WO2007104219A1

WO2007104219A1 - A process for the preparation of the intermediate of β-methyl carbapenem

Info

Publication number: WO2007104219A1
Application number: PCT/CN2007/000396
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
Also published as: CN1824666A; CN100347175C

Abstract

A process of preparation of the intermediate of β-methyl carbapenem is disclosed, in which 4-acetylazacyclobutanone as the raw material is firstly reacted with α-bromopropionamide having a big inductive group. Since this reaction is highly stereoselectivity, most of the product is the required parent nucleus of β-methyl carbapenem, a product of β-configuration. Compared with the prior art, the process of the present invention is highly-yielding, cost-effective and can be used for large scale production.

Description

A Process for the Preparation of the Intermediate of p-Methyl Carbapenem

Technical Field The present invention relates to a process for the preparation of the intermediate of β-methyl carbapenem.

Background of the Invention

Up to now there have been many reports for large amount of natural or synthetic β-lactamase inhibitors which are classified according to the chemical structure as oxapenams, penems, carbapenems and monocyclic β- lactam oxapenams, among which carbapenems, especially β-methyl carbapenems such as imipenem, meropenem and biapenem are highly resistant to many drug-fast bacteria. Especially, due to having strong inhibitory effect to B-type enzyme, they are a series of unique inhibitors for inhibiting β-lactamase. Since it was found that thienamycin has potential antimicrobial activity to gram negative bacteria and gram positive bacteria, studies to the synthesis of carbapenem or penem derivatives similar to thienamycin have been developed widely.

At present, the commercialized carbapenem and β-methyl carbapenem antibiotics include (4R,5S,6S,8R,2' S,4' S)-3-[2-dimethylaminocarbonyl] pyrrolidinylthio]-4-methyl-6-(l-hydroxyethyl)-l-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylic acid (meropenem) (I) by Sumitomo Pharmaceuticals Co., Ltd.;

( I) N-formimidoyl thienamycin (imipenem) (II) by Merck & Co., Inc.;

( II)

(lR,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[l,2-a] [1,2,4] triazolium-6-yl)]-thio-6-[(R)-l-hydroxyethyl]-l-methyl-2-em-3-carboxylate (III)(biapenem) by Lederle Ltd.;

( III)

and the like.

For the preparation of the parent nucleus of β-methyl carbapenem, there are many synthetic routes, among which scheme A (USP4933333) by Sumitomo Pharmaceuticals Co., Ltd. and scheme B (USP4990613) by Lederle Ltd. are listed as follows:

Scheme A:

(XI)

Scheme B:

B

The raw materials used in the scheme by Sumitomo Pharmaceuticals Co., Ltd. are simple and readily available, but the yield is negatively affected because a large amount of optical isomers of the compound of formula (V) needs to be separated; the steps of the scheme by Lederle Ltd. are very simple, but the raw material (XII) is costly and not available easily.

Summary of the Invention

The purpose of the invention is to provide a process for the preparation of the parent nucleus of β-methyl carbapenem. The process according to the present invention is readily operated, the product thereof is easy to be separated, the content and yield of the product thereof are high, and the cost is reduced, so that the deficiencies in the prior art can be overcome.

According to the purpose of the present invention, scheme C is used to synthesize the parent nucleus of β-methyl carbapenem.

In the present invention, "the compound having the molecular formula (I)" is abbreviated as

"the compound of formula (I)" or "compound (I)" for brief, and other compounds are abbreviated similarly.

In the present invention, abbreviations are used to represent the following substances:

TBDMS: t-butyldimethylsilicyl;

PNZ: p-nitrobenzyloxycarbonyl;

PNB: p-nitrophenylmethyl;

Ph: phenyl;

Ac: acetyl;

Ms: methylsulphonyl; t-Bu: t-butyl;

Me: methyl; and

Et: ethyl.

