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WO2014088315A1 - Monohydrate de doripénème cristallin et son procédé de préparation - Google Patents

Monohydrate de doripénème cristallin et son procédé de préparation Download PDF

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WO2014088315A1
WO2014088315A1 PCT/KR2013/011163 KR2013011163W WO2014088315A1 WO 2014088315 A1 WO2014088315 A1 WO 2014088315A1 KR 2013011163 W KR2013011163 W KR 2013011163W WO 2014088315 A1 WO2014088315 A1 WO 2014088315A1
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doripenem
pnb
monohydrate
phosphate
water
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PCT/KR2013/011163
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English (en)
Korean (ko)
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이병구
최수진
윤희균
김월영
이경호
안진우
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주식회사 대웅제약
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Priority to JP2015546382A priority Critical patent/JP2016501259A/ja
Publication of WO2014088315A1 publication Critical patent/WO2014088315A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

Definitions

  • the present invention relates to a method for preparing doripenem monohydrate, and more specifically, a step of deprotecting by reacting doripenem-PNB represented by the following Chemical Formula 2 with zinc powder in a mixed solvent composed of an organic solvent and an aqueous solution of phosphate (step One); Removing phosphate from the product of step 1 (step 2); And a method for preparing doripenem monohydrate, which is prepared through the step (step 3) of crystallizing doripenem monohydrate represented by Chemical Formula 1 using the product of step 2 as a solvent for crystallization.
  • penicillin has been known as a miracle medicine by saving the lives of many patients with infectious diseases.
  • staphylococcus resistant to this emerged and in the 1960s, methicillin, a semisynthetic penicillin, was developed and used to treat penicillin-resistant staphylococcal infections.
  • methicillin-resistant staphylococcus aureus (MRSA) resistant to methicillin began to develop, various cephalosporin preparations and various antibiotics such as quinolone, carbapenem, monobactam, and glycoside were developed in the 1980s and clinically Used in
  • Carbapenem antibiotics have the strongest antibacterial effect among the beta-lactam antibiotics, and have been used to treat severe patients of children or elderly people with weak immunity due to its excellent safety and therapeutic effects. In addition, since it shows an excellent antibacterial effect to the resistant bacteria difficult to treat, it has been used as a treatment for this.
  • Carbapenem antibiotics are prepared by total synthesis and are generally stereoselectively synthesized using 4-acetoxyazetidinone as a key intermediate. Beta-methyl group is introduced from 4-acetoxyazetidinone through stereoselective reaction, and then a multi-step reaction is a key intermediate of various carbapenem antibiotics (meropenem, attafenim, viafenim, doripenem, etc.). Beta-methyl vinyl phosphate carbapenem is synthesized.
  • Doripenem monohydrate (DoripenemH 2 O, chemical name: (4R, 5S, 6S) -6-((R) -1-hydroxyethyl) -4-methyl-7-oxo-3-((3S, 5S) ) -5-((sulfamoylamino) methyl) pyrrolidin-3-ylthio) -1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid hydrate) is a gram-positive bacterium And compounds having broad antibiotic efficacy against Gram-negative bacteria.
  • doripenem monohydrate is prepared by a deprotection reaction of doripenem-PNB in which a carboxyl group is protected by a p-nitrobenzyl group.
  • MAP is subjected to a coupling reaction with a side chain to prepare doripenem-PNB, in which a carboxyl group is protected with p-nitrobenzyl, and an appropriate amount thereof.
  • WO2006-117763 discloses doripenem-PNB in a mixed solvent of ethyl acetate and N-methylmorpholine / acetic acid buffer solution (pH 6.0-7.0), and 5% palladium-carbon was added at room temperature under hydrogen atmosphere. After reacting for 4 hours, the catalyst filtration and the aqueous layer are separated, added to methyl alcohol at room temperature, and crystallized to obtain a desired doripenem. Compared to the European Patent Registration No.
  • EP 0528678 B1 the method performs catalytic hydrogenation in a solvent mixture of ethyl acetate and a buffer without using tetrahydrofuran, so that the process is directly performed from an aqueous solution without column chromatography, lyophilization, separation and recovery. There is an advantage that the desired compound can be obtained.
  • the inventors of the present invention are studying a method for preparing doripenem monohydrate through a safe process without requiring special equipment and expensive catalysts, and zinc powder instead of expensive metal catalysts and hydrogen gas in a deprotection reaction.
  • the present invention was completed by confirming that a high yield of doripenem monohydrate can be obtained using an aqueous solution of phosphate.
  • the present invention comprises the step of reacting the doripenem-PNB represented by the formula (2) with zinc powder in a mixed solvent consisting of an organic solvent and an aqueous solution of phosphate (step 1); Removing phosphate from the product of step 1 (step 2); And crystallizing doripenem monohydrate represented by the following Chemical Formula 1 using the product of step 2 as a crystallization solvent (step 3).
  • the step 1 is, in order to deprotect the carboxyl protecting group PNB (4-nitrobenzyl) and the amine protecting group PNZ (4-nitrobenzyl oxy carbonyl) from the doripenem-PNB represented by the formula (2), the zinc powder is It is a step of performing deprotection reaction into a mixed solvent of an organic solvent and phosphate aqueous solution in which doripenem-PNB is represented.
  • the zinc powder is preferably used four to twelve times the weight of doripenem-PNB, and in order to prevent decomposition of the target compound due to rapid exotherm, it is preferable to gradually divide and maintain the appropriate temperature.
  • the phosphate is preferably any one or more selected from the group consisting of KH 2 PO 4 , K 2 HPO 4 , H 3 PO 4 , NaH 2 PO 4, and Na 2 HPO 4 .
  • the organic solvent is preferably any one or more selected from the group consisting of tetrahydrofuran, acetonitrile, acetone, ethyl acetate, methylene chloride and chloroform.
  • the pH of the mixed solvent is preferably 4 to 7, and the concentration of the phosphate in the mixed solvent is preferably 0.5 M to 2 M. If the reaction proceeds out of the pH range or the phosphate concentration range, only the nitro portion of the protecting group stays in the intermediate which is reduced to the amine, so that the target compound cannot be obtained to the maximum, which may cause a problem in yield reduction.
  • Step 1 is preferably carried out at 20 °C to 40 °C for 0.5 hours to 3 hours. If the temperature is less than 20 ° C., the reaction may proceed only to the primary reduced amine intermediate, thereby preventing a complete reaction. When the temperature exceeds 40 ° C., the reaction rate and the degree of completion may be increased, whereas a large amount of the target compound may be decomposed to reduce yield and purity.
  • the washing is preferably performed using a mixture of an organic solvent and water used in the reaction, the organic solvent is methyl acetate, butyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, isopropyl ether, methyl ethyl ketone Or dichloromethane can be removed via extraction. If the concentration is performed to remove the organic solvent, a problem may occur in that the target compound is gradually decomposed in the weakly acidic reaction solution to lower the yield and content.
  • Step 2 is a step of removing the phosphate from the product of step 1, it can be carried out using the adsorption resin slurry extraction method or co-precipitation method.
  • the adsorption resin slurry extraction method means that the product of step 1 is added to the adsorption resin, stirred and slurried, and then filtered with water to remove phosphate.
  • the adsorption resin may be SP-207, Amberlite XAD-4, Amberlite XAD-7, Diaion HP-20 or HP-40, but is not limited thereto.
  • the water may be used 50 to 200 times the weight of the doripenem-PNB, preferably 50 to 100 times.
  • the mixed solution is preferably used 10 to 100 times the weight of the doripenem-PNB.
  • the phosphate removal method using the conventional adsorption resin was carried out by filling the adsorption resin in a special facility, adsorbing doripenem, washing with excess water, removing phosphate, and concentrating for a long time at 50 ° C. or lower using an eluent. Therefore, a special facility is required, and a large amount of impurities are generated by heat and concentration time, so that there is a problem in that yield and purity are lowered.
  • the adsorption resin slurry extraction method of the present invention can be carried out in a general reactor without a special resin column installation, a polar organic having greater affinity with the adsorption resin than doripenem adsorbed on the adsorption resin without mixing with water as eluent
  • a polar organic having greater affinity with the adsorption resin than doripenem adsorbed on the adsorption resin without mixing with water as eluent
