WO2015070394A1 - Procédé de préparation d'un intermédiaire d'antibiotiques pénem - Google Patents

Procédé de préparation d'un intermédiaire d'antibiotiques pénem Download PDF

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Publication number
WO2015070394A1
WO2015070394A1 PCT/CN2013/087038 CN2013087038W WO2015070394A1 WO 2015070394 A1 WO2015070394 A1 WO 2015070394A1 CN 2013087038 W CN2013087038 W CN 2013087038W WO 2015070394 A1 WO2015070394 A1 WO 2015070394A1
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reaction
chemical formula
compound represented
compound
formula
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PCT/CN2013/087038
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English (en)
Chinese (zh)
Inventor
洪浩
马建国
李九远
董长明
张磊
Original Assignee
凯莱英医药集团（天津）股份有限公司
凯莱英生命科学技术(天津)有限公司
天津凯莱英制药有限公司
凯莱英医药化学（阜新）技术有限公司
吉林凯莱英医药化学有限公司
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Application filed by 凯莱英医药集团（天津）股份有限公司, 凯莱英生命科学技术(天津)有限公司, 天津凯莱英制药有限公司, 凯莱英医药化学（阜新）技术有限公司, 吉林凯莱英医药化学有限公司 filed Critical 凯莱英医药集团（天津）股份有限公司
Priority to PCT/CN2013/087038 priority Critical patent/WO2015070394A1/fr
Publication of WO2015070394A1 publication Critical patent/WO2015070394A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

