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WO1998007690A1 - Procede de preparation stereoselective de 4-acetoxyazetidinones - Google Patents

Procede de preparation stereoselective de 4-acetoxyazetidinones Download PDF

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Publication number
WO1998007690A1
WO1998007690A1 PCT/KR1997/000071 KR9700071W WO9807690A1 WO 1998007690 A1 WO1998007690 A1 WO 1998007690A1 KR 9700071 W KR9700071 W KR 9700071W WO 9807690 A1 WO9807690 A1 WO 9807690A1
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Prior art keywords
general formula
group
compound
process according
reaction
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PCT/KR1997/000071
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English (en)
Inventor
Mi-Jung Lee
Taek-Hyun Yoon
In-Hee Lee
Hee-An Kwon
Tae-Seop Hwang
Su-Jin Lee
Chan-Yong Ahn
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Choongwae 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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Publication date
Application filed by Choongwae Pharmaceutical Co., Ltd. filed Critical Choongwae Pharmaceutical Co., Ltd.
Priority to AU27131/97A priority Critical patent/AU2713197A/en
Priority to JP51060498A priority patent/JP4108130B2/ja
Publication of WO1998007690A1 publication Critical patent/WO1998007690A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to a process for stereoselective preparation of (3R,4R)-4-acetoxy-3- ⁇ [( 1 'R)- 1 '-t-butyldimethylsilyloxy] ethyl ⁇ -2-azetidinