of solvents selected from the group consisting of ethyl acetate, methyl ene chloride, and diisopropyl, etc.; i o 2. the organic phase is washed with phosphate buffer solution of pH 5 to 6 for from 5 to 6 times, then with brine, dried with anhydrous magnesium sulfate, and after condensation is used as the raw material of the next step; 8-15 equivalent volume of ethyl acetate based on Compound

(IX) can also be added, then compound (XXIV) is added as crystal seed and allow to crystal under stirring.

The synthesis of 4-thiolpyrrolindine derivates of the present invention (meropenem side chain), i.e. the compound of formula (XX), can be carried out by various methods, preferably, is prepared from trans-4-hydroxyl-L-proline, according to the following synthetic route:

1). preparing the compound of formula (XXV) from the compound of formula (XXVI); T). preparing the compound of formula (XXI) from the compound of foπnula (XXV);

3). preparing the compound of formula (XXII) from the compound of formula (XXI); 4). preparing the compound of formula (XEX) from the compound of formula (XXII); 5). preparing the compound of formula (XXIII) from the compound of formula (XIX); 6). preparing the compound of formula (XX) from the compound of formula (XXIII); and the synthetic route is:

CXXII) (XIX)

Step 1): The reaction can be carried out by various known methods, generally, by the methods to protect the amino of amino acid, for example, to react with p-nitro-benzyl chloroformate in the present of bases. Step T) : The reaction can be carried out by various known methods. The carboxyl react with, i i for example, isopropyl chloroformate to give reaction-active derivates, then it react with dimethylamine or hydrochloride thereof in the presence of organic base to generate amido.

Step 3), 4): The reaction can be carried out by various known methods. The hydroxyl group is converted into protected thiol group. For example, the hydroxyl of (XXI) is converted into active mesylate (XXII), then reacts with various sulfur compounds such as potassium thioacetate, triphenyl methanthiol, and the like.

The step can also be carried out by the reaction of alcohol derivates with sulfur compounds in inert solvent (such as tetrahydrofuran, etc.) and in the present of triphenylphosphine and diethyl azodicarboxylate. Step 5): In this step, the removal of thio protecting group and the oxidation of sulfide is carried out at the same time to produce stable disulfide crystal ( XXIII). the reaction is carried out in the presence of nickel acetate and in inert solvent (such as tetrahydrofuran etc.).

Step 6): Disulfide crystal (XXIII) is reduced by tributylphosphine into thiol derivates in the presence of nickel acetate. The invention take the following advantages by comparison to the prior art:

1. In the present invention, compound (XXIV) can be obtained by one-pot process from compound (IX); compound (IX) can be obtained by one-pot process from compound (VI); and compound (VI) can be obtained by one-pot process from compound (FV). The method can obtain the product in one reaction, whereas which requires multiple reactions previously, thus greatly shortens the reaction period, increases efficiency of productivity, decreases the costs in industrialization, reduces the kinds and the amount of the solvents used, reduces environmental pollution and decreases the commercial production costs.

2. The process of the present invention can be easily carried out, the product is readily separated, and the purity and yield of the product is increased. 3. The starting material used in the invention is readily obtained, thereby saving production costs.

The invention will be further illustrated in detail by the following drawings and specific embodiments for the purpose of better understanding. The scope of the present invention is not limited by these examples. Detail description of the invention

The experimental material, unless other specified, is commercially available.

I Example 1 ] Synthesis of (4R,5S,6S)- 4-Nitrobenzyl-3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-l-[[(4-nitrobenzyl)oxy]carbonyl]-3-pyrr olidinyl]thio] -6- [( 1 R)- 1 -hydroxyethyl] -4-methyl-7-oxo- 1 -azabicyclo[3 ,2,0]hept-2-ene-2-carboxyl ate(XXTV). diazo-ketone ester [(IX). 4Og, 0.102mol] and ethyl acetate (200 ml) were added to a flask equipped with returning current condenser. The mixture was heated to 60⁰C, and rhodium octanoate (140 mg) was added. The mixture were strongly stirred for 30 min at the same temperature until the diazo-ketone ester reacted completely. The solution of 4- β -methyl azadicycloketo ester(X) was obtained. The reaction solution was used in the next step without separation.