Scheme C is listed as follows:

( XI)

Scheme C comprises two steps in essentials:

A. reacting the compound of formula (IV) with the compound of formula (XV) to produce the compound of formula (VI); and B. preparing β-methyl carbapenem intermediate of formula (XI) from the compound of formula (VI); wherein step A and step B are carried out according to the following synthetic route:

Since the reaction of the raw material 4-acetylazacyclobutanone (IV) with α-bromopropionamide (XV) having a big inductive group is highly stereoselectivity and can generate a product with great majority of β-confϊguration, the yield of the parent nucleus of β-methyl carbapenem is enhanced greatly.

The above step A may further comprises the following two steps:

Al. reacting the compound of formula (IV) with the compound of formula (XV) to produce the compound of formula (XIV); and

A2. hydrolyzing the compound of formula (XIV) into the compound of formula (VI), wherein step Al and step A2 are conducted according to the following synthetic routes:

Preferably, compound (VI) is prepared from compound (IV) by a one-pot synthetic process. That is, from step Al a reaction solution containing the compound of formula (XIV) is prepared, and this reaction solution or the concentrate thereof is then used directly for the reaction of step A2 without further separation.

Step Al : The reaction may be carried out by various known methods (Tanabe Seiyaku Co., Ltd, USP: 5,847,115, for example), and after completion of the reaction, different methods may be used for treatment. Toluene with a low polarity is added into the reaction solution, which is then washed by 4N hydrochloric acid to a weakly acidic pH, followed by the wash of brine for the next step.

Step A2: The reaction may be carried out by various known methods, or it may be carried out by the following process: to the solution resulted from the above step hydrogen peroxide and lithium hydroxide are added for hydrolysis, and then a treatment after hydrolysis is conducted to adjust the reaction mixture to be acidic, after the aqueous layer containing most hydrogen peroxide is separated, the mixture is adjusted to be alkaline. After that, the aqueous sodium sulfite solution is added into the mixture to reduce the remaining hydrogen peroxide, the spiro compound is filtrated, the organic substance in the aqueous solution is washed by organic solvent, and then hydrochloric acid is added to educe the crystals of compound (VI). The yield is enhanced greatly by the combination of the two steps.

The above step B may further comprises the following two steps: Bl. Preparing the compound of formula (IX) from the compound of formula (VI); and B2. preparing the parent β-methyl carbapenem (XI) from the compound of formula (EX), wherein steps Bl and B2 are carried out according to the following synthetic route:

Furthermore, the above step Bl comprises three substeps below: BLl. preparing the compound of formula (VII) from the compound of formula (VI); B 1.2. preparing the compound of formula (VIET) from the compound of formula (VII); and B 1.3. preparing the compound of formula (IX) from the compound of formula (VIET), wherein the substeps B 1.1, B 1.2 and B 1.3 are carried according to the following synthetic route:

Preferably, a one-pot synthetic method can be used to prepare compound (IX) from compound (VI). That is, the reaction solution containing the compound of formula (VII) is prepared by substep B 1.1 or the concentrate thereof may be used directly for the reaction of substep B 1.2 without further separation; and similarly, the reaction solution containing the compound of formula (VIII) prepared by substep B 1.2 or the concentrate thereof may be used directly for the reaction of substep B 1.3 without further separation.

In substep B 1.1, the reaction may be carried out by various known methods (orthodox reagent method, for example), the solution in ethyl acetate obtained by reaction and treatment will be used in the next step without further separation.

In substep B 1.2, the reaction may be carried out by various known methods, with the improvement that reaction is directly carried out in the above solution. The resultant solution is treated and then concentrated to form a concentrate, which will be used directly in the next step without further separation. In substep B 1.3, the reaction may be carried out by various known methods. After the reaction, the solution is treated, concentrated and pass through the silica column. By the combination of the above three steps, the yield is enhanced greatly.

Further, the above step B2 may comprises two substeps as follows:

B2.1. reacting the compound of formula (IX) to produce the compound of formula (X); and B2.2. preparing the parent β-methyl carbapenem (XI) from the compound of formula (X), wherein substeps B2.1 and B2.2 are carried out according to the following synthetic route:

Preferably, a one-pot synthetic method can be used to prepare compound (XI) from compound (IX). That is, the reaction solution containing the compound of formula (X) prepared by substep B2.1 or the concentrate thereof may be used directly for the reaction of substep B2.2 without further separation.

