(19)
(11)EP 2 426 131 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
17.08.2016 Bulletin 2016/33

(21)Application number: 10769220.4

(22)Date of filing:  30.04.2010
(51)Int. Cl.: 
C07D 477/20  (2006.01)
(86)International application number:
PCT/CN2010/000607
(87)International publication number:
WO 2010/124531 (04.11.2010 Gazette  2010/44)

(54)

INTERMEDIATES OF CARBAPENEM, COMPOSITIONS CONTAINING THEM AND PREPARATION METHODS THEREOF

CARBAPENEM-ZWISCHENPRODUKTE, DIESE ENTHALTENDE ZUSAMMENSETZUNGEN UND HERSTELLUNGSVERFAHREN DAFÜR

INTERMÉDIAIRES DU CARBAPÉNÈME, COMPOSITIONS LES CONTENANT ET LEURS PROCÉDÉS DE PRÉPARATION


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

(30)Priority: 30.04.2009 CN 200910136995

(43)Date of publication of application:
07.03.2012 Bulletin 2012/10

(73)Proprietor: CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
Hebei 050035 (CN)

(72)Inventors:
  • SHI, Ying
    Shijiazhuang Hebei 050035 (CN)
  • LI, Kun
    Shijiazhuang Hebei 050035 (CN)
  • XIE, Zan
    Shijiazhuang Hebei 050035 (CN)
  • ZHAO, Xuebin
    Shijiazhuang Hebei 050035 (CN)
  • LV, Jian
    Shijiazhuang Hebei 050035 (CN)
  • YU, Xiuqin
    Shijiazhuang Hebei 050035 (CN)

(74)Representative: Eisenführ Speiser 
Patentanwälte Rechtsanwälte PartGmbB Postfach 10 60 78
28060 Bremen
28060 Bremen (DE)


(56)References cited: : 
WO-A2-03/026572
CN-A- 101 362 760
WO-A2-2008/062279
US-A- 5 872 250
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    FIELD OF THE INVENTION



    [0001] The present invention relates to an intermediate of Ertapenem, and a composition comprising the same and preparation methods thereof.

    BACKGROUND OF THE INVENTION



    [0002] Ertapenem of formula (1) has chemical name (4R,5R,6S)-3-[(3S,5S) -5-[(3-carboxyphenyl)amino]formyl]-pyrrolidine-3-yl]thio-6-[(1R)-1-hydro xyethy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, which is a new carbapenem antibiotic joint developed by Merck and Astrazeneca, and has good antibacterial activity against gram-positive bacteria and gram-negative bacterium.



    [0003] Ertapenem is obtained by deprotection of the intermediate of Ertapenem of formula (2).

    Np represents

    P1 and P2 represent carboxyl protecting groups; and P3 represents carboxyl protecting groups, H or Na.

    [0004] Compound 2 is typically prepared by condensing the carbapenem parent nucleus 3 with the side chain of Ertapenem 4 in the presence of base. The synthesis route is shown in Scheme 1:



    [0005] US 5,478,820A discloses compound 2, wherein P1, P2 and P3 are all allyl, or compound 2 wherein P1 and P2 are p-nitrobenzyl (referred to as PNB hereinafter) and P3 is allyl, and their preparation methods.

    [0006] US 6504027 B1 provides a one-pot-process for producing Ertapenem sodium, which comprises condensing the carbapenem parent nucleus 3 (P1 is PNB) with the side chain of Ertapenem 4 (Np is

    and P3 is H) and deprotection by hydrogenolysis. WO 02/057266 and WO 03/026572 reported similar processes.

    [0007] WO 98/02439 provides a process for producing compound 2 wherein P1 and P2 are both PNB and P3 is H, which comprises condensing the carbapenem parent nucleus 3 (P1 is PNB)with the side chain of Ertapenem 4 ( P2 is PNB, and P3 is H) in the presence of base such as diisopropylamine with a conversion rate greater than 98%. But the aftertreatment and products obtained were not reported therein.

