WO2007009354A1 - Intermediaires d'un derive de pyrrolidine, leur preparation et leur utilisation - Google Patents

Intermediaires d'un derive de pyrrolidine, leur preparation et leur utilisation Download PDF

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Publication number
WO2007009354A1
WO2007009354A1 PCT/CN2006/001664 CN2006001664W WO2007009354A1 WO 2007009354 A1 WO2007009354 A1 WO 2007009354A1 CN 2006001664 W CN2006001664 W CN 2006001664W WO 2007009354 A1 WO2007009354 A1 WO 2007009354A1
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WO
WIPO (PCT)
Prior art keywords
nitrobenzyloxycarbonyl
preparation
sulfamoylamino
hydroxyethyl
carboxylic acid
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Application number
PCT/CN2006/001664
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English (en)
Chinese (zh)
Inventor
Dayong Xu
Yun Tang
Wuchun Zhou
Yuan Yu
Zhongrong Liu
Bogang Li
Original Assignee
Chengdu Di'ao Jiuhong Pharmaceutical Factory
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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Publication date
Application filed by Chengdu Di'ao Jiuhong Pharmaceutical Factory filed Critical Chengdu Di'ao Jiuhong Pharmaceutical Factory
Priority to CNA2006800077492A priority Critical patent/CN101137621A/zh
Publication of WO2007009354A1 publication Critical patent/WO2007009354A1/fr

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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a novel pyrrolidine derivative intermediate and a preparation method thereof, and belongs to the field of chemical synthesis. Background technique
  • Carbapenem antibiotics have received attention due to their extensive antibacterial activity.
  • the drugs that have been marketed include imipenem, meropenem, etc.
  • imipenem is a new 1 ⁇ -methyl carbapenem antibiotic, and the 2-position side chain is aminosulfonate. Amide substituted tetrahydropyrrole ring.
  • the structure-activity relationship study showed that the acylation or sulfonylation of the side chain amino group of doripenem was beneficial to the increase of antibacterial activity, and the inhibitory activity against Gram-positive bacteria was higher than that of meropenem, against Gram-negative bacteria.
  • the inhibitory activity is higher than that of imipenem, and it is also effective against imipenem-resistant bacteria. It is stable to serine (3-lactamase and renal dehydropeptidase, and can be used for the treatment of severe infections in the brain, kidneys and lungs). [Chinese Journal of New Drugs 2003, Vol. 12, No. 9, 700-703].
  • Route 1 is based on (lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1- Methyl-1-carbo-2-penemene-3-carboxylic acid benzhydryl ester and (2S,4S)-1-tert-butoxy-oxyl-2-(N-tert-butoxycarbonyl-N- Reaction of sulfamoylamino)methyl-4-mercaptopyrrolidine to form protected pyrrolidinyl carbapenem, followed by deprotection with Lewis acid aluminum trichloride to prepare doripenem (Organic Process Research & Development 2003, 7,846 -850; CN1032257 ), the process route is as follows:
  • the diphenyl phthalate intermediate used in this route has no raw material supply in China, and the cost is very high.
  • This route uses sulfuric acid to remove tert-butoxycarbonyl and acetyl to prepare (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-sulfamoylamino)indolyl-4-hydrazinopyrrolidine.
  • the produced carbon cations bring more side reactions, and the generated impurities are difficult to remove. If the carbon cation trapping agent is added, the production cost is increased, and the intermediate obtained by desulfurization of sulfuric acid is an oil at normal temperature, and is industrially produced. Measuring and feeding brings difficulties. Summary of the invention
  • the technical proposal of the present invention is to provide a novel pyrrolidine derivative intermediate, and another technical solution of the present invention is to provide a preparation method of the intermediate and to apply the same to the preparation of 1 ⁇ -mercaptocarbapene antibiotic-multiple Niperan.
  • the pyrrolidine derivative intermediate provided by the invention has the structure of formula (I):
  • PNZ represents p-nitrobenzyloxycarbonyl and R is -H or a thiol protecting group.
  • the thiol protecting group generally includes an acyl group, an aryl-substituted lower alkyl group such as a benzyl group, a phenethyl group, a triphenylsulfonyl group, a diphenylfluorenyl group and the like.
  • the invention provides a method for preparing a pyrrolidine derivative intermediate of the formula (I), which comprises (2S,4S)-4-acetylthio-1-pyridyloxycarbonylpyrrolidine-2-methanol and N-
  • the reaction of p-nitrobenzyloxycarbonylsulfonamide is carried out, and the process route is as follows:
  • the p-nitrobenzyl alcohol is firstly reacted with chlorosulfonyl isocyanate to form N-p-nitrobenzyloxycarbonylaminosulfonyl chloride, and then subjected to N-acylation reaction to obtain N-p-nitrobenzyloxycarbonyl group.
  • (2S,4S)-4-acetylthio-1- 1-p-nitrobenzyloxypyrrolidino-2-nonanol, N-p-nitrobenzyloxycarbonyl The sulfonamide and triphenylphosphine are dissolved, and diisopropyl azodicarboxylate (formed as a condensing agent with triphenylphosphine) is added dropwise under ice cooling. After the addition is completed, the reaction is continued to room temperature and the reaction is continued 30 - After 240 minutes, the reaction solution was concentrated under reduced pressure, and then dissolved in anhydrous ethanol. The precipitate was precipitated to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N- Sulfonamide aminomethyl-4-acetylthiopyrrolidine.
  • the preparation method of doripenem provided by the invention is prepared by using the above pyrrolidine derivative intermediate as a raw material, and comprises:
  • the method for deacetylating in the step a is: (2S, 4S) small p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indolyl-4- Acetylthiopyrrolidine is dissolved in an organic solvent such as tetrahydrofuran, and an aqueous solution of an inorganic base (sodium hydroxide, potassium hydroxide or lithium hydroxide) is added in a water bath to hydrolyze the acetyl group to obtain (2S, 4S)-1-p-nitro group.
  • an organic solvent such as tetrahydrofuran
  • an aqueous solution of an inorganic base sodium hydroxide, potassium hydroxide or lithium hydroxide
  • the nucleophilic substitution reaction in step b is: (lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryl group having a molar ratio of 1:1-1.5 Oxy-1-inden-1-carbo-2-penem-2-carboxylic acid p-nitrobenzyl ester and (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N- p-Nitrobenzyloxycarbonyl-N-sulfamoylamino)methyl-4-mercaptopyrrolidine is dissolved in DMF (N,N-dimethylformamide), and a tertiary amine (diisopropylethylamine) is added under cooling in a water bath.
  • DMF N,N-dimethylformamide
  • reaction mixture is diluted with ethyl acetate, washed successively with hydrochloric acid, saturated sodium hydrogencarbonate and saturated brine to wash off the tertiary amine, DMF, and the resulting diphenyl phosphate, anhydrous After drying over sodium sulfate, it is concentrated to a small volume, and a precipitate is added to the solvent to precipitate, which is filtered and dried.
  • step c The method of deprotection described in step c is: (lR,5R,6S)-2-[(3S,5S)-1- 1-p-Nitrobenzyloxy 5-(N-p-nitrobenzyloxytt-N-sulfamoylamino)decylpyrrolidine-3 -yl]thio-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbo-2-penems-3-carboxylic acid p-nitrobenzyl ester dissolution, hydrogenolysis reduction (lR,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrolidin-3-yl]thio- 1-Methyl-1-carbo-2-penem-3-carboxylic acid.
  • the process route is as follows:
  • the novel pyrrolidine derivative intermediate provided by the invention does not contain a tert-butoxycarbonyl (Boc) protecting group, and the preparation method is simple, and is used for preparing doripenem, thereby avoiding side reactions caused by acid hydrolysis, and giving products Purification brings convenience.
  • (2S,4S)-1-p-nitrobenzyloxyl group obtained by deacetylation of the intermediate 2-(N-p-Nitrobenzyloxycarbonyl-N-sulfamoylamino)nonyl-4-mercaptopyrrolidine is a solid powder, which facilitates the metering of industrial production.
  • the preparation of the doxorphane of the invention uses a novel pyrrole oxime derivative intermediate, which is not a k-butoxycarbonyl (Boc) protecting group, is used for preparing doripenem, has a simple preparation method and avoids the use of sulfuric acid.
  • Mercaptopyrrolidine is a solid powder, which facilitates the metering of materials in industrial production.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne des composés de formule générale (I), dans laquelle PNZ représente le p-nitrobenzyl-oxycarbonyle, R représente Ac ou H, ainsi que le procédé de préparation de ces composés, et leur utilisation en tant qu'intermédiaires dans la préparation d'un nouvel antibiotique doripénème 1β-méthylcarbapénème, ainsi que le procédé de préparation du doripénème. Ces intermédiaires à base de dérivés de pyrrolidine ne comportent pas de groupe protecteur Boc et n'entraînent pas de réaction secondaire due à l'acidolyse. Le procédé selon la présente invention est donc simple, adapté à la purification du produit, et peu coûteux.
PCT/CN2006/001664 2005-07-15 2006-07-13 Intermediaires d'un derive de pyrrolidine, leur preparation et leur utilisation WO2007009354A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNA2006800077492A CN101137621A (zh) 2005-07-15 2006-07-13 吡咯烷衍生物中间体及其制备方法和用途

Applications Claiming Priority (2)

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CN200510021270.1 2005-07-15
CNB2005100212701A CN100460389C (zh) 2005-07-15 2005-07-15 吡咯烷衍生物中间体及其制备方法和用途

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Publication number Priority date Publication date Assignee Title
CN101376656A (zh) * 2007-08-30 2009-03-04 山东轩竹医药科技有限公司 培南衍生物
CN102093278B (zh) * 2011-03-09 2012-10-03 北京莱瑞森医药科技有限公司 一种多尼培南的中间体的制备工艺
CN102174047A (zh) * 2011-03-19 2011-09-07 湖南欧亚生物有限公司 一种多尼培南的新型制备工艺
CN102731505B (zh) * 2011-04-13 2015-09-02 石药集团中奇制药技术（石家庄）有限公司 一种多尼培南的制备方法
CN102249970A (zh) * 2011-05-09 2011-11-23 黄山市歙县宏辉化工有限公司 一种多尼培南侧链的合成工艺
CN102372714B (zh) * 2011-12-07 2014-04-16 凯莱英医药集团（天津）股份有限公司 一种制备多尼培南的方法
KR101910048B1 (ko) * 2014-04-28 2018-10-22 제이더블유중외제약 주식회사 도리페넴의 신규한 결정 및 이의 제조방법

Citations (1)

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Publication number Priority date Publication date Assignee Title
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Title
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KUME M. ET AL.: "Efficient and practical synthesis of 1beta-methylcarbapenems", TETRAHEDRON, vol. 53, no. 5, 1997, pages 1635 - 1646, XP004105251 *
NISHINO Y. ET AL.: "Practical Large-Scale Synthesis of Doripenem: A Novel 1b-Methylcarbapenem Antibiotic", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 7, no. 6, 2003, pages 846 - 850, XP002396087 *
NISHINO Y. ET AL.: "Practical Large-Scale Synthesis of the 2-Aminomethylpyrrolidin-4-ylthio-Containing Side Chain of the Novel Carbapenem Antibiotic Doripenem", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 7, no. 5, 2003, pages 649 - 654, XP003007096 *

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Publication number Publication date
CN101137621A (zh) 2008-03-05
CN1896057A (zh) 2007-01-17
CN100460389C (zh) 2009-02-11

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