In substep B2.1, one or more than one kinds of solvents selected from a group consisting of ethyl acetate, tetrahydrofuran and dichloromethane are used as solvent, the amount of which is 1 to 10 times, preferably 3 to 5 times relative to the volume of compound (IX); rhodium acetate or rhodium caprylate is used as catalyst, the amount of which is 0.1%-l%, preferably 0.25% to 0.5% molar equivalents relative to the amount of compound (IX); and the reaction temperature is from 25°C to lOO^°C.

In substep B2.2, the inert solvent used in the reaction is one or more than one kinds of solvents selected from a group consisting of dioxane, tetrahydrofuran, dimethyl formamide, dimethyl sulphoxide, acetonitrile and hexamethylphosphoramide. Acetonitrile and dimethyl formamide are preferred ones.

The base used in the reaction is a compound which will be ionized to generate hydroxide radical as the only anion. The base can be, for example, various inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like; or various organic bases such as potassium tert-butoxide, pyrimidine, various dimethylpyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine and the like. Organic bases such as diisopropylethylamine, triethylamine and diisopropylethylamine are preferred. In a preferred embodiment, diisopropylethylamine is selected as the base for reaction.

The amount of the base should be sufficient to carry out a complete reaction. Usually the molar equivalent ratio between the base and the compound (IX) is 1 : 1~2, preferably 1: 1 - 1.5.

The product of the induced reaction of enol ester is diphenyl chlorophosphate, the amount of which should be sufficient to carry out a complete reaction. Usually the molar equivalent ratio between the diphenyl chlorophosphate and compound (IX) is 1 : 1~2, preferably 1 : 1-1.2.

The reaction temperature is -20 °C to 50 °C , preferably - 10 ^°C to 0 ^°C . According to another aspect, the present invention also provides a process for preparing meropenem by means of the intermediate of β -methyl carbapenem of the present invention. The meropenem of formula (I) is prepared by reacting the intermediate prepared by the above method (compound XI) with the compound (XX) of meropenem side chain and converting the resulted compound in the presence of catalyst. The synthesis of the compound of meropenem side chain (4-thiolpyrrolindine derivates), 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); 2). preparing the compound of formula (XXI) from the compound of formula (XXV); 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 (XIX); 6). preparing the compound of formula (XX) from the compound of formula (XXIII); and the synthetic route is:

i o

P-XII) (xm

Me₂

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 2): The reaction can be carried out by various known methods. The carboxyl react with, 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. Compared with the prior art, the present invention has the following advantages: i i 1. In the above scheme C, a one-pot synthetic method can be used to prepare compound (VI) from compound (IV), to prepare compound (IX) from compound (VI), and to prepare compound (XI) from compound (IX). Due to this method, the purpose can be achieved at a time, which otherwise need several steps to reach before. As a result, the period of reaction is reduced greatly, the labor productivity is enhanced, the investment of device for commercialization is cut down, the species and amount of the solvents are reduced, the pollution to the environment is lighten and the production cost of the factory is saved.

2. The preparation process according to this invention can be simply operated, the product thereof is easily to be separated with a purity and a yield enhanced greatly (a yield of 70 to 90% is achieved).

3. The raw material (XXV) used in the preparation process according to this invention is readily available, so that the cost of manufacture is reduced.

Detailed Description of the Invention All the substances for experiment are commercially available if not specified otherwise.

Example 1 Synthesis of (3S,4R)-3-[(lR)-l-t-butyldimethylsilioxyethyl] -4-[(1R)-I -methyl- 1 -carboxyethyl] -azacyclocyclobutan-2-one (VI)

Zn powder (34g, 0.523mol) was added into anhydrous tetrahydrofuran (60ml). The resultant mixture was heated to boil under stirring, and then a mixed solution of (3S,4R)-4-acetoxy-3-[(lR)-l-t-butyldimethylsiloxyethyl]azacyclobutan-2-one (IV) (5Og, 0.174mol) and 3-(2-bromopropyl)-spiro [2,3-dihydro-4H -l,3-benzoxazin-2,l'-cyclohexan-4-one (XV) (9Og, 0.256mol) in 180ml anhydrous tetrahydrofuran was added at a speed which will not to cause the reaction solution boiling acutely. After completion of the addition, the reaction mixture was refluxed for 30 min, and then cooled to room temperature. Celite (5g) was added into the reaction mixture, which was then filtered by suction. Filter residue was washed with a proper amount of tetrahydrofuran, and the wash solution was combined into the filtrate. After the addition of toluene (60ml), the mixture was adjusted by the addition of 2N hydrochloric acid (200ml) to pH 5 to 6. The organic phase was separated and washed with brine by 2 times to get the solution of 3-{(2R)-2-[(3S,4R)-3-[(lR)-l-t-butyldimethylsiloxyethyl]-2-ketoazacyclobut -4-yl]propyl}-spiro[2,3-dihydro-4H-l,3-benzoxazin-2,l'-cyclohexyl]-4-one (XIV) in tetrahydrofuran-toluene. The resultant mixture was used for the next step without isolation.

To the above reaction mixture was added tetrahydrofuran (150 ml) at 5⁰C to 15⁰C. Hydrogen peroxide (30%, 96g) was added under stirring, followed by the addition of lithium hydroxide monohydrate (2Ig). The reaction was carried out under stirring for 3 hr at the same temperature. After the reaction was completed, the reaction mixture was adjusted by the addition of 4N hydrochloric acid (about 130ml) under stirring to pH 2, and then the separated organic phase was washed with brine by 3 times. At 5^°C to 15 ^"C₅ the organic phase was adjusted by the addition of sodium hydroxide (6%, about 200ml) under stirring to pH 10, and then sodium sulfite (17%, about 50ml) was added into the solution until the color of the starch KlI test paper will not change any more. After filtration by suction, the filter residue was washed with water by 3 to 4 times, and the washing solution was combined into the filtrate. The aqueous phase was further washed with ethyl acetate by 3 to 4 times, and then ethyl acetate in the aqueous phase was vaporized under vacuum. After that, at 5°C to 15^°C the reaction mixture was adjusted by the addition of 4N hydrochloric acid under stirring to pH 2, and at that time, a large quantity of crystals were separated out. The reaction was continued for 2 hr while the temperature was kept unchanged. The resultant mixture was filtered, the crystals were washed with water, and dried to get (3 S,4R)-3 - [( 1 R)- 1 -t- butyldimethylsilioxyethyl] -4- [(I R)- 1 -methyl- 1 -carboxyethyl]

-azacyclocyclobutan-2-one (VI) (42.5g, yield: 81%) as white crystals. Mp: 146— 147^°C lR_max"^ec"(cm¹): 1740, 1465, 1330, 1255, 1043, 837.

NMR: 0.08(6H, s), 0.7(9H, s), 1.24(3H, d, J=7), 1.30(3H, d, J=7.5), 2.78(1H, m), 3.06(1H, m), 3.98(1H, m), 4.24(1H, m), 6.37(1H, wide)_o

Example 2 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)

Compound (VI) (25g, 86mmol) was added into anhydrous acetonitrile (300ml). After the addition of carbonyldiimidazole (17.5g, llOmmol) under stirring, the resultant mixture was stirred continuously at the room temperature for 30 min. Subsequently, anhydrous magnesium mono-p-nitrobenzyl malonate (55.5g, llOmmol) was added, and then the resultant reaction mixture was stirred at 25 to 35 ^°C for 18 hr. After the reaction was completed, ethyl acetate (450ml) and IN hydrochloric acid (450ml) were added under stirring to adjust the pH of the aqueous phase within the range of 2 to 3. The organic phase was washed thoroughly with brine, 5% solution of potassium carbonate in water, and brine successively to get a solution of (3S,4R)-3-[(lR)-l-t-butyldimethylsilyloxyethyl]-4-[(lR)-l-methyl-4-[(4-nitrobenzyl)oxy]-2,4-d ioxobutyl]azetidin-2-one (VII) in ethyl acetate, which may be used for the next step without isolation.