    [0008] WO 2008/062279 provides a process for producing compound 2 wherein P1 and P2 are both PNB and P3 is H or Na+. For the aftertreatment of compound 2 with P3 being H, the reaction mixture was poured into buffer solution (pH=7) or water, or a mixture of buffer solution (pH=7) (or water) with ethyl acetate, and compound 2 was obtained after subsequent treatment. For the former situation, it is readily to bring about adhesion of the product and result in difficulties in aftertreatment and a poor purity (below 90%) of the product; for the latter situation, the product can not be obtained in form of solid and the process went against environmental protection due to the use of organic solvent. This application doesn't provide the physicochemical properties of the product, nor perform structure identification of the product. This application also reports a process for producing compound 2 with P3 being Na+ and amorphous form thereof. The introduction of sodium source results in increase of total amount of inorganic salts in subsequent reactions and thus the aftertreatment is not readily to be performed, which goes against the crystallization of product.

    [0009] Consequently, there is no report on the physicochemical properties of compound 2 with P3 being H in prior art, and compound 2 with P3 being H can not be obtained in a high purity by the prior art. In other words, using the prior art, compound 2 with P3 being H can not be obtained thereby structure identification and physicochemical properties measurement can be performed.

    SUMMARY OF THE INVENTION



    [0010] In the studies on Ertapenem, it is surprising that the inventors obtained an intermediate of Ertapenem of formula 2a in amorphous form, which has a high purity and good storage stability, and the preparation method used is easy and good for industrialization.

    [0011] Accordingly, in one aspect, the present invention provides an intermediate of Ertapenem of formula 2a, preferably, an intermediate of Ertapenem of formula 2a in amorphous form:

    wherein Np represents

    P1 and P2 represent carboxyl protecting groups.

    DETAILED DESCRIPTION OF THE INVENTION



    [0012] The carboxyl protecting group is selected from the group consisting of allyl or substituted allyl; benzyl or substituted benzyl; substituted ethyl; substituted silyl; methyl substituted by an aromatic ring; phenyl or substituted phenyl; acetonyl; t-butyl and other suitable carboxyl protecting group known by the skilled in the art.

    [0013] Preferably, substituted allyl is 2-chloro allyl.

    [0014] Preferably, substituted benzyl is selected from benzyl substituted by nitro and benzyl substituted by methoxyl.

    [0015] Preferably, benzyl substituted by nitro is p-nitrobenzyl.

    [0016] Preferably, substituted ethyl is selected from 2,2,2-trichloroethyl, 2-bromo ethyl and 2-(trimethylsilyl)ethyl.

    [0017] Preferably, methyl substituted by aromatic ring is selected from 2-menaphthyl, benzhydryl, trityl and 4-pyridyl methyl.

    [0018] Preferably, substituted silyl is selected from trimethylsilyl, t-butyl-dimethylsilyl and t-butyl-diphenylsilyl.

    [0019] Preferably, substituted phenyl is p-methyl phenyl.

    [0020] Preferably, the intermediate of Ertapenem of formula 2a includes:

    p-nitrobenzyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N -(p-nitrobenzyloxycarbonyl-pyrrolidine-3-yl]thio-6-[(1R)-1-hydroxyethy]-4 -methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,

    p-nitrobenzyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl) carbamoyl]-pyrrolidine hydrochloride-3-yl]thio-6-[(1R)-1-hydroxyethy]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate,

    o-nitrobenzyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N-(o-nitrobenzyloxy)carbonyl-pyrrolidine-3-yl]thio-6-[(1R)-1-hydroxyethy]-4 -methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,

    p-methoxybenzyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N-(p-methoxybenzyloxycarbonyl-pyrrolidine-3-yl]thio-6-[(1R)-1-hydroxye thy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,

    allylmethyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N-(allyloxycarbonyl-pyrrolidine-3-yl)thio-6-[(1R)-1-hydroxyethy]-4-methyl-7 -oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,

    2,2,2-trichloroethyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl) carbamoyl]-N-(2,2,2-trichloroethyloxycarbonyl-pyrrolidine-3-yl)thio-6-[(1 R)-1-hydroxyethy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxyl ate,

    benzhydryl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N-(benzhydryloxycarbonyl-pyrrolidine-3-yl)thio-6-[(1R)-1-hydroxyethy]-4-m ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,

    trimethylsilyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N -(trimethylsilyloxycarbonyl-pyrrolidine-3-yl)thio-6-[(1R)-1-hydroxyethy]-4 -methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,

    t-butyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N-(t-butyloxycarbonyl-pyrrolidine-3-yl)thio-6-[(1R)-1-hydroxyethy]-4-methyl -7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,



    [0021] More preferably, the intermediate of Ertapenem of formula 2a includes:

    p-nitrobenzyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-N-(4-nitrobenzyloxycarbonyl-pyrrolidine-3-yl]thio-6-[(1R)-1-hydroxyethy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, and

    p-nitrobenzyl (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-pyrrolidine hydrochloride-3-yl]thio-6-[(1R)-1-hydroxyethy]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate.



    [0022] In another aspect, the present invention provides a method for preparing intermediate of Ertapenem of formula 2a, particularly intermediate of Ertapenem of formula 2a in amorphous form. The method comprises condensing the carbapenem parent nucleus of formula 3 with the side chain of Ertapenem of formula 4a, characterized in that, when the reaction is finished, the reaction mixture is poured into an aqueous acid solution to yield compound of formula 2a as a solid.

    [0023] The side chain of Ertapenem of formula 4a according to the present invention has the following structure:

    wherein Np represents

    and P2 represent carboxyl protecting groups.

    [0024] The preparation of the carbapenem parent nucleus 3 is disclosed in, for example, J. Am. Chem. Soc. 1980, 102, 6161-6163.

    [0025] The preparation of the side chain of Ertapenem 4a is disclosed in, for example, WO98/02439 and J. Org. Chem. 2002, 67, 4771-4776.

    [0026] The acid is selected from an inorganic acid, an organic acid or any combination thereof, which exists in any suitable concentrations.

    [0027] Preferably, the inorganic acid is selected from hydrochloride, sulfuric acid, sulfurous acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, or any combination thereof.

    [0028] More preferably, the inorganic acid is selected from hydrochloride, sulfuric acid, phosphoric acid, sodium dihydrogen phosphate, or any combination thereof.

    [0029] In one preferable embodiment, the inorganic acid is hydrochloride.

    [0030] In one preferable embodiment, the inorganic acid is sulfuric acid.

    [0031] In one preferable embodiment, the inorganic acid is phosphoric acid.

    [0032] Preferably, the organic acid is selected from formic acid, acetic acid, propanoic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, oxalic acid, chloroacetic acid, trichloroacetic acid, trifluroacetic acid, or any combination thereof.

    [0033] More preferably, the organic acid is selected from acetic acid, p-toluenesulfonic acid, or any combination thereof.

    [0034] The pH value of the aqueous acid solution is 2∼6.

    [0035] Preferably, the pH value of the aqueous acid solution is 2∼5.

    [0036] More preferably, the pH value of the aqueous acid solution is 2.5∼4.5.

    [0037] Further preferably, the pH value of the aqueous acid solution is 2.5∼4.

    [0038] Most preferably, the pH value of the aqueous acid solution is pH 3∼4.

    [0039] In a further aspect, the present invention provides a composition, which comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the intermediate of Ertapenem of formula 2a, preferably, intermediate of Ertapenem of formula 2a in amorphous form, and the impurity as banlance. The impurity includes the unreacted side chain of Ertapenem of formula 4a, raw material and degradation products etc.

    [0040] For the method according to the present invention, in the aftertreatment, the solvent used is water, such that organic solvent is avoided and thus the method is economic and green; the product is obtained in the form of free acid, thereby reducing the introduction of inorganic salts and thus is good for treatment of the consequent reaction; the product is in amorphous form, and the solid has high purity and is free flowable and readily for storage, and is good for treatment of the subsequent deprotection reaction.

    BRIEF DESCRIPTION OF THE DRAWINGS



    [0041] Fig. 1 is powder X-ray diffraction pattern of the compound 2a obtained in Example 1 of the present invention.

    SPECIFIC MODES FOR CARRYING OUT THE INVENTION



    [0042] The invention will be further described in combination with examples below, which however do not limit the present invention.

    Instruments and test conditions:


    1. Powder X-ray analysis



    [0043] 

    Instrument: Rigaku D/MAX 2550 X-Ray diffractometer

    Scan conditions: from 5° to 80°/ step length 0.02°/time spent 0.12 sec, Cu(40KV,150mA), I(max)282 (peak intensity for the strongest peak 1=282 )(counts per sec).


    2. HPCL analysis



    [0044] 

    Instrument: Agilent 1100 Series,

    Column: Gemini C18 (5µ, 250×4.6mm)

    Test conditions: wavelength:230nm; mobile phase: 0.05% phosphate aqueous solution / acetonitrile = 40:60 (v/v).


    3. H-NMR analysis



    [0045] 

    Instrument: BRUKER AVANCE II500MHz NMR Analyzer

    Solvent: DMSO-d6


    4. MS analysis



    [0046] 

    Instrument: Applied Biosystems API4000 LC-MS,

    Test conditions: Positive ion ALL SCAN MODE (ESI ion source), MW range: 100-1500 amu, curtain gas (CUR): 25L/min, shealthgas (Gs1): 35 L/min, aux gas (Gs2): 45L/min, Ion Source (IS) voltage: 5000V, ion source temperature: 500°C, Declustering Potential (DP): 40V, and ColliSion Cell Entrance Potential (EP): 10V.

    Mobile phase: 2mM ammonium acetate aqueous solution containing 0.5% of formic acid: methanol (50:50, V/V).



    [0047] Unless indicated specifically, the above tests were performed according to the recommended program of manufacturer.

    [0048] Example 1: Preparation of compound 2a wherein Np repesents

    and P1 and P2 are both PNB

    [0049] 36.0g (0.0605mmol) of carbapenem parent nucleus 3 (P1 is PNB) was dissolved in 300ml DMF, then 26.7g (0.0599mol) of the side chain of Ertapenem 4a (P2 is PNB) was added. To the reaction mixture, 9.4g (0.0727mol) of N,N-diisopropylethylamine was added slowly at-35 °C. The reaction was performed under stirring. Upon completion of reaction, the reaction mixture was poured into aqueous HCl solution (pH=4) filtered, 46.6g of solid was obtained as white or off-white powder. Purity: 98.2% (by HPLC). Yield: 98.5%. The obtained solid was analyzed by powder x-ray diffraction and the results showed the solid was in amorphous form. Figure 1 is powder X-ray diffraction pattern of the product. H-NMR (DMSO-d6) :δ1.18 (d, 3H) ; 1.20 (d, 3H) : 1.95 (m, 1H) ; 2.81 (m, 1H) ; 3.18-3.47 (m, 3H) ; 3.60-4.50 (m, 6H) ; 5.04-5.44 (m, 5H) ; 7.30-8.30 (m, 12H) ; 10.27 (d, 1H) MS : 788.9 (M-1), 812.7 (M+Na) .

    [0050] Example 2: Preparation of compound 2a wherein Np represents



    [0051] Using the preparation method of Example 1, except that carbapenem parent nucleus of formula 3 (P1 represents PNB) and the side chain of Ertapenem 4a(Np represents

    ) were used as the reactants. 38.4g of solid as white or off-white powder was obtained. Purity: 98.0% (by HPLC). Yield: 98.3%. The obtained solid was analyzed by powder x-ray diffraction and the results showed the solid was in amorphous form.

    [0052] MS : 645.2 (M-1), 669.1 (M+Na) .

    [0053] Examples 3∼9: preparation of compound 2a wherein Np represents

    and P1 and P2 represent carboxyl protecting other groups

    [0054] Using the preparation method of Example 1, except that carbapenem parent nucleus 3 and the side chain of Ertapenem 4a(Np represents

    ) were used as the reactants, wherein P1 and P2 are both o-nitrobenzyl, p-methoxylbenzyl, allyl, 2,2,2-trichloroethyl, benzhydryl, trimethylsilyl and t-butyl. The results are shown in table 1:
    Table 1 The results of Examples 3-9
    Number of exampleP1, P2Yield (%)Purity (by HPLC, %)MS (M-1)Description
    3 o-nitrobenzyl 98.5 98.3 788.9  
    4 p-methoxylbenzyl 98.0 98.2 758.9  
    5 allyl 97.2 97.9 598.8 solid in amorphous form
    6 2,2,2-trichloroeth yl 96.2 97.0 781..4
    7 benzhydryl 96.5 96.8 851.1
    8 trimethylsilyl 95.8 97.2 663.0  
    9 t-butyl 97.5 97.0 630.9  


    [0055] Conclusion: Using the preparation method of the present invention, condensation of the carbapenem parent nucleus 3 and the side chain of Ertapenem 4a having various protecting groups can obtain solid in amorphous form.

    [0056] Examples 10∼17: the effect of concentration of acid on the product

    [0057] Using the preparation method of Example 1, except that the pH value of aqueous HCl solution was changed to 2, 2.5, 3, 3.5, 4.5, 5, 5.5 and 6, the results of the experiments are shown in table 2.
    Table 2 The results of Examples 10∼17
    Number of examplepH value of aqueous HCl solutionProduct Weight (g)Yield (%)HPLC (by purity, %)Description
    10 2 46.0 97.2 97.7 white or
    11 2.5 46.4 98.1 98.0 off-white amorphous solid
    12 3 46.5 98.3 98.4
    13 3.5 46.6 98.5 98.3
    14 4.5 46.4 98.1 98.1
    15 5 46.0 97.2 97.5
    16 5.5 45.7 96.6 97.0
    17 6 45.2 96.2 96.0


    [0058] Conclusion: The pH value of 2∼5 of aqueous HCl solution is the preferred concentration of acid, since the yield and purity of the products are both over 97%. When the pH value of aqueous HCl solution is in the range of 2.5 to 4.5, the yield and purity of the products are both over 98%.

    [0059] Examples 18~22 The effect of the kind of acids on the product

    [0060] Using the preparation method of Example 1, except that sulfuric acid, phosphoric acid, sodium dihydrogen phosphate, acetic acid and p-toluenesulfonic acid were used instead of hydrochloride, the results were showed in table3.
    Table 3 The results of Examples 18~22
    Number of exampleaqueous acid sotionProduct Weight (g)Yield (%)HPLC (by purity, %)Description
    18 H2SO4 46.3 97.9 98.2 white or off-white amorphous solid
    19 H3PO4 46.1 97.5 98.0
    20 NaH2PO4 46.2 97.7 97.9
    21 acetic acid 46.0 97.2 97.6
    22 p-toluenesulfonic acid 45.8 96.8 96.6

    Conclusion: Different kinds of inorganic acid and organic acid can be used in the invention, and the yield and purity of the obtained products are over 96%.

    Comparative examples: experimental results the examples of compound 2a (P1 and P2 are both PNB) in related patent WO2008062279.



    [0061] Comparative example 1: experimental result of example 1 of WO2008062279 8.3g of the side chain of Ertapenem 4a (Np represents

    and P2 is PNB) was dissolved in 30mL DMF, to which 10g of carbapenem parent nucleus 3 (P1 is PNB) was added. To the reaction mixture, 5.4g of diisopropylethylamine (DIPEA) was added at -30°C and stirred. Upon completion of reaction, the reaction mixture was diluted with 60mL of THF, and was poured into a mixture of buffer solution (pH=7) and 300mL of ethyl acetate. The organic layer was separated, the filtrate was washed with aqueous NaCl solution and treated with activated carbon. Solvent was removed by concentration under reduced pressure at 40 °C. The residue was stirred with 50mL of ethyl acetate, and no solid was precipitated.

    [0062] Comparative example 2: experimental result of example 3 of WO2008062279 8.3g of the side chain of Ertapenem 4a (Np represents

    and P2 is PNB) was dissolved in 30mL DMF, to which 10g of carbapenem parent nucleus 3 (P1 is PNB) was added. To the reaction mixture, 5.4g of diisopropylethylamine (DIPEA) was added at -30 °C and stirred. Upon completion of reaction, the reaction mixture was poured into water and stirred. The product adhered to conglobation. After filtered under reduced pressure, the solid obtained was difficult to wash. The solid was dried and determined to find the purity is 86% (by HPLC). Recrystallization was performed using one or more kinds of solvent system such as ester, ketone, halohydrocarbon, alkane, aromatic hydrocarbon, alcohol, ether, non-protonic solvent and water, and no solid was precipitated.

    [0063] Conclusion: it can be known from the results of comparative examples 1 and 2, by the preparation methods disclosed in the examples 1 and 3 of WO2008062279, no solid could be obtained, or the obtained solid has a poor purity which is not suitable for storage, and can not be used for structure identification.


    Claims

    1. An intermediate of Ertapenem of formula 2a in amorphous form:

    wherein Np represents

    and
    P1 and P2 represent carboxyl protecting groups.
     
    2. The intermediate of Ertapenem according to claim 1, wherein the carboxyl protecting group is selected from the group consisting of allyl or substituted allyl, preferably 2-chloro allyl; benzyl or substituted benzyl, preferably benzyl substituted by nitro and benzyl substituted by methoxyl; substituted ethyl, preferably 2,2,2-trichloroethyl, 2-bromo ethyl, 2-trimethylsilyl ethyl; substituted silyl, preferably trimethylsilyl, t-butyl-dimethylsilyl, t-butyl-diphenylsilyl; methyl substituted by aromatic ring, preferably 2-menaphthyl, benzhydryl, trityl, 4-pyridyl methyl; phenyl or substituted phenyl, preferably p-methyl phenyl; acetonyl and t-butyl.
     
    3. The intermediate of Ertapenem according to claim 1, wherein Np represents

    P1 and P2 are both p-nitrobenzyl, o-nitrobenzyl, p-methoxylbenzyl, allyl, 2,2,2-trichloroethyl, benzhydryl, trimethylsilyl, t-butyl, preferably P1 and P2 are both p-nitrobenzyl.
     
    4. The intermediate of Ertapenem according to claim 1, wherein Np represents

    and P1 represents p-nitrobenzyl, o-nitrobenzyl, p-methoxylbenzyl, allyl, 2,2,2-trichloroethyl, benzhydryl, trimethylsilyl, t-butyl, preferably P1 represents p-nitrobenzyl.
     
    5. A method for preparing the intermediate of Ertapenem of formula 2a:

    wherein Np represents

    Pi and P2 represent carboxyl protecting groups,
    comprising condensing the carbapenem parent nucleus of formula 3

    wherein P1 represent carboxyl protecting groups,
    with the side chain of Ertapenem of formula 4a,

    wherein Np represents

    and P2 represent carboxyl protecting groups,
    characterized in that, when the reaction is finished, the reaction mixture is poured into an aqueous acid solution.
     
    6. The method according to claim 5, characterized in that, the acid is selected from an inorganic acid, an organic acid or a combination thereof, and said acid is presented in any suitable concentration.
     
    7. The method according to claim 6, characterized in that, the acid is selected from hydrochloride, sulfuric acid, sulfurous acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, formic acid, acetic acid, propanoic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, oxalic acid, chloroacetic acid, trichloroacetic acid, trifluroacetic acid.
     
    8. The method according to claim 6, characterized in that, the acid is selected from hydrocholoride, sulfuric acid , phosphoric acid, sodium dihydrogen phosphate, acetic acid and p-toluenesulfonic acid.
     
    9. The method according to claim 6, characterized in that, the acid is hydrocholoride.
     
    10. The method according to claim 6, characterized in that, the acid is sulfuric acid.
     
    11. The method according to claim 6, characterized in that, the acid is phosphoric acid.
     
    12. The method according to claim 6, characterized in that, the pH value of the aqueous acid solution is 2∼6, preferably 2∼5, more preferably 2.5∼4.5, further more preferably 2.5∼4, most preferably 3∼4.
     
    13. A composition comprising at least 95%, at least 96%, at least 97%, or at least 98% of the intermediate of Ertapenem of formula 2a according to claim 1, together with impurity as balance.
     


    Ansprüche

    1. Zwischenprodukt von Ertapenem der Formel 2a in amorpher Form:

    wobei Np

    darstellt, und
    P1 und P2 Carboxylschutzgruppen darstellen.
     
    2. Zwischenprodukt von Ertapenem gemäß Anspruch 1, wobei die Carboxylschutzgruppe gewählt ist aus der Gruppe bestehend aus Allyl oder substituiertes Allyl, vorzugsweise 2-Chlorallyl; Benzyl oder substituiertes Benzyl, vorzugsweise Benzyl substituiert mit Nitro und Benzyl substituiert mit Methoxyl; substituiertes Ethyl, vorzugsweise 2,2,2-Trichlorethyl, 2-Bromethyl, 2-Trimethylsilylethyl; substituiertes Silyl, vorzugsweise Trimethylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl; Methyl substituiert mit aromatischem Ring, vorzugsweise 2-Menaphthyl, Benzhydryl, Trityl, 4-Pyridylmethyl; Phenyl oder substituiertes Phenyl, vorzugsweise p-Methylphenyl; Acetonyl und t-Butyl.
     
    3. Zwischenprodukt von Ertapenem gemäß Anspruch 1, wobei Np

    darstellt, P1 und P2 beide p-Nitrobenzyl, o-Nitrobenzyl, p-Methoxylbenzyl, Allyl, 2,2,2-Trichlorethyl, Benzhydryl, Trimethylsilyl, t-Butyl sind, vorzugsweise P1 und P2 beide p-Nitrobenzyl sind.
     
    4. Zwischenprodukt von Ertapenem gemäß Anspruch 1, wobei Np

    darstellt, und P1 p-Nitrobenzyl, o-Nitrobenzyl, p-Methoxylbenzyl, Allyl, 2,2,2-Trichlorethyl, Benzhydryl, Trimethylsilyl, t-Butyl darstellt, vorzugsweise P1 p-Nitrobenzyl darstellt.
     
    5. Verfahren zur Herstellung des Zwischenproduktes von Ertapenem der Formel 2a:

    wobei Np

    darstellt, P1 und P2 Carboxylschutzgruppen darstellen,
    umfassend die Kondensierung des Carbapenem Mutterkerns der Formel 3

    wobei P1 Carboxylschutzgruppen darstellt, mit der Seitenkette von Ertapenem der Formel 4a,

    wobei Np

    darstellt, und P2 Carboxylschutzgruppen darstellt,
    dadurch gekennzeichnet, dass die Reaktionsmischung in eine wässrige Säurelösung gegossen wird, wenn die Reaktion beendet ist.
     
    6. Verfahren gemäß Anspruch 5, dadurch gekennzeichnet, dass die Säure gewählt ist aus einer anorganischen Säure, einer organischen Säure oder einer Mischung davon, und dass die besagte Säure in jeglicher angemessener Konzentration vorgelegt wird.
     
    7. Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass die Säure gewählt ist aus Hydrochlorid, Schwefelsäure, schweflige Säure, Phosphorsäure, Kaliumdihydrogenphosphat, Natriumdihydrogenphosphat, Ameisensäure, Essigsäure, Propansäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Benzoesäure, Oxalsäure, Chloressigsäure, Trichloressigsäure, Trifluoressigsäure.
     
    8. Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass die Säure gewählt ist aus Hydrochlorid, Schwefelsäure, Phosphorsäure, Natriumdihydrogenphosphat, Essigsäure und p-Toluolsulfonsäure.
     
    9. Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass die Säure Hydrochlorid ist.
     
    10. Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass die Säure Schwefelsäure ist.
     
    11. Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass die Säure Phosphorsäure ist.
     
    12. Verfahren gemäß Anspruch 6, dadurch gekennzeichnet, dass der pH-Wert der wässrigen Säurelösung 2 - 6 ist, vorzugsweise 2 - 5, weiter bevorzugt 2,5 - 4,5, weiter bevorzugt 2,5 - 4, am meisten bevorzugt 3 - 4.
     
    13. Zusammensetzung umfassend mindestens 95 %, mindestens 96 %, mindestens 97 % oder mindestens 98 % des Zwischenproduktes von Ertapenem der Formel 2a gemäß Anspruch 1, zusammen mit Verunreinigungen als Rest.
     


    Revendications

    1. Un intermédiaire d'Ertapenem de formule 2a en forme amorphe:

    où Np représente

    et
    P1 et P2 représentent de groupes protecteurs de carboxyle.
     
    2. L'intermédiaire d'Ertapenem selon la revendication 1, où le groupe protecteur de carboxyl est choisi dans le groupe constitué par allyle ou allyle substitué, de preference 2-chloroallyle; benzyle ou benzyle substitué, de préférence benzyle substitué par nitro et benzyle substitué par méthoxyle; éthyle substitué, de préférence 2,2,2-trichloroéthyle, 2-bromo éthyle, 2-trimethylesilyle éthyle; silyle substitué, de préférence trimethylsilyle, t-butyle-dimethylsilyle, t-butyle-diphenylsilyle; méthyle substitute par noyau aromatique, de preference 2-ménaphthyle, benzhydryle, trityle, 4-pyridylméthyle; phényle ou pnényle substitué, de préférence p-méthyle phényle; acétonyle et t-butyle.
     
    3. L'intermédiaire d'Ertapenem selon la revendication 1, où Np représente

    tous les deux P1 et P2 sont p-nitrobenzyle, o-nitrobenzyle, p-méthoxylebenzyle, allyle, 2,2,2-trichloroéthyle, benzhydryle, triméthylsilyle, t-butyle, de préférence tous les deux P1 et P2 sont p-nitrobenzyle.
     
    4. L'intermédiaire d'Ertapenem selon la revendication 1, où Np représente

    et P1 représente p-nitrobenzyle, o-nitrobenzyle, p-méthoxylebenzyle, allyle, 2,2,2-trichloroéthyle, benzhydryle, triméthylsilyle, t-butyle, de préférence P1 représente p-nitrobenzyle.
     
    5. Un procédé de préparation de l'intermédiaire d'Ertapenem de formule 2a:

    où Np représente

    P1 et P2 représentent de groupes protecteurs de carboxyle,
    comprenant la condensation du noyau parent de Carbapénem de formule 3

    où P1 représente de groupes protecteurs de carboxyle,
    avec la chaîne laterale d'Ertapenem de formule 4a,

    où Np représente

    et P2 représente de groupes protecteurs de carboxyle,
    charactérisé en ce que le mélange de réaction est versé dans une solution acide aqueuse quand la réaction est finie.
     
    6. Le procédé selon la revendication 5, charactérisé en ce que l'acide est choisi parmi un acide inorganique, un acide organique ou une combinaison de ces deux éléments et lesdits acides sont présentés en une concentration appropriée.
     
    7. Le procédé selon la revendication 6, characterize en ce que l'acide est choisi parmi chlorhydrate, acide sulforique, acide sulfureux, acide phosphorique, dihydrogenophosphate potassique, dihydrogenophosphate de sodium, acide formique, acide acétique, acide propanoïque, acide benzesulfonique, acide p-toluensulfonique, acide benzoïque, acide oxalique, acide chloroacetique, acide trichloroacétique, acide trifluoroacétique.
     
    8. Le procédé selon la revendication 6, characterisé en ce que l'acide est choisi parmi chlorhydrate, acide sulforique, acide phosphorique, dihydrogenphosphate de sodium, acide acétique et acide p-toluensolfonique.
     
    9. Le procédé selon la revendication 6, characterize en ce que l'acide est chlorhydrate.
     
    10. Le procédé selon la revendication 6, characterize en ce que l'acide est acide sulforique.
     
    11. Le procédé selon la revendication 6, characterize en ce que l'acide est acide phosphorique.
     
    12. Le procédé selon la revendication 6, characterisé en ce que la valeur pH de la solution acide aqueuse est 2 ~ 6, de préférence 2 ∼ 5, plus préférablement 2,5 ~ 4,5, plus préférablement encore 2,5 ~ 4, idéalement 3 ∼ 4.
     
    13. Une composition comprenante au moins 95 %, au moins 96 %, au moins 97 % ou au moins 98 % de l'intermédiaire d'Ertapenem de formule 2a selon la revendication 1, conjointement avec de l'impurité comme équilibrage de poid.
     




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    REFERENCES CITED IN THE DESCRIPTION



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