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WO2010022590A1 - Procédé de préparation du méropénèm - Google Patents

Procédé de préparation du méropénèm Download PDF

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Publication number
WO2010022590A1
WO2010022590A1 PCT/CN2009/000982 CN2009000982W WO2010022590A1 WO 2010022590 A1 WO2010022590 A1 WO 2010022590A1 CN 2009000982 W CN2009000982 W CN 2009000982W WO 2010022590 A1 WO2010022590 A1 WO 2010022590A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
organic
xviii
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2009/000982
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English (en)
Chinese (zh)
Inventor
卢兆强
龙利松
陈曦
邹灼天
张恒利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHENZHEN HAIBIN PHARMACEUTICAL CO Ltd
Original Assignee
SHENZHEN HAIBIN PHARMACEUTICAL CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by SHENZHEN HAIBIN PHARMACEUTICAL CO Ltd filed Critical SHENZHEN HAIBIN PHARMACEUTICAL CO Ltd
Publication of WO2010022590A1 publication Critical patent/WO2010022590A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07D477/10—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

Definitions

  • the present invention relates to a process for the preparation of a beta-methyl carbapenem antibiotic (Carbapenem), and more particularly to a process for the preparation of meropenem (Meropenem). Background technique
  • Reaction Route A (USP4933333) from Sumitomo Pharmaceuticals Co., Ltd., as follows:
  • the second is Lederle Ltd.'s Reaction Route B (USP4990613), as shown below:
  • Route A is readily available and is widely used. However, due to the long reaction route and the need to separate a variety of intermediates, especially chiral intermediates, it does not meet the requirements of atomic economy, which brings some trouble to the operation. It also causes pollution to the environment; in addition, because of the need to make compound (X) With the noble metal ruthenium compound as a catalyst, with the shortage of precious metal ruthenium and the increasing price, the preparation cost of the route is also increasing, which is not an ideal preparation method.
  • route B is shorter than route A, it is not a good preparation method because the raw material (XII) is not easily obtained and has the same defects as route A.
  • the technical problem to be solved by the present invention is to provide a new preparation of meropenem 0 with a short synthesis step, convenient operation, easy separation of products, high yield, avoidance of use of precious metal ruthenium catalyst, and less influence on the environment. method.
  • the present invention provides a preparation method of meropenem, which comprises the following steps:
  • step 1 The compound of the formula (IV) has a good stereoselective reaction with ⁇ -bromopropionamide (XIV) having a large inducing group, and most of the product forms a ⁇ -configuration product.
  • the present invention adopts the method of Chinese Patent Application No. 200610083362.7.
  • the compound of the formula (VI) is prepared by a "one-pot” synthesis method from the compound of the formula (IV), that is, a 3- ⁇ (2R)-2-[(3S, 4R)-3-[ 1)-1-tert-butyldimethylsilyloxyethyl]-2-carbonylazetidin-4-yl]propyl ⁇ -spiro[2,3-dihydro-4H-1,3-benzo
  • the compound of the formula (VI) and the compound of the formula (XV) are in N, ⁇ '-carbonyldiimidazole. (CDI) or dicyclohexanediamine (DCC) and 4-dimethylaminopyridine (DMAP) are reacted in an organic solvent to produce a compound of the formula (XVI) having a meropenem branch in a higher yield.
  • the reaction time is 2 to 12 hours, and the reaction temperature is 0 to 4 (TC, preferably room temperature.
  • the organic solvent used may be selected from the group consisting of acetone, acetonitrile, toluene, diphenylbenzene, ethyl acetate, tetrahydrofuran, isopropyl ether, methyl tert-butyl Ether, methyl t-butanone, dichloromethane, chloroform, etc., preferably dichloromethane.
  • the crude product obtained is used in the next step without purification, and the solvent can be recycled after simple recovery.
  • step 3 the compound of the formula (XVI) and p-nitrobenzyl chloroacetoate (XVII) are reacted in an organic solvent under the action of a base to give a compound of the formula (XVIII) in a higher yield.
  • the molar ratio of p-nitrobenzyl chloroacetoate (XVII) to the compound of formula (XVI) is usually from 1.5 to 3:1, preferably 2:1.
  • the base used may be an inorganic base such as sodium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate, sodium hydrogen phosphate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydrogen phosphate, potassium hydride, etc.; bases such as pyridine, triethylamine, diisopropyl ethyl amine (DIPEA), 4 - dimethylaminopyridine (DMAP), 2, 6- lutidine and the like, preferably an organic base such as pyridine.
  • the amount of the base should be such that the reaction proceeds sufficiently.
  • the molar ratio of the base to the p-nitrobenzyl chlorobenzyl ester (XVII) is usually from 1 to 2:1, preferably 1.5:1.
  • the organic solvent used is selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran (THF), dioxane, methyl tert-butyl ether, benzoin, dichlorodecane, chloroform, acetone, hydrazine, hydrazine-difluorenyl.
  • the reaction time is 1 to 3 hours, and the reaction temperature is -20 to 5 ° C, preferably - 10 to 0 ° C.
  • the crude product obtained was used in the next step without purification, and the solvent was recycled after simple recovery.
  • the compound of the formula (XVIII) is first reacted with an organophosphorus reagent in an inert solvent to form a phosphorus ylide, and the meropenem precursor compound (XIX) is formed by a Wittig reaction under the action of a catalyst.
  • the organophosphorus reagent used in the reaction may be in an organic scale reagent such as triphenylphosphine, tri-n-butylphosphine, triethyl phosphite, tridecyl phosphite, triisopropyl phosphite or diethyl methyl phosphate.
  • the amount of the organic monument reagent is such that the reaction proceeds sufficiently, and the molar ratio of the organophosphorus reagent to the compound of the formula (XVIII) is usually from 2 to 10:1, preferably 2.5:1.
  • the catalyst can be selected from phenol and hydroquinone, preferably hydroquinone.
  • the inert solvent may be selected from solvents which do not react with the organophosphorus reagent, such as saturated alkanes (n-heptane, n-octane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), preferably xylene.
  • the reaction can be carried out under normal pressure to nitrogen pressure, preferably at atmospheric pressure.
  • the reaction time is preferably 5 to 12 hours.
  • the reaction solution was concentrated under reduced pressure to recover the solvent, and the crude product obtained was purified by ethyl acetate. The purity and content were over 97%.
  • the solvent used for the reaction and recrystallization can be recycled after being recovered by the cartridge.
  • the compound of the formula (XIX) is hydrolyzed by an acid, a fluorine-containing compound or a mixture of a fluorine-containing compound and an acid in an organic solvent to form a meropenem precursor compound of the formula (XX) in a higher yield. .
  • the acid may be an inorganic acid such as dilute hydrochloric acid, hydrofluoric acid or the like, or an organic acid such as acetic acid;
  • the fluorine-containing compound may be ammonium hydrogen fluoride or the like; and the combination of the fluorine-containing compound and the acid is preferably tetrabutylammonium fluoride ( Combination of TBA) and acetic acid.
  • the organic solvent to be used may be tetrahydrofuran, acetone, N,N-dimethylformamide, dichloromethane, ethyl acetate, N-methylpyrrolidone or the like, preferably tetrahydrofuran.
  • the reaction temperature is 0 to 40 ° C, and room temperature is preferred.
  • the reaction time is 24 to 72 hours.
  • the solvent used can be recycled after being recovered by the cartridge. The product was directly charged to the next step without further purification.
  • the target compound of the formula (I) is produced from the compound of the formula (XX) by catalytic reduction under the action of a catalyst and hydrogen, and the catalyst used is palladium, palladium/carbon or palladium hydroxide, preferably palladium/ carbon.
  • the solvent used in the reaction is an organic solvent or an aqueous organic solvent selected from the group consisting of alcohols, ethers, organic acids and the like, and may be a mixture of one or more.
  • the alcohol is selected from the group consisting of methanol, ethanol, etc.
  • the ether is selected from the group consisting of tetrahydrofuran and dioxane
  • the organic acid may be acetic acid or the like.
  • the base used in the reaction is a compound in which all of the anions formed during ionization are hydroxide ions, and may generally include; and are not salty, such as N-dimercaptoaniline, N-methylmorpholine, diisopropyl B. Amine, 2,6-lutidine, sodium hydrogencarbonate, potassium hydrogen phosphate, and the like.
  • the base added to the reaction can be used to adjust the pH of the reaction solution, and the molar ratio of the base to the compound of the formula (XX) is usually from 1 to 10:1, preferably from 1 to 4:1.
  • the reaction is carried out at atmospheric pressure or in a hydrogenation environment at a temperature of 0 to 100 ° C, preferably 0 to 40 ° C.
  • the invention has the following advantages:
  • the synthetic route is short and easy to operate.
  • meropenem (I) can be obtained by a six-step reaction from the compound of the formula (IV), and the conventional route (for example, Reaction Route A of Sumitomo Pharmaceuticals Co., Ltd., Lederle Ltd.) Reaction route B) requires a seven-step reaction, and the present invention meets the requirements of atomic economy.
  • the reaction intermediates of each step except the compound of the formula (XIX) and the formula (VI) need to be purified by recrystallization, and the other reaction products are directly input into the next step without further purification, thereby greatly shortening the production cycle. , the operation of the tube.
  • the solvent used in each step of the reaction can be recycled simply by simple recycling, which reduces the amount of solvent used and environmental pollution, and reduces the production cost of the plant.
  • the raw material cylinder of the invention is easy to obtain, the price is low, and the reaction yield is high in each step.
  • the invention does not need to apply the noble metal ruthenium catalyst which is increasingly expensive, thereby greatly saving the production cost. detailed description
  • test materials used in the present invention are commercially available products unless otherwise stated.
  • 1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (IV) and 319.50g (0.909 mol) 3-(2-bromopropyl)-spiro[2,3-dihydrogen -4H-1, 3-benzoxazine-2,1,-cyclohexyl]-4-one (XIV) is a mixed solution of 640 ml of anhydrous tetrahydrofuran, and the reaction rate is preferably such that the reaction liquid does not bounce.
  • the mixture was refluxed for 30 minutes, cooled to room temperature, 18 g of diatomaceous earth was added to the reaction mixture, the reaction mixture was suction filtered, the residue was washed with an appropriate amount of tetrahydrofuran, and the filtrate and the washings were combined, and 215 ml of toluene was added thereto, and 710 ml of the mixture was added thereto.
  • reaction mixture was added 535 ml of tetrahydrofuran, the temperature was controlled at 5 15 ° C, 96 g of 30% hydrogen peroxide was added under stirring, and 74.55 g of lithium hydroxide monohydrate was added thereto, and the reaction was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was adjusted to pH 2 with about 460 ml of 4N hydrochloric acid under stirring, and the organic phase was washed three times with brine.
  • the organic phase was adjusted to pH 10 by adding 700 ml of a 6 % sodium hydroxide solution under stirring at 5 to 15 ° C, and then 180 ml of a 17% sodium hydroxide solution was added until the solution starch KI test paper did not change color. After suction filtration, the filter residue was washed 3 to 4 times with water, and the filtrate and washing solution were combined. The aqueous phase was washed again with ethyl acetate for 3 times, and the ethyl acetate in the aqueous phase was vacuum-purified.
  • IR ⁇ cm' 1 1755, 1627, 1393, 1252, 1130
  • the resulting mixture was subjected to a hydrogen pressure of 1.8 MPa. The reaction was carried out for 1.5 hours.
  • the catalyst was removed by filtration, and the filtrate was diluted with 750 ml of acetone under stirring. Then, 400 ml of acetone was added dropwise at 5 to 15 ° C, and after stirring, the mixture was stirred for 30 minutes, and crystals were collected by filtration, and the crystals were washed with 50 ml of acetone.
  • the invention provides a method for preparing meropenem, which has the advantages of short synthesis step, simple operation, high yield, avoiding the use of precious metal ruthenium catalyst, less influence on the environment, lowering the preparation cost of the product, and facilitating industrialization. Sustainable production and environmental development.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation du méropénèm comprenant les étapes suivantes: 1) le composé de formule (IV) réagit avec le composé de formule (XIV) pour obtenir le composé de formule (VI); 2) le composé de formule (VI) réagit avec le composé de formule (XV) pour obtenir le composé de formule (XVI); 3) le composé de formule (XVI) réagit avec le composé de formule (XVII) pour obtenir le composé de formule (XVIII); 4) le composé de formule (XVIII) est utilisé pour préparer le composé de formule (XIX); 5) le composé de formule (XX) est obtenu par hydrolyse du composé de formule (XIX); 6) le méropénèm de formule (I) est obtenu par réduction au moyen de catalyseurs et d'hydrogène du composé de formule (XX). Le procédé décrit dans l'invention présente un processus de préparation relativement court et facile à exécuter, utilise des réactifs faciles d'accès et permet d'éviter l'utilisation du rhodium en tant que catalyseur.
PCT/CN2009/000982 2008-08-29 2009-08-28 Procédé de préparation du méropénèm Ceased WO2010022590A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2008101421375A CN101348486B (zh) 2008-08-29 2008-08-29 一种美罗培南的制备方法
CN200810142137.5 2008-08-29

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Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101348486B (zh) * 2008-08-29 2010-09-29 深圳市海滨制药有限公司 一种美罗培南的制备方法
CN102233278B (zh) * 2010-04-29 2013-11-06 湖北益泰药业有限公司 培南类药物生产中回收铑催化剂的方法
CN101935321A (zh) * 2010-07-20 2011-01-05 深圳市海滨制药有限公司 1β甲基碳青霉烯类抗生素的合成方法
CN102336756A (zh) * 2010-07-20 2012-02-01 湖北益泰药业有限公司 美罗培南合成中脱保护基的方法
CN101962383A (zh) * 2010-11-12 2011-02-02 上海巴迪生物医药科技有限公司 一种美罗培南的合成方法
CN102532139A (zh) * 2010-12-07 2012-07-04 重庆医药工业研究院有限责任公司 一种替比培南的制备方法
CN102532140B (zh) * 2010-12-21 2015-03-11 北大方正集团有限公司 一种美罗培南三水合物的制备方法
CN102603745A (zh) * 2011-01-18 2012-07-25 深圳市海滨制药有限公司 β-甲基碳青霉烯化合物的制备方法
CN102267997B (zh) * 2011-07-15 2013-01-23 海南美兰史克制药有限公司 一种美罗培南化合物及其制法
CN102372715A (zh) * 2011-12-07 2012-03-14 凯莱英医药集团（天津）股份有限公司 一种制备美罗培南的方法
CN103894210B (zh) * 2014-04-29 2015-08-12 西安凯立化工有限公司 一种可套用的美罗培南合成用钯炭催化剂

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035300A2 (fr) * 2004-09-30 2006-04-06 Ranbaxy Laboratories Limited Procede de preparation de meropenem
WO2007031858A2 (fr) * 2005-09-15 2007-03-22 Orchid Chemicals And Pharmaceuticals Limited Procede ameliore de preparation d'un antibiotique beta-lactame
CN1948312A (zh) * 2006-03-14 2007-04-18 深圳市海滨制药有限公司 美罗培南的制备方法
CN101348486A (zh) * 2008-08-29 2009-01-21 深圳市海滨制药有限公司 一种美罗培南的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035300A2 (fr) * 2004-09-30 2006-04-06 Ranbaxy Laboratories Limited Procede de preparation de meropenem
WO2007031858A2 (fr) * 2005-09-15 2007-03-22 Orchid Chemicals And Pharmaceuticals Limited Procede ameliore de preparation d'un antibiotique beta-lactame
CN1948312A (zh) * 2006-03-14 2007-04-18 深圳市海滨制药有限公司 美罗培南的制备方法
CN101348486A (zh) * 2008-08-29 2009-01-21 深圳市海滨制药有限公司 一种美罗培南的制备方法

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CN101348486B (zh) 2010-09-29

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