  • the invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of a Pein-like antibiotic intermediate. Background technique
  • Pein-type drugs such as meropenem, doripenem and ertapenem are a class of broad-spectrum antibiotics for ⁇ -lactam injection. It is well known that the compound represented by the formula (la) is a card catalyzed by ruthenium.
  • the synthetic route shown in Reaction Scheme 2 is currently widely used.
  • the compound of the formula (la) can be subjected to CDI activation, nucleophilic addition reaction and decarboxylation reaction, and removal of TBS (t-butyl group) by ⁇ -methyl-ADC-8 (4-oxime, compound of formula (V)).
  • Dimethylsilyl hydrazine and the diazotization reaction involving t-decylbenzenesulfonyl azide are conveniently prepared. 0. Am. Chem. Soc, 1980, 102 6161-6163).
  • a difficulty with this route is the preparation of a compound represented by the chiral ⁇ -methyl formula (V).
  • 4-Acetylazetidinone (4AA, a compound of formula (VIII)) is generally used to prepare 4-BMA (reviewed in detail: Tetrahedron, 1996, 52, 33 1 -375).
  • 4-BMA (US53 10897, US4873324, EP230792, reaction formula 3) can be produced in a high yield and high selectivity by an asymmetric hydrogenation reaction.
  • the preparation of the compound of the formula (IX) is difficult.
  • the compound of the formula (XIV) can be obtained by a series of reactions of 4AA by a coupling reaction of isopropylidene methylmalonate, N-silylation and solvolysis of methyl isopropylidene malonate.
  • the acid-catalyzed asymmetric hydrolysis and removal of the protecting group can then give 4-indole at a ⁇ -selectivity of >10:1.
  • a primary object of the present invention is to provide a simple and commercially valuable synthetic route for the preparation of a compound of the formula by a two-step reaction of a compound of formula (II).
  • Another object of the present invention is to provide a high ⁇ -selective method for direct Mannich addition of a compound of the formula (II) using a compound of the formula ⁇ ).
  • the present invention also provides optimum reaction conditions for the Mannich reaction.
  • the present invention provides a process for preparing a penicillin antibiotic intermediate represented by the chemical formula ⁇ ), which comprises the steps shown in Reaction Scheme 7.
  • the compound represented by the chemical formula ⁇ ) is abbreviated as the compound ⁇ ), and the other compounds are also referred to as corresponding abbreviations.
  • TBS tert-butyldimethylsilyl
  • the functional group represented by R 1 includes, but is not limited to, methyl (Me), ethyl (Et), p-nitrobenzyl (PNB), benzyl (Bn), allyl (Allyl), 4-chlorobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl;
  • R 2 includes, but is not limited to, acetyl (Ac), benzoyl (Bz);
  • R 2 The functional groups represented by R 2 include, but are not limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS).
  • TMS trimethylsilyl
  • TBS tert-butyldimethylsilyl
  • the compound of the formula (III) can be easily synthesized by a conventional method.
  • Equation 7 The content in Equation 7 consists essentially of two steps:
  • Step h The compound of the formula ( ⁇ ) is reacted with a compound of the formula ⁇ ) to obtain a compound of the formula (XVI);
  • Step 2 The compound represented by the chemical formula (XVI) is prepared, that is, ⁇ - Methylpenic antibiotic intermediate.
  • Steps 1 and 2 are carried out according to the following reaction conditions:
  • step 1 the reaction can be carried out under a variety of known Lewis acid catalyzed direct Mannich reactions. After the reaction is completed, various methods can be used for post treatment.
  • the Lewis acid used in the Mannich reaction may be any of the existing acids used in the Mannich reaction, including but not limited to titanium tetrachloride (TiCl 4 ), titanium tetrabromide (TiBr 4 ), silicon tetrachloride (SiCl 4 ).
  • lanthanum trichloride LaCl 3
  • zinc chloride ZnCl 2
  • zinc bromide ZnBr 2
  • magnesium chloride MgCl 2
  • boron tribromide BBr 3
  • copper chloride CuCl 2
  • Copper triflate Cu(OTf) 2
  • cuprous triflate CuOTf
  • cuprous iodide Cul
  • boron trichloride BC1 3
  • the molar ratio of the Lewis acid to the compound of the formula (II) is 0.8 to 3.0:1, preferably 1.0 to 1.5: l o If less Lewis acid is used, the reaction cannot be completed.
  • a Lewis base is also present in the reaction of step 1.
  • the Lewis base may be any of the bases currently used in the Mannich reaction, including but not limited to triethylamine, diisopropylethylamine, tri-n-butylamine, tetramethylethylenediamine, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, N-methyl Pyrrolizine, N-methylpiperidine, diethylamine, diisopropylamine, pyrrole, piperidine, hexamethylphosphoric triamide, pyridine, 3-methylpyridine, and combinations thereof. It is preferred to use a tertiary amine therein.
  • the molar ratio of the Lewis base to the compound of the formula (II) is from 1.2 to 4.0:1, preferably
  • the reaction of the step 1 is usually carried out by dissolving the compound of the formula in an organic solvent, cooling, then adding a Lewis acid and a Lewis base, stirring, adding a compound of the formula ( ⁇ ), and then reacting until the end.
  • the solvent includes methylene chloride, 1,2-dichloroacetonitrile, toluene, acetonitrile, tetrahydrofuran, methyl t-butyl ether, 2-methyltetrahydrofuran or a combination thereof.
  • methylene chloride, 1,2-dichloroethane or a combination thereof is used.
  • the solvent is used in an amount of 8 to 30 mL/g based on the compound of the formula ( ⁇ ) (i.e., 8 to 30 mL of the solvent per gram of the compound represented by the formula ( ⁇ ), preferably 12 to 20 mL/g.
  • the molar ratio of the compound of the formula (III) to the compound of the formula ( ⁇ ) is 1.0 to 2.0: 1, preferably 1.2 to 1.5: 1.
  • the reaction temperature in the step 1 is -60 to 10 ° C, preferably -30 to 0 ° C.
  • a suitable temperature for the addition of the Lewis acid and the Lewis base is -60 to 0 ° C, preferably -50 to 30 ° C.
  • the appropriate stirring time before the addition of the compound of the formula (II) should be 10 to 60 minutes, preferably 20 to 30 minutes.
  • a suitable temperature for the addition of the compound of the formula (II) is -60 to 0 ° C, preferably -40 to 20 ° C.
  • a suitable temperature for the reaction is -40 to 10 ° C, preferably -20 to 0 ° C.
  • the reaction will proceed very slowly at lower temperatures.
  • the appropriate reaction time should be within 4 hours and, if possible, the reaction should be completed within 2.5 hours. Longer reaction times result in more impurities and lower yields.