  • the coprecipitation method means that the phosphate salt is crystallized by mixing the product of step 1 with an organic solvent of methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile and a mixed solvent of water to remove phosphate.
  • the mixed solvent is preferably used 10 times to 40 times the weight of the doripenem-PNB, and the mixed solution is preferably cooled to 0 °C to 10 °C to prevent the generation of impurities by heat generation. Do.
  • the coprecipitation method of the present invention excludes the resin process conventionally used conventionally, the target compound can be recovered without concentrating the eluate. Therefore, the generation of impurities by heat and concentration time can be minimized, and doripenem of high purity and high yield can be obtained.
  • step 2 doripenem recovered after phosphate removal is added dropwise to methanol, ethanol, isopropyl alcohol, acetone or tetrahydrofuran, followed by filtration and drying in vacuo at room temperature to produce amorphous doripenem monohydrate. It is preferable to include as.
  • Step 3 is a step of crystallizing the product of step 2 with a solvent for crystallization in order to obtain crystalline doripenem monohydrate.
  • the solvent for crystallization is preferably water or a mixed solvent of water and methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.
  • the method for producing doripenem monohydrate according to the present invention can be carried out under mild conditions of room temperature and atmospheric pressure without expensive metal catalysts and special facilities, and economical and safe as well as high yield of doripenem monohydrate can be obtained. .
  • the manufacturing method of this invention can be usefully applied to the industrial field related to doripenem monohydrate.
  • 1 is a graph showing a powder X-ray diffraction analysis of doripenem monohydrate according to an embodiment of the present invention.
  • FIG. 2 shows the thermogravimetric analysis (TGA) of doripenem monohydrate according to an embodiment of the present invention.
  • Figure 3 shows the results of differential scanning calorimetry (DSC) analysis of doripenem monohydrate according to an embodiment of the present invention.
  • Doripenem-PNB was prepared according to Scheme 2 below. 98 g of the compound represented by the formula (3) was added to 490 ml of methanol, and 25 ml of sulfuric acid was slowly added thereto, followed by reaction for 3 hours while maintaining the internal temperature of 60 ° C to 65 ° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol, and extracted with 100 ml of water and 100 ml of ethyl acetate. The organic layer was recovered and washed with water and 5% brine. Anhydrous magnesium sulfate was used to remove the water remaining in the organic layer and concentrated under reduced pressure.
  • Example 1 Preparation of amorphous doripenem monohydrate-adsorption resin slurry extraction method
  • the resin was filtered and washed with 1 L of water to remove the potassium phosphate salt and impurities used in the reaction.
  • a mixed solution of 200 ml of ethyl acetate and 100 ml of water was added to the reactor, followed by stirring, followed by filtration to elute doripenem.
  • the eluate was separated and the aqueous layer containing doripenem was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C. to 5 ° C. for 1 hour. Filtration and drying under reduced pressure at room temperature yielded 10.26 g of amorphous doripenem monohydrate (yield 90%).
  • the resin was filtered and washed with 1 L of water to remove the potassium phosphate salt and impurities used in the reaction. 10 L of ethyl acetate and 5 L of water were added to the reactor, followed by stirring, followed by filtration and washing to elute doripenem. The eluate was separated and the aqueous layer containing doripenem was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C. to 5 ° C. for 1 hour. Filtration and drying under reduced pressure at room temperature gave 0.51 kg of amorphous doripenem monohydrate (yield 90%).
  • amorphous doripenem monohydrate was prepared using two doses.
  • Isopropyl alcohol was added dropwise to the aqueous layer and stirred for 30 minutes to crystallize the phosphate.
  • the crystals were filtered to remove potassium phosphate salts and impurities.
  • the filtrate was added dropwise to isopropyl alcohol to precipitate crystals, stirred at 0 ° C to 5 ° C for 1 hour, filtered and dried under reduced pressure at room temperature to give 10.81 g of amorphous doripenem monohydrate (yield 95%).
  • the crystals were filtered to remove potassium phosphate salts and impurities.
  • the filtrate was added dropwise to isopropyl alcohol to precipitate crystals, stirred for 1 hour at 0 ° C to 5 ° C, filtered and dried under reduced pressure at room temperature to give 0.54 kg of amorphous doripenem monohydrate (yield 95%).