To the above solution of (VII) in ethyl acetate was added methanol (100ml), and then added 6N hydrochloric acid (100ml) at 20 °C to 25°C.The reaction mixture was stirred at the same temperature for 2 hr, and after the reaction was completed, saturated aqueous sodium chloride (500ml) was added into the resulted mixture. The organic phase was washed with 10% sodium phosphate dibasic (2><500ml ) and then with saturated aqueous sodium chloride, dried on anhydrous magnesium sulphate, and concentrated under vacuum to get the concentrate (3 S ,4R)-3 -[( 1 R)- 1 -hydroxyethyl] -4- [( 1 R)- 1 -methyl-4- [(4-nitrobenzyl)oxy] -2,4-dioxobutyl] azetidi n-2-one (VIII), which may be used in the next step without isolation. Acetonitrile (140ml) was added and solved in the above concentrate under stirring. At 0°C to 5⁰C, p-dodecylbenzene sulfonyl azide (30.3g, 86mmol) and triethylamine (9.6g, 95mmol) were added into the mixture and then the mixture was stirred for 2 hr. 0.5N hydrochloric acid (220ml) was added to wash the mixture under stirring. The organic phase was washed thoroughly with water and brine successively, dried on anhydrous magnesium sulphate, and concentrated under vacuum to get an oily product. The oily product was chromatographed by 250 silica column (the eluent: ethyl acetate :petroleum ether) to get (3S,4R)-3-[(lR)-l-hydroxyethyl] -4-[(lR)-l-methyl-3-diazo-4- [(4- nitrobenzyl)oxy]-2,4-dioxobutyl]azetidin-2-one (IX) as a faint yellow crystal (25g, yield: 77.2%). [α]_D ²¹=-50.4°(c=2.5, CH₂Cl₂) IR_aJ^ cm^"1: 2140,1750, lq720, 1650.

NMRδ(CDCl₃): 1.22(3H, d, J=6.0 Hz), 1.32(3H, d, J=6.0 Hz)₃ 2.38(1H, d, J=3.2 Hz), 2.92(1H, 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 3: Synthesis of PNB -(4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyc Io [3 ,2,0]hept-2-ene-2-carboxylate. (XI) .

The compound (IX) (4Og, 0.102mol) and ethyl acetate (200ml) were added into a flask equipped with a reflux cooler to form a mixture, which was then heated to 60 °C under stirring. Rhodium caprylate (140mg) was added, and the mixture was stirred intensively at the same temperature for 30 mill until the reaction of the compound (IX) was completed to form a solution of 4-β-methyl azabicyclic ketone ester (X). The reaction solution was directly used for the next step without isolation.

The above solution of 4-β-methyl azabicyclic ketone ester (X) was cooled to -10 to -15 °C by ice bath and under the protection of nitrogen gas, diisopropylethylamine (14.57g, 0.113mol) and diphenyl chlorophosphate (27.54g, 0.102mol) were added. The reaction mixture was stirred at the same temperature for 5 hr until compound (X) disappeared. Many white crystals were separated out from the reaction mixture, and then petroleum ether (300ml) and the aqueous solution of sodium phosphate monobasic (3.5%, 300ml) were added into the reaction mixture to wash the crystals under stirring. After filtration, the filter cake was washed with petroleum ether (100ml) and water (500ml) respectively and then dried to get PNB (4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicycl o[3,2,0]hept-2-ene-2-carboxylate. (XI) (49.3g, yield: 81%; purity: 98%).

[α]D25=+40~+44°(c=0.5 MeOH); Mp: 125-126°C ; IRmaxKBr cm-1: 1780, 1745, 1605.

NMRδ(CDC13): 1.24(3H, d), 1.35(3H, d), 2.38(1H, d, J=3.2 Hz), 3.35(1H, dd,), 3.52 (IH, m), 4.26 (IH, dd), 4.3O(1H, m), 5.24 |π 5.41(2H, ABq).7.29(10H,m), 7.58 and 8.18(2H, d).

Example 4: Synthesis of (4R,5S,6S)- 3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-3-ρyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl- 7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (I)

Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-thio-l-PNZ-pyrrolindine (XX)L-hydoxyproline (XXVI) (26.2 g, 0.20 mol) was added to a solution of sodium hydroxide (220 ml, 2N) and cooled to O⁰C to 5⁰C. 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 O⁰C 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.

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.

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- pyrrolidine (XXII) (yield 73%) as white crystal, m.p. : 115~-116^°C.

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.

To the oily residue (XIX) in above step, was added tetrahydrofunan (200 ml) and nickel acetate tetra 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^"1 1705, 1650, 1515

¹H NMR(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). 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— 119.5⁰C

[ ^α ]D²⁰=+9.60° (C=1.0, CHCl₃) MS: M+l=354 IR: cm⁴ 1705, 1650, 1515

¹H NMR(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). To the above compound (XI) of example 3 1Og ( 16.8mmol) was added acetonitrile (dry, 100 ml) and the mixture was cooled to -10 — -15 ⁰C in ice-salt bath. Then, [2S,4S]-l-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidne (XX) 6. Ig (17.3mmol),and diisopropylethamine 2.5g (19.3mmol) 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 (150 ml) and washed with 3.5% 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 11.2 g, quantified by HPLC containing 10.7 g of targeted compound (XXIV), (91.3% yield) was directly used in the follow step.

The resulting residue in the above step 12 g, quantified by HPLC containing 10.7 g (15.3mmol) of the said compound (XXIV) 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 (6.0 g) and Pa/C (2.7 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 (880 ml) and seed crystals were added at 5^°C to 15°C. After 30 min, substantive crystals were precipitated. Acetone (440 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-[(lR)-l-hydroxyethyl]-4-methyl- 7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (I) as light yellow crystal (5.2 g, assay: 94%, yield 73%).

The physical data of compound (I): UV_mαx ^fflOnm: 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). The description to the above preferred embodiments shall not be misconstrued as limitation to the present invention. One skilled in this art will readily recognize that various changes and modifications may be made therein without departure from the spirit of this invention, which should also be contained by the attached claims.

Claims

ClaimsWhat we claim is:

1. A process for preparing the intermediate of β-methyl carbapenem, comprising the steps of:

A. reacting the compound of formula (IV) with the compound of formula (XV) to produce the compound of (VI); and

B. preparing the intermediate of β-methyl carbapenem of formula (XI) from the compound of formula (VI),

Wherein the synthesis route as follows:

( XI)

2. The process according to claim 1, wherein said step A further comprises: Al. Reacting the compound of formula (IV) with the compound of formula (XV) to obtain the compound of formula (XTV); and

A2. Hydrolyzing the compound of formula (XIV) into the compound of formula (VI), The synthesis route as follows:

3. The process according to claim 1, wherein said step B further comprises:

2 O Bl. Preparing the compound of formula (IX) from the compound of formula (VI); and B2. Preparing the intermediate of β-methyl carbapenem of formula (XI) from the compound of formula (IX)

The synthesis route as follows:

OH ^OTBDMS . A-A_. V™

y™ ₀+-^m ° ° loom. _s ^{< VI) ( E>} (Xi)

4. The process according to claim 2, wherein a reaction solution containing the compound of formula (XIV) is obtained from step Al, and then said reaction solution or the concentrate thereof is used for the reaction of step A2 without further separation.

5. The process according to claim 4, wherein after the reaction of the compound of formula 0 (IV) with the compound of formula (XV), toluene is added into the reaction liquid, which is then washed to an acidic pH by a 4N hydrochloric acid; after that, both hydrogen peroxide and lithium hydroxide are added into said solution for hydrolysis, the reaction product thereof is adjusted to be acidic to separate the aqueous layer containing most of the hydrogen peroxide, and then the aqueous layer is adjusted to be alkaline, followed by the addition of an aqueous solution of 5 sodium sulfite to reduce the remaining hydrogen peroxide; finally, after the step of filtration, the organic substance in the filtrate is washed out by an organic solvent, and hydrochloric acid is added into the filtrate to separate out the compound of formula (VI).