To the above solution of 4- β -methyl azadicycloketo ester (X) was added acetonitrile (dry, 300 ml) and the mixture was cooled to -10 — -15⁰C in ice-salt bath. Diisopropylethanamine (14.57g, O.lBmol) and diphenyl chlorophosphonate (27.54g, 0.102mol) was then added. The mixture were stirred for 5 h at the same temperature until the 4- β -methyl azadicycloketo ester (X) reacted completely. Then,

[2S,4S]-l-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidne (XX) (34g, 0.096 mol) and diisopropylethamine (15.4g, 0.133mol) were added at the same temperature and the mixture was stirred for 5-8 h. After completion of the reaction, the reaction solution was diluted by ethyl acetate (500 ml) and washed with aqueous sodium phosphate monobasic solution. The organic phase was dried with anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue (75 g, quantified by HPLC containing 60 g of targeted compound, 84% yield) may be either directly used in the next step, or be crystallized as following: 250 ml ethyl acetate and then seed crystal was added and stirred at 10-15 ^°C for 3-5 h, then substantive crystals were precipitated, and the crystals were collected by filtration and dried, to obtain crystalline (4R,5S,6S)-

4-Nitrobenzyl-3 - [[(3 S ,5 S)-5- [(dimethylamino)carbonyl] - 1 - [[(4-nitrobenzyl)oxy] carbonyl] -3 -pyrr olidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxyl ate (XXTV) (53.4g, yield 75%).

The physical data of compound (XXTV):

\R_max"^eat (cm ¹): 1780, 1745, 1705, 1650, 1605, 1515, 1342, 1257.

NMR 5 (CDCl₃): 1.49(3H, d, J=6 Hz), 2.99(3H, s), 3.11(3H, s), 5.25(4H, s), 5.23 ^P 5.46(2H, ABq, J=14 Hz), 7.53(4H, d, J=8.5 Hz), 7.62(2H, d, J=8.5 Hz), 8.18(6H, d, J=8.5 Hz).

[ α ]z)²⁸ + 7.7° (c=0.303, acetone)

[ Example 2 ] Synthesis of (4R,5S,6S)- 3-[[(3S,5S)-5-[(dimethylamino)carbonyl]- 3 -pyrrolidinyl]thio]-6-[(l R)- 1 -hydroxyethyl] -4-methyl-7-oxo- 1 -azabicyclo [3 ,2,0]hept-2-ene-2-ca rboxylic acid (I) (4R,5S,6S)- 4-Nitrobenzyl-3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-l-[[(4- nitrobenzyl)oxy] carbonyl] -3 -pyrrolidinyl] thio] -6- [( 1 R)- 1 -hydroxyethyl] -4-methyl-7-oxo- 1 -azabic yclo[3,2,0]hept-2-ene-2-carboxylate (XXIV) (the resulting residue in the previous step) (15 g, quantified by HPLC containing 12.5 g of the said compound) was dissolved in tetrahydrofunan (250 ml), and water (200 ml) was added while stirring. The solution was put into 1 L autoclave, and 2,6-dimethylpyridine (5.5 g) and Pa/C (2 g, 10%) were then added. The resulting mixture was hydrogenated at hydrogen gas pressure of 1.8 MPa for 1 h. The catalyst was removed by filtration, the filtrate was diluted with acetone (800 ml) and seed crystals were added at 5°C to 15 ⁰C. After 30 min, substantive crystals were precipitated. Acetone (400 ml) was added dropwise at the same temperature. After the mixture was stirred for 30 min, the crystals were collected by filtration and washed with acetone (50 ml). The crystals were dried at 40 ^°C under vacuum to give trihydrate of (4R,5S,6S)- 3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-

3-pyrrolidinyl]thio]-6-[( 1 R)- 1 -hydroxyethyl] -4-methyl-7-oxo- 1 -azabicyclo [3 ,2,0]hept-2-ene-2-ca rboxylic acid (I) as light yellow crystal (5.1 g, yield 65%).

The physical data of compound (I): W_max ^mow&: 297

1755, 1627, 1393, 1252, 1130.

NMR δ (D₂O): 1.25(3H, d, J=6.4 Hz), 1.81-1.96(1H, m), 2.96(3H, s), 3.03(3H, s), 3.14-3.20 (3H, m), 3.31-3.41(2H, m), 3.62-3.72(1H, m), 3.90-4.00(1H, m), 4.14-4.26(2H, m), 4.63(1H, t, J=8.5 Hz). [ Example 3 ] Synthesis of (4R.5S.6S)- 3-[[(3S,5S)-5~[(dimemylamino)carbonyl]- 3-pyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-ca rboxylic acid (I)

(4R,5S,6S)- 4-Nitrobenzyl-3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-l-[[(4- nitrobenzyl)oxy] carbonyl]-3 -pyrrolidinyljthio] -6- [( 1 R)- 1 -hydroxyethyl]-4-methyl-7-oxo~ 1 -azabic yclo[3,2,0]hept-2-ene-2-carboxylate (XXIV) (1Og, the crystal in the example 1) was dissolved in tetrahydrofunan (250 ml), and water (200 ml) was added while stirring. The solution was put into 1 L autoclave, and 2,6-dimethylpyridine (5.5 g) and Pa/C (2 g, 10%) were then added. The resulting mixture was hydrogenated at hydrogen gas pressure of 1.8 MPa for 1 h. The catalyst was removed by filtration, the filtrate was diluted with acetone (800 ml) and seed crystal was added at 5- 15 "C. After 30 min, substantive crystals were precipitated. Acetone (400 ml) was added dropwise at the same temperature. After the mixture was stirred for 30 min, the crystals were collected by filtration and washed with acetone (50 ml). The crystals were dried at 40 °C under vacuum to give trihydrate of (4R,5S,6S)- 3-[[(3S,5S)-5-[(dimethylamino)carbonyl]- 3 -pyrrolidinyl]thio]-6- [( 1 R)- 1 -hydroxy ethyl] -4-methyl-7-oxo- 1 -azabicyclo [3 ,2,0]hept-2-ene-2-ca rboxylic acid (I) as light yellow crystal (4.5 g, yield 71.8%). The physical data of compound (I):

IR,,^ cm^"1: 1755, 1627, 1393, 1252, 1130. NMR δ (D₂O): 1.25(3H, d, 1=6.4 Hz), 1.81-1.96(1H, m), 2.96(3H, s), 3.03(3H, s),

3.14-3.20 (3H, m), 3.31-3.41(2H, m), 3.62-3.72(1H, m), 3.90-4.00(1H, m), 4.14-4.26(2H, m), 4.63(1H, t, J=8.5 Hz).

[Example 4] Synthesis of (3S,4R)-3-[(lR)-l-hydroxyethyl] -4-[(lR)-l-methyl-3-diazo-4- [(4- nitrobenzyl)oxy] -2,4-dioxobutyl] azetidin-2-one (IX) (3S,4S)-4-[(lR)-l-methyl-l-carboxyethyl]-3-[(lR)-l-(t-butyldimethylsilyloxy) ethyl] -2-azetidinone (VI) (25g, 86mmol) was added to anhydrous acetonitrile (300 ml), to which was added carbonyldiimidazole (17.5g, llOmmol) with stirring. After the mixture was stirred at room temperature for 30 min, anhydrous magnesium mono-p-nitrobenzyl malonate (55.5 g, 110 mmol) was added. The reaction mixture was stirred at 25-35 °C for 18 h. After completion of the reaction, to the reaction mixture was added ethyl acetate (450 ml) and hydrochloric acid (450 ml, IN) to acidify the aqueous phase at pH 2-3. The organic phase was washed successively with brine, aqueous potassium carbonate solution (5%), and brine. The ethyl acetate solution of (3S,4R)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-methyl-4-[(4- nitrobenzyl)oxy]-2,4-dioxobutyl]azetidin-2-one(VII) is obtained. The product could be used in the next step without separation.

To the above ethyl acetate solution of

(3S,4R)-3-[(lR)-l-t-butyldimethylsilyloxyethLyl]-4-[(lR)-l-methyl-4-[(4-nitrobenzyl)oxy]-2,4-di oxobutyl]azetidin-2-one( (VII) was added methanol (100 ml), then added hydrochloric acid (100 ml, 6N) at 20-25⁰C. The reaction mixture was stirred at the same temperature for 2 h. After completion of the reaction, saturated brine (500 ml) was added. The organic phase was further washed with sodium phosphate dibasic (10%, 2x500ml), then washed with saturated brine, dried with anhydrous magnesium sulfate, and condensed under vacuum. The concentrate was mainly (3S,4R)-3-[(lR)-l-hydroxyethyl]-4-[(lR)-l-methyl-4-[(4-nitrobenzyl)oxy]-2,4-dioxobutyl]azetid in-2-one (VIII). The product could be used in the next step without separation. The above concentrate was added to acetonitrile (140 ml) and stirred to dissolve.

Dodecylbenzene sulfonyl azide (30.3 g, 86 mmol) and triethylamine (9.6g, 95mmol) were then added and the reaction mixture was stirred for 2 hours. The organic phase was washed with hydrochloric acid (220 ml, 0.5 N), and then washed thoroughly with water and brine, dried with anhydrous magnesium sulfate, and concentrated under vacuum to give oil. Purification by column chromatography (elution: ethyl acetate : petroleum ether = 2 : l(v:v)) on silica gel (250 ml) gave (3S,4R)-3-[(lR)-l-hydroxyethyl] -4-[(lR)-l-methyl-3-diazo-4- [(4- nitrobenzyl)oxy]-2,4-dioxobutyl]azetidin-2-one (IX) (25g, 77.2% yield) as pale yellow crystal. The physical data of compound (I): [ α ]_D ²¹=-50.4° (c=2.5, CH₂Cl₂)

2140,1750, lq720, 1650.

NMR S (CDCl₃): 1.22(3H, d, J=6.0 Hz), 1.32(3H, d, J=6.0 Hz),2.38(lH, d, J=3.2 Hz), 2.92QH, dd, J=2.4, 7.6 Hz), 3.77 (IH, m), 3.86 (IH, m), 4.15(1H, m), 5.38(2H, s).5.90(lH,s), 7.57and 8.30(2H, m). [ Example 5 ] Synthesis of (3S,4R)-3-[(lR)-l-t-butyldimethylsilyloxyethyl] -4-[(1R)-I -methyl-1 -carboxyethyl]azetidin-2-one(VI) Zinc (34g, 0.523) powder was added in anhydrous tetrahydrofonan (60 ml), the mixture was heated to boiling, and the solution of(3S,4R)-4-acetyloxy-3-[(lR)-l-t-butyldimethylsilyloxyethyl]azetidin-2-one (IV) (50 g, 0.174 mol) and 3-(2-boropropyl)-spiro[2,3-dihydro-4H-l,3-benzooxazine-2_:,r-cyclohexyl]-4-one (XV) (90 g, 0.256 mol) in anhydrous tetrahydrofunan (180 ml) were then added at a speed sufficient to avoid burst boiling. The reaction mixture was refluxed for 30 min and then cooled to room temperature. To the reaction mixture was added 5 g celite, and the reaction mixture was filtered under vacuum. The filter residue was washed with appropriate amount of tetrahydrofunan, and the filtrate and the wash were combined. Toluene (60 ml) was added. To the mixture was added hydrochloride (200 ml, 2 N) to adjust pH 5-6, the organic phase was washed by brine twice. The solution of

3-{(2R)-2-[(3S,4R)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-2-ketoazetidin-4-yl]propyl}-spiro[2, 3-dihydro-4H-l,3-benzooxazine-2,l'-cyclohexyl]-4-one(XIV) in tetrahydrofunan-toluene was obtained. The mixture was used in the next step without separation. To the above reaction mixture was added tetrahydrofunan (150 ml) and the temperature was controlled at 1°C to 15°C. With stirring, to the mixture was added hydrogen peroxide (30%, 96 g), then lithium hydroxide monohydrate (21 g), and stirred at the same temperature for 3 h. After completion of reaction, to the reaction mixture was added hydrochloric acid (4 N, 130 ml) to adjust to pH 2. The organic phase was washed with brine (x 3). To the organic phase was added a solution of sodium hydroxide (6%, about 200 ml) to adjust to pH 10, then a solution of sodium sulfite (17%, about 50 ml) until the starch-KI paper are colorless. The mixture was filtered under vacuum, and the filter residue was washed with water for 3-4 times. The filtrate and the wash solution were combined. The aqueous phase was washed with ethyl acetate for 3 to 4 times and was evaporated under vacuum to remove ethyl acetate thoroughly. Then, to the reaction mixture was added hydrochloric acid (4 N) to adjust to pH 2, and substantive crystals was precipitated. The mixture was stirred at the same temperature for 2 h and filtered. The filter residue was washed with water, dried and yield

(3S,4R)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-methyl-l-carboxyethyl]azetidin-2-one (VI) (46 g, yield 87.7%) as white crystal. The physical data of compound (VI) : Mp: 146~147°C

IW*⁰'(cm^"1): 1740, 1465, 1330, 1255, 1043, 837.

NMR: 0.08(6H₃ s), 0.7(9H, s), 1.24(3H, d, J=T), 1.30(3H, d, J=7.5), 2.78(1H₅ m), 3.06(1H, m), 3.98(1H, m), 4.24(1H, m), 6.3T(IH, broad). C Example 6] Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-acetylthio-l-PNZ-pyrrolidine (XIX)

1. Synthesis of trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XV) L-hydoxyproline (XXVI) (26.2 g, 0.20 mol) was added to a solution of sodium hydroxide

(220 ml, 2N) and cooled to 0^°C to 5°C. The solution, of p-nitrobenzyl chloroformate dissolved in methylene chloride (40 ml) was added dropwise. After stirred at the same temperature for 1 h, the phase of methylene chloride was separated. The aqueous phase was washed with methylene chloride (70 ml) and acidified with concentrated sulfuric acid (36.6 g) at a temperature of 0°C to 5 °C . Substantive crystals were precipitated, collected by filtration under vacuum, washed with water, dried, and afford trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XXV) (57.8 g, yield 93%), m.p.: 134~135.5^°C.

2. Synthesis of (2S,4R)-2-dimethylaminocarbonyl -4-hydroxyl-l-PNZ-pyrrolidine (XXI)

To methylene chloride (150 ml) was added Compound (XXV) (31.0g, O.lmol), and triethylamine (15.2g, 0.15 mol) with stirring. At a temperature of -10°C to 0°C, isopropyl chlorocarbonate (18.4g, 0.15mol) was added. The mixture was stirred at the same temperature for 1 h, and then dimethylamine hydrochloride (16.3 g, 0.20 mol) was added . At a temperature of -10°C to 0°C, triethylamine (30.3 g, 0.30 mol) was added dropwise and the resulting mixture was stirred for 1 h. The reaction mixture was washed thoroughly with IN hydrochloride, brine, sodium bicarbonate (5%) and brine , dried with anhydrous magnesium sulfate, filtered ,and afford the solution of (2S,4R)-2-dimethylaminocarbonyl-4-hydroxyl-l-PNZ-pyrrolindine (XXI) in methylene chloride, which was used in the next step without further separation.

3. Synthesis of (2S,4R)-2-dimethylaminocarbonyl -4-mesyloxy-l-PNZ- pyrrolindine(XXH) To the solution of the above compound (XXI) in methylene chloride was added triethylamine (21.8 g, 0.24 mol). At a temperature of -10^°C to 0^°C, methylsufonyl chloride (16.8 g, 0.15 mol) was added dropwise, and the mixture was stirred at the same temperature for 1 h. The reaction mixture was washed thoroughly with brine, sodium bicarbonate (5%) and brine, dried with anhydrous magnesium sulfate, filtered, the filtrate was evaporated under vacuum to remove solvent, and the oily residue was recrystallized in methanol-petroleum ether (2:1, v/v) to give (2S,4R)-2-dimethylaminocarbonyl -4-mesyloxy-l-PNZ- pyrrolindine (XXII) (yield 73%) as white crystal, m.p. : 115~116°C. 4. Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-acetylthio-l -PNZ- pyrrolindine (XIX)

Compound (XXII) (20.8g, 0.05mol) and potassium thioacetate (8.55g, 0.075mol) was added to the mixed solvent of DMF (60 ml) and toluene (60 ml), and the resulting mixture was stirred at a temperature of 67 to 70 ^"C for 6 h. After cooling, the reaction mixture was diluted with toluene (300 ml) and water (200 ml). The aqueous phase was extracted with toluene. The combined organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, the filtrate was evaporated under vacuum to remove solvent, and afford (2S,4S)-2-dimethylaminocarbonyl -4-acetylthio-l -PNZ- pyrrolindine as the oily residue used in the next step without further separation. t Example 7 ] Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-thio- 1 -PNZ-pyrrolindine (XX)

To the oily residue (XIX) in the step 4 of Example 6, was added tetrahydrofunan (200 ml) and nickel acetate terra hydrate (15g, 60 mmol), and the mixture was stirred and heated to reflux for 2 h. After completion of reaction, the temperature was dropped and toluene (100 ml) was added. The mixture was washed with water and brine, and the organic phase was dried with anhydrous magnesium sulfate, and evaporated under vacuum to remove solvent. After addition of methanol (150 ml), the mixture was cooled to the temperature of about 10°C. Substantive crystals were precipitated, filtered and afford bi[(2S,4S)-2-dimethylaminocarbonyl-l-PNZ-pyrrolindin-4-yl]disulfide (XXIII) as pale yellow powder. MS: M+l=705

IR: cm^"11705, 1650, 1515

¹HNMR(CDCl₃): 1.9O(1H, d), 2.97(3H₅ s), 3.08(3H, s), 5.19(2H, s), 7.48(2H, d), 8.15(2H, d).

Bi[(2S,4S)-2-dimethylaminocarbonyl-l-PNZ-pyrrolindin-4-yl]disulfide (XXIII) (15 g, 21 mmol) was suspended in the mixed solvent of tetrahydrofunan (80 ml) and water (80 ml). Under the nitrogen atmosphere, n-tributylphosphine (6g, 60mmol) was added dropwise with stirring. After stirring for 30 min, ethyl acetate (200 ml) and water (200 ml) was added and stirred. The organic phase was dried with anhydrous magnesium sulfate, and evaporated under vacuum to remove solvent. To the residue was added ethyl acetate (100 ml), and the mixture was stirred to crystallize. After substantive crystals were precipitated, petroleum ether (50 ml) was added, and the mixture was filtered to collect crystals. The crystals were dried to give (2S,4S)-2-dimethylaminocarbonyl-4-thio-l-PNZ-pyrrolindine (XX) (13.5g, yield 90%) as pale yellow crystal.

Mp: 118.5— 119.5¹O

MS: M+l=354

IR: cm^"11705, 1650, 1515

¹HNMR(CDCl₃): 1.9O(1H, d), 2.97(3H, s), 3.08(3H, s), 5.19(2H, s), 7.48(2H, d), 8.15(2H, d). The description of the preferred embodiments above are not intended to limit the invention, one skilled in the art can make various modifications or changes without depart from the scope of the invention, and all of these modifications and changes are within the scope of the claims attached.

Claims

1. A process for preparing meropenem, which comprises the following steps: a) reacting the compound of Formula (IV) with the compound of Formula (XV) to obtain the compound of Formula (VI); b) preparing the compound of Formula (IX) from the compound of Formula (VI); c) preparing the compound of Formula (XT) from the compound of Formula (IX); d) reacting the compound of Formula (XI) with the compound of Formula (XX) to form the compound of Formula (XXTV); e) converting the compound of Formula (XXIV) to meropenem of Formula (I) in the presence of catalyst; wherein the synthetic route as follows:

2. A process for preparing meropenem, which comprises the following steps: a) reacting the compound of Formula (IV) with the compound of Formula (XV) to obtain the compound of Formula (VI); b) preparing the compound of Formula (IX) from the compound of Formula (VI); c) preparing the compound of Formula (XXTV) from the compound of Formula (FX); d) converting the compound of Formula (XXIV) to meropenem of Formula (I) in the presence of catalyst; wherein the synthetic route as follows:

3. The process of claim 1 or 2, wherein after the reaction of the compound of Formula (IV) with the compound of Formula (XV), toluene is added to the reaction solution and it is washed with 4 N of hydrochloric acid to be acidic; then hydrogen peroxide and lithium hydroxide are added to the solution and it is subjected to hydrolysis; after the hydrolysis, the reactant is adjusted to be acidic and the aqueous layer containing much hydrogen peroxide is separated; then the aqueous layer is adjusted to basic again, and sodium sulfite is added to reduce the remaining hydrogen peroxide; finally, after filtration, the filtrate is washed with organic solvent to remove the organic material, then hydrochloric acid is added to precipitate the compound (VI).

4. The process of Claim 1, wherein in step c), the organic solvent is one or more than one kinds of solvents selected from a group consisting of ethyl acetate, tetrahydrofunan, and methylene chloride, and its amount is from 1 to 10 times of the amount of the compound of Formula (DQ by volume; rhodium acetate or rhodium caprylate is used as catalyst, and its amount is from 0.1% to 1% of the amount of the compound of Formula (IX) by molar; after 1- β -methyldicycloketo ester (X) is obtained at a temperature of 25 to 100⁰C, the compound of Formula (X) reacts with diphenyl chlorophosphate to give the compound of Formula (XI) in inert solvent selected from the group consisting of dioxane, tetrahydrofunan, dimethyl formamide, dimethyl sulfoxide, acetonitrile, hexamethyl phosphoramide and mixtures thereof in the present of organic base employed in a amount of 1 to 2 molar equivalents relative to the amount of the compound of Formula (IX) at a temperature of -15°C to 0°C, and the amount of diphenyl chlorophosphate employed is a amount of 1 to 2 equivalents relative to the amount of the compound of Formula (IX) .

5. The process of claim 1, wherein in step d), the reaction is carried out in inert solvent selected from a group consisting of dioxane, tetrahydrofunan, dimethyl formamide, dimethyl sulfoxide, acetonitrile, hexamethyl phosphoramide and mixtures thereof with organic base at a temperature of -78⁰C to 60⁰C .

6. The process of claim 1, wherein in step e), the reaction is carried out in solvent with base at a temperature of 0^°C to 100^°C in hydrogen atmosphere at atmospheric pressure or elevated pressure, said solvent is organic solvent or aqueous organic solvent, and the said catalyst is platinum or palladium on carbon.

7. The process of claim 2, wherein in step c), the reaction solution of the compound of Formula (XI) is prepared from the compound of Formula (IX), and the reaction solution or concentrate thereof is directly used to prepare the compound of Formula (XXIV) without further separation in inert solvent with base at a temperature of -78 ^°C to 6O⁰C .

8. The process of claim 1, wherein the preparation of the compound of Formula (XX), comprising: 1). preparing the compound of formula (XXV) from the compound of formula (XXVI);

2). preparing the compound of formula (XXI) from the compound of formula (XV);

3). preparing the compound of formula (XXII) from the compound of formula (XXI);

4). preparing the compound of formula (XIX) from the compound of formula (XXII);

5). preparing the compound of formula (XXIII) from the compound of formula (XTX); 6). preparing the compound of formula (XX) from the compound of formula (XXIII); the synthetic route as follows-.

(XXlT) CXIX)

9. The process of claim 8, wherein in step 5), the reaction is carried out in inert solvent with nickel acetate; and in step 6), the compound of Formula (XXIII) is reduced by tributylphosphine into the compound of the Formula (XX) in aqueous organic solvent.

10. The process of claim 1 or 2, wherein the process of isolation of the compound of Formula (XXTV) comprising the steps: the reactant is diluted with hydrophobic organic solvent selected from the group consisting of ethyl acetate, methylene chloride, diisopropyl and mixtures thereof, and the organic phase is washed with phosphate buffer solution of pH 5 to 6 for 5 to 6 times, then with saline, dried with anhydrous magnesium sulfate, and the product is directly used as the raw material of the next step after condensation.

11. The process of claim 10, wherein the process of isolation of the compound of Formula (XXIV) further comprises the step of obtaining the crystals of the compound of Formula (XXTV).