  • amorphous doripenem was prepared.
  • adsorption resin SP-207 30 L was charged to the resin column and the doripenem mother liquor was passed through to adsorb the doripenem.
  • 50 liters of water was run on a resin column to remove the potassium phosphate salt and impurities used in the reaction.
  • 100 L of 70% isopropyl alcohol (IPA) was then developed on the resin column to recover doripenem from the adsorption resin.
  • Fractions containing doripenem were collected and concentrated to 5 times volume by weight of doripenem-PNB. The concentrated solution was added dropwise to isopropyl alcohol to precipitate crystals and stirred at 0 ° C to 5 ° C for 1 hour. Filtration and drying gave 0.68 kg of amorphous doripenem monohydrate (yield 60%).
  • Example 1 and Example 2 were more remarkable than the preparation methods of Comparative Example 1 and Comparative Example 2. It was found that amorphous doripenem monohydrate can be obtained with improved yields.
  • Diffraction Angle (2 ⁇ ) 10.91 °, 13.07 °, 15.0 °, 15.90 °, 16.64 °, 18.10 °, 20.63 °, 21.09 °, 23.47 °, 23.89 °, 24.19 °, 24.47 °, 26.06 °, 26.96 °, 27.53 ° , 28.23 °, 28.91 ° and 34.15 °.
  • thermogravimetric analysis was performed at 35 ° C. to 250 ° C. and 10 ° C./min rate, and the results are shown in FIG. 2.
  • doripenem monohydrate showed a weight loss of 5.19% monohydrate at 125.24 ° C. to 132.74 ° C., and a weight loss due to decomposition of doripenem at 17.25% at 168.38 ° C. to 187.61 ° C. .
  • Differential scanning calorimetry of doripenem monohydrate prepared in Examples 1 and 2 was performed. The temperature of the melting endothermic peak was recorded as the melting point. Data obtained from differential scanning calorimetry (DSC) is influenced by several factors such as heating rate, sample purity, crystal size and sample size. Thus, the following melting points are representative of the samples produced by the above examples. For analysis, differential scanning calorimetry (DSC) was performed using 3.30 mg of doripenem monohydrate prepared in Examples 1 and 2, and the results are shown in FIG. 3.
  • the doripenem monohydrate of Examples 1 and 2 exhibited an endothermic peak at 180.02 °C.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de monohydrate de doripénème et, plus particulièrement, un procédé de préparation de monohydrate de doripénème produit par les étapes suivantes : la réalisation d'une réaction de déprotection par mise en réaction de doripénème-PNB avec une poudre de zinc dans une solution de mélange contenant un solvant organique et une solution aqueuse de phosphate (étape 1) ; l'élimination du phosphate du produit de l'étape 1 (étape 2) ; et la cristallisation du produit de l'étape 2 en utilisant un solvant pour la cristallisation pour cristalliser le monohydrate de doripénème (étape 3). Selon le procédé de préparation du monohydrate de doripénème, le procédé peut être réalisé à température ambiante et à une pression atmosphérique modérée sans utiliser un catalyseur métallique coûteux et un équipement spécial. Le procédé est ainsi économique et sûr, et le monohydrate de doripénème peut être obtenu en un rendement élevé. Le procédé de préparation de la présente invention peut ainsi être appliqué de manière utile dans un domaine industriel associé au monohydrate de doripénème.
PCT/KR2013/011163 2012-12-04 2013-12-04 Monohydrate de doripénème cristallin et son procédé de préparation WO2014088315A1 (fr)

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KR20160109904A (ko) * 2015-03-13 2016-09-21 주식회사 대웅제약 결정형 도리페넴의 제조방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117763A2 (fr) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Procede de preparation de doripeneme
WO2008006298A1 (fr) * 2006-07-03 2008-01-17 Chengdu Di'ao Jiuhong Pharmaceutical Factory Nouvelle forme cristalline de doripenem, préparation, procédé et utilisations de celle-ci
KR20100103427A (ko) * 2009-03-13 2010-09-27 주식회사 대웅제약 아연 분말을 이용한 메로페넴의 개선된 제조방법
US20120035357A1 (en) * 2009-02-26 2012-02-09 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of carbapenem antibiotic

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117763A2 (fr) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Procede de preparation de doripeneme
WO2008006298A1 (fr) * 2006-07-03 2008-01-17 Chengdu Di'ao Jiuhong Pharmaceutical Factory Nouvelle forme cristalline de doripenem, préparation, procédé et utilisations de celle-ci
US20120035357A1 (en) * 2009-02-26 2012-02-09 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of carbapenem antibiotic
KR20100103427A (ko) * 2009-03-13 2010-09-27 주식회사 대웅제약 아연 분말을 이용한 메로페넴의 개선된 제조방법

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