6. The process according to claim 3, wherein said step Bl further comprises:

B 1.1. preparing the compound of formula (VII) from the compound of formula (VI); 0 Bl .2. preparing the compound of formula (VIII) from the compound of formula (VII); and

B 1.3. preparing the compound of formula (IX) from the compound of formula (VIII); The synthesis route as follows:

7. The process according to claim 6, wherein a reaction solution containing the compound of formula (VII) is obtained from sub step B 1.1, and then said reaction solution or the concentrate thereof is directly used for the reaction of sub step B 1.2 without further separation; and a reaction solution containing the compound of formula (VIII) is obtained from sub step B 1.2, said reaction solution or the concentrate is used directly for the reaction of sub step B 1.3 without further separation.

8. The process according to claim 7, wherein after the compound of formula (VII) is prepared from the compound of formula (VI), the reaction solution containing the compound of formula (VII) is used directly for the reaction for preparing the compound of formula (VIII) without further separation, the solution resulted from the reaction is treated and concentrated to form a concentrate, said concentrate is directly used for the reaction for preparing the compound of formula (IX) without further separation, the solution resulted from the reaction is treated and concentrated, then it passes through the silica column to get the compound of formula (IX).

9. The process according to claim 3, wherein said step B2 further comprises

B2.1. reacting the compound of formula (IX) in an organic solvent with the presence of a catalyst to produce the compound of formula (X), with the reaction temperature being 25 to 100 ^"C, the amount of said organic solvent being 1 to 10 times of the amount of the compound of Formula (IX) by volume, and the amount of said catalyst being 0.1%-l% of the amount of the compound of Formula (FX) by molar; and

B2.2. preparing the compound of formula (XI) from the compound of formula (X), the reaction being carried out in an inert solvent containing a base at the temperature of -20 to 50 "C, the synthetic route as follows:

<XΪ)

10. The process according to claim 9, wherein a reaction solution containing the compound of formula (X) is obtained from substep B2.1, and then said reaction solution or the concentrate thereof is directly used for the reaction of substep B2.2 without further separation.

11. The process according to claim 9, wherein in substep B2.1, said organic solvent is one or more than one kinds of solvents selected from the group consisting of ethyl acetate, tetrahydrofuran and dichloromethane, the amount of which is 3 to 5 times of the amount of the compound of Formula (IX) by volume; and said catalyst is rhodium acetate or rhodium caprylate, the amount of which is 0.25% to 0.5% of the amount of the compound of Formula (FX) by molar .

12. The process according to claim 9, wherein in substep B2.2, the compound of formula (X) is reacted with diphenyl chlorophosphate in a amount of 1 to 2 molar equivalents relative to the amount of the compound of Formula (IX) to produce the compound of formula (XI); said inert solvent is one or more than one kinds of solvents selected from the group consisting of dioxane, tetrahydrofuran, dimethyl formamide, dimethyl sulphoxide, acetonitrile and hexamethylphosphoramide; said base is an organic base, the molar equivalent ratio between the base and the compound of formula (FX) being 1: 1~2; and the reaction temperature is -10°C to 0^°C.

13. The process according to claim 12, wherein said inert solvent is acetonitrile or dimethyl formamide.

14. A process for preparing meropenem, which comprises the folio whig steps:

A. reacting the compound of formula (IV) with the compound of formula (XV) to produce the compound of (VI); B. preparing the intermediate of β-methyl carbapenem of formula (XI) from the compound of formula (VI), and

C. reacting the compound of formula (XI) with the compound of formula (XX) to form the compound of formula (XXIV); D converting the compound of formula (XXIV) to meropenem of formula (I) in the presence of catalyst; the synthetic route as follows: