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WO2008134923A1 - Procédé de préparation d'un dérivé de thiol en tant qu'intermédiaire de chaîne latérale pour la synthèse d'un dérivé de carbapénem - Google Patents

Procédé de préparation d'un dérivé de thiol en tant qu'intermédiaire de chaîne latérale pour la synthèse d'un dérivé de carbapénem Download PDF

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Publication number
WO2008134923A1
WO2008134923A1 PCT/CN2008/000814 CN2008000814W WO2008134923A1 WO 2008134923 A1 WO2008134923 A1 WO 2008134923A1 CN 2008000814 W CN2008000814 W CN 2008000814W WO 2008134923 A1 WO2008134923 A1 WO 2008134923A1
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WO
WIPO (PCT)
Prior art keywords
compound
derivative
branched
chain intermediate
iii
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/CN2008/000814
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English (en)
Chinese (zh)
Inventor
Jianping Cai
Enhai Fan
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.)
ZHEJIANG NEXCHEM PHARMACEUTICAL CO Ltd
Original Assignee
ZHEJIANG NEXCHEM 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.)
Filing date
Publication date
Application filed by ZHEJIANG NEXCHEM PHARMACEUTICAL CO Ltd filed Critical ZHEJIANG NEXCHEM PHARMACEUTICAL CO Ltd
Publication of WO2008134923A1 publication Critical patent/WO2008134923A1/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
    • 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

Definitions

  • the present invention relates to the field of organic chemistry and medicinal chemistry, and in particular, to a method for preparing a thiol derivative of a medicinal branched intermediate of piran. Background technique
  • Peron (carbampenal) drugs such as imipenem, meropenem and biapenem have good antibacterial activity against many resistant bacteria, especially for B-type enzymes.
  • (2S, 4S)-Substituted carbamoyl-4-mercapto- 1-(N-substituted) pyrrolizole (i) is an important branched intermediate of piranol drugs such as meropenem.
  • a lower decyloxycarbonyl group, a halogenated decyloxycarbonyl group, a fluorenyloxycarbonyl group having a aromatic diameter, and a trimethylsilyl group, and R 4 and R 5 represent the same or different hospitals containing d-Cs carbon atoms.
  • ⁇ can be tert-butoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trimethyl A silyl group or a tert-butyldimethylsilyl group; and R 2 may be an ethoxycarbonyl group, a tert-butoxycarbonyl group, an isopropoxycarbonyl group, a methanesulfonyl group or a p-toluenesulfonyl group.
  • R 4 and R 5 may be the same or different and include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, propenyl, butenyl, phenyl, substituted phenyl, pyridyl, 2 Pyridinemethyl, 3-pyridylmethyl, 4-pyridylmethyl.
  • the first method is to use t ns-4-hydroxy-L-proline as the raw material, protected by the amino group on the pyrrole ring, the 2-position carboxyl group is protected to form an ester, the 4-position hydroxyl group is substituted to obtain a vapor, and then the second position is hydrolyzed.
  • the carboxylic acid, the amidation, and the 4-position hydrolysis are carried out in a total of 6 steps to obtain the compound (i), and the reaction route is as follows:
  • Another method is to use trans- 4-hydroxy-L-proline as a raw material, protected by an amino group on a pyrrole ring, and the 2-position carboxyl group is directly reacted with a secondary amine to obtain an amide, and then substituted at the 4-position to obtain a compound (i). ), its synthetic route is as follows:
  • Patent W09902513 mentions another route which uses amino-protected trans-4-hydroxy-L-proline as a raw material, is protected by a 2-carboxyl group, a 4-hydroxyl group, is ring-closed, and is ring-opened to obtain a compound (i).
  • the synthetic route is as follows:
  • the object of the present invention is to provide a preparation method of a perylene-based drug branched-chain intermediate-thiol derivative, and the synthetic route of the preparation method is as shown in formula 4:
  • a method for preparing a peronal drug branched-chain intermediate monothiol alcohol derivative characterized in that the method comprises the following steps:
  • the compound (vi) is hydrolyzed under basic conditions to obtain a thiol derivative (i) of a perindanic branched intermediate.
  • a thiol derivative (i) of a perindanic branched intermediate represents an acyl compound.
  • the compound (iii) and the compound (iv) are isolated, and the compound (v) is obtained in a one-pot method.
  • the first two steps use a one-pot method to make the compound (iii) and the compound (iv) directly obtain the compound (v) without isolation, which simplifies the operation and reduces the production cost.
  • the preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that: from the compound (V) to the target (i), the compound (vi) is directly subjected to hydrolysis without drying treatment.
  • the desired product thiol derivative (i) is obtained.
  • the L-proline derivative (ii) is protected by a carboxyl group under the catalysis of an organic base to obtain a compound (iii) wherein the ratio of the organic base to the L-proline derivative (ii) is 1 to 4:1. Temperature is - 20 to 30 ° C;
  • the compound (iii) is obtained by directly adding methylsulfonyl chloride for 0.4 to 3 hours without isolation to obtain a compound (iv) wherein the ratio of the methylsulfonyl chloride to the raw material L-proline derivative (ii) is 0.5 to 2 : 1, the reaction temperature is -35 ° C - 10 ° C;
  • the compound (vi) is hydrolyzed in a basic alcohol solution to obtain the desired product thiol derivative (i), and the reaction temperature is -35 to 35° (the alkali solution concentration is 0.1 to 5 mol/L).
  • the preparation method of the peronic drug branched-chain intermediate-monothiol derivative is characterized in that -
  • the organic base used in the step A is triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine, tri-n-propylamine or tri-n-butyl amine;
  • the preparation method of the peronic drug branched-chain intermediate-monothiol derivative characterized in that - the aprotic solvent in step D is hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethyl methoxide Acetylamine, acetonitrile, dimethyl sulfoxide or pyridine.
  • the alkaline solution in the crucible is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide in methanol or ethanol.
  • the beneficial effects of the present invention are as follows: A method for preparing a peronic drug branched-chain intermediate-thiol derivative is provided, and the first two steps of the preparation method adopt a one-pot method to make the compound (iii) and the compound (iv) need not be used. Separation, direct compound (v), simplifies operation and reduces production costs. At the same time, by changing the process route, the product is easier to purify and the yield is improved. Compared with the prior patent literature, the invention has simple method, the intermediate does not need to be separated, the yield is high, the operation is easy, and the method is suitable for large-scale production. detailed description

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un dérivé de thiol en tant qu'intermédiaire de chaîne latérale pour la synthèse d'un dérivé de carbapénem. Le procédé débute avec un dérivé de trans-4-hydroxy-L-proline en tant que matière première, qui est soumis à un procédé en un pot unique selon lequel le groupement 2-carbonyle est protégé, le groupement 4-hydroxy est protégé et la position 2 est substituée pour obtenir le dérivé 2-amide proline. La position 4 est ensuite substituée et la position 4 est hydrolysée en présence d'une base pour obtenir un dérivé à chaîne latérale thiol qui constitue un intermédiaire important pour le Méropénem. Le présent procédé est simple, ne nécessite pas de séparer les intermédiaires, présente un rendement élevé et est facile à mettre en œuvre. Il présente également des avantages par rapport aux procédés brevetés antérieurement. Il convient à la production industrielle.
PCT/CN2008/000814 2007-04-28 2008-04-21 Procédé de préparation d'un dérivé de thiol en tant qu'intermédiaire de chaîne latérale pour la synthèse d'un dérivé de carbapénem Ceased WO2008134923A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710068259.X 2007-04-28
CNA200710068259XA CN101041632A (zh) 2007-04-28 2007-04-28 一种培南类药物支链中间体——硫醇衍生物的制备方法

Publications (1)

Publication Number Publication Date
WO2008134923A1 true WO2008134923A1 (fr) 2008-11-13

Family

ID=38807449

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/000814 Ceased WO2008134923A1 (fr) 2007-04-28 2008-04-21 Procédé de préparation d'un dérivé de thiol en tant qu'intermédiaire de chaîne latérale pour la synthèse d'un dérivé de carbapénem

Country Status (2)

Country Link
CN (1) CN101041632A (fr)
WO (1) WO2008134923A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012079289A1 (fr) * 2010-12-16 2012-06-21 珠海亿邦制药股份有限公司 Poudre amorphe et forme polymorphique d'un dérivé de carbapénème, leur procédé de synthèse et leurs applications
CN105439932B (zh) * 2014-08-27 2018-06-29 北大方正集团有限公司 一种培南类药物中间体及其制备方法
CN105439933B (zh) * 2014-08-27 2017-11-24 北大方正集团有限公司 一种培南类药物硫醇支链的制备方法
CN114163371B (zh) * 2021-12-21 2024-05-14 天津市敬业精细化工有限公司 一种美罗培南侧链光学异构体及其制备方法和应用、美罗培南侧链杂质的检测方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943569A (en) * 1983-05-09 1990-07-24 Sumitomo Pharmaceuticals Co., Ltd. B-lactam compounds
WO1999002513A1 (fr) * 1997-07-09 1999-01-21 Novo Nordisk A/S Preparation de diaryl-benzopyrans

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943569A (en) * 1983-05-09 1990-07-24 Sumitomo Pharmaceuticals Co., Ltd. B-lactam compounds
WO1999002513A1 (fr) * 1997-07-09 1999-01-21 Novo Nordisk A/S Preparation de diaryl-benzopyrans

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAKOTO S. ET AL.: "A novel carbapenem antibiotic, SM-7338 structure-activity relationships", THE JOURNAL OF ANTIBIOTICS, vol. 43, no. 5, pages 519 - 532, XP002912928 *

Also Published As

Publication number Publication date
CN101041632A (zh) 2007-09-26

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