  • the reaction is quenched with an aqueous solution such as aqueous sodium chloride solution, aqueous sodium hydrogencarbonate solution, aqueous sodium dihydrogen phosphate solution, aqueous potassium dihydrogen phosphate solution, aqueous magnesium chloride solution, aqueous calcium chloride solution or purified water, preferably using pure water.
  • an aqueous solution such as aqueous sodium chloride solution, aqueous sodium hydrogencarbonate solution, aqueous sodium dihydrogen phosphate solution, aqueous potassium dihydrogen phosphate solution, aqueous magnesium chloride solution, aqueous calcium chloride solution or purified water, preferably using pure water.
  • concentration of the aqueous solution is a concentration of a common quenching solution, and preferably the mass percentage of the solute may be 5% to 25%.
  • the amount of the quenching solution is 3 to 30 mL/g, preferably 5 to 10 mL/g, based on the compound of the formula ( ⁇ ).
  • the compound of the formula (XVI) obtained in the step 1 can be directly used for the next reaction, or can be further purified, preferably using methanol, methanol-water, ethanol, ethanol-water, acetone, acetone-water, acetonitrile.
  • Solvents such as isopropanol, n-hexanol, n-glycol, toluene, petroleum ether, etc. are purified by recrystallization, more preferably by recrystallization from methanol-water.
  • the amount of the recrystallization solvent is from 3 to 20 mL/g, preferably from 4 to 8 mL/g, based on the compound of the formula (II). Using more solvent will reduce the yield.
  • the reaction can be carried out under various reaction conditions in which the acid is removed by the removal of the t-butyldimethylsilyl group or the trimethylsilyl group. After the completion of the reaction, various methods can be used for the post treatment.
  • the acid used for removing tert-butyldimethylsilyl or trimethylsilyl protection includes hydrochloric acid (HC1), sulfuric acid (H 2 S0 4 ), methanesulfonic acid (MeS0 3 H), benzenesulfonate. Acid (PhS0 3 H) and trifluoroacetic acid, preferably hydrochloric acid.
  • the concentration of the hydrochloric acid for protecting the tert-butyldimethylsilyl or trimethylsilyl group is 0.5-4 mol/L, preferably 1.0 to 2.0 mol/L.
  • the reaction of the step 2 is carried out in a solvent selected from the group consisting of a mixed solvent of acetonitrile-water, methanol-water, acetone-water, tetrahydrofuran-water, etc., wherein the volume concentration of the organic solvent ranges from 40% to ⁇ 80%, preferably an acetonitrile-water solution having a volume concentration of 40% to 80% acetonitrile is used as a reaction solvent.
  • the amount of the solvent used is 4 to 15 mL/g, preferably 6 to 10 mL/g, based on the compound of the formula (XVI).
  • the suitable temperature for the step 2 reaction is 0 to 30 ° C, preferably 15 to 20 ° C.
  • the preparation method provided by the present invention has obvious advantages.
  • the reaction step is greatly shortened, and it is required to prepare a compound represented by the chemical formula ⁇ ) from the compound represented by the chemical formula ⁇ )
  • the preparation method used in the present invention requires only 2 steps, so the reaction cycle is greatly shortened, labor costs are saved, equipment investment for commercial production is reduced, and the types and amounts of solvents used are reduced. The pollution is also relatively reduced, while saving the production costs of the factory.
  • the preparation method of the present invention is easily obtained as a raw material, and the selectivity and yield of the obtained product are remarkably improved as compared with the prior art. detailed description
  • the compound of formula (Ilia) (188 g) was dissolved in dichloromethane (1500 mL), cooled to -40 ° C, and titanium tetrachloride (104 g) in dichloromethane (300 mL) was slowly added. The resulting yellow slurry was stirred for a further 30 minutes. Triethylamine (105 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, then a solution of 4AA (150 g) in dichloromethane (300 mL) was slowly added. After stirring at -20 °C for 3 hours, the reaction was warmed to 5 ° C then quenched with water (750 mL).
  • the compound of formula (XVIa) (51 g) is suspended in acetonitrile with 40% by volume of acetonitrile.
  • Step reaction should be. .
  • the crude crude product of the chemical compound represented by the above-mentioned chemical formula ((XXVVIIIIbb)) is added at about 2200 ° ° CC, toluene benzene ((330000 mm LL) And triethyltriethylamine ((3355..44 gg)), and then post-drip plus p-dodecyldiphenylbenzenesulfonyl-lacide azide nitrogen (227700 ..44 gg)). . After the drop is completed, 5 will return to the room temperature and the reaction should be 55 hours. .
  • the reaction system is concentrated and concentrated to about 220000 ⁇ 330000 mmLL, and then added to the positive gengbeng ((550000 mmLL)), and the ice-cold water bath is cooled by cooling and stirred. Mix about 55 hours. .
  • the filter cake is washed and washed with Zheng Geng Geng, dried and dried to obtain the chemical compound represented by the chemical formula ((nniibb)) ((112266) Gg,, yield yield: 6677%%)), liquid-liquid phase purity purity 9999..44%%. .
  • Methyl 3-oxopentanoate (30 g), toluene (150 mL) and triethylamine (11.6 g) were added at about 15 ° C, then p-dodecylbenzenesulfonyl azide (89.1 g) was added dropwise. After the dropwise addition, the mixture was naturally returned to room temperature for 5 hours. The reaction system was concentrated to a fraction. The crude product was purified by silica gel column chromatography to give the compound of formula (IIIc) (33.8 g, yield 94%), and the liquid phase purity was 98.5%.
  • Titanium tetrachloride (13.2 g) was slowly added at -40 ° C, and the resulting yellow slurry was stirred for further 30 minutes.
  • Triethylamine (14.1 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, then a solution of 4AA (20 g) of dichloromethane (40 mL) was slowly added. After stirring at -20 ° C for 3 hours, The reaction was warmed to rt then EtOAc (EtOAc)EtOAc. The mixture was allowed to stand for separation, the methylene chloride phase was separated, and then concentrated to give a crude product of the formula (XVId).
  • Titanium tetrachloride (13.2 g) was slowly added at -40 ° C, and the resulting yellow slurry was stirred for further 30 minutes.
  • Triethylamine (14.1 g) was slowly added, then the reaction mixture was warmed to -20 ° C and stirring was continued for 1 hour, then a solution of 4AA (20 g) of dichloromethane (40 mL) was slowly added. After stirring at -20 °C for 3 hours, the reaction was warmed to EtOAc EtOAc. The mixture was allowed to stand for separation, and the methylene chloride phase was separated, and then concentrated to give 47.4 g of crude compound of formula (XVI).

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

Abstract

La présente invention concerne un procédé de préparation d'un intermédiaire d'antibiotiques pénem. Le procédé comprend les étapes suivantes : étape 1 : préparation d'un composé intermédiaire par une réaction de Mannich; et étape 2 : conversion du composé intermédiaire en un intermédiaire d'antibiotiques pénem. Le procédé raccourcit la durée de la réaction, réduit le coût et réduit la pollution de l'environnement, et on obtient aisément les produits de la réaction; de plus la sélectivité et le rendement du procédé sont remarquablement améliorés par comparaison avec la technique antérieure.
PCT/CN2013/087038 2013-11-13 2013-11-13 Procédé de préparation d'un intermédiaire d'antibiotiques pénem WO2015070394A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315299A (zh) * 2015-09-22 2016-02-10 盐城开元医药化工有限公司 一种头孢唑肟母核7-anca的合成方法
CN105906529A (zh) * 2016-06-07 2016-08-31 江西富祥药业股份有限公司 4-卤代-2-重氮-3-氧代-戊酸(4-硝基苯)甲酯及其制备方法
CN117186116A (zh) * 2023-09-07 2023-12-08 浙江荣耀生物科技股份有限公司 一种头孢维星中间体的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4841043A (en) * 1985-12-23 1989-06-20 Bristol-Myers Company Stereoselective synthesis of 1-β-alkyl carbapenem antibiotic intermediates
CN1610663A (zh) * 2002-03-25 2005-04-27 高砂香料工业株式会社 氮杂环丁酮化合物的制备方法
CN102936217A (zh) * 2012-11-08 2013-02-20 浙江新东港药业股份有限公司 一种培南中间体的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4841043A (en) * 1985-12-23 1989-06-20 Bristol-Myers Company Stereoselective synthesis of 1-β-alkyl carbapenem antibiotic intermediates
CN1610663A (zh) * 2002-03-25 2005-04-27 高砂香料工业株式会社 氮杂环丁酮化合物的制备方法
CN102936217A (zh) * 2012-11-08 2013-02-20 浙江新东港药业股份有限公司 一种培南中间体的制备方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315299A (zh) * 2015-09-22 2016-02-10 盐城开元医药化工有限公司 一种头孢唑肟母核7-anca的合成方法
CN105315299B (zh) * 2015-09-22 2017-06-27 盐城开元医药化工有限公司 一种头孢唑肟母核7‑anca的合成方法
CN105906529A (zh) * 2016-06-07 2016-08-31 江西富祥药业股份有限公司 4-卤代-2-重氮-3-氧代-戊酸(4-硝基苯)甲酯及其制备方法
CN105906529B (zh) * 2016-06-07 2018-11-27 江西富祥药业股份有限公司 4-卤代-2-重氮-3-氧代-戊酸(4-硝基苯)甲酯及其制备方法
CN117186116A (zh) * 2023-09-07 2023-12-08 浙江荣耀生物科技股份有限公司 一种头孢维星中间体的制备方法
CN117186116B (zh) * 2023-09-07 2024-06-07 浙江荣耀生物科技股份有限公司 一种头孢维星中间体的制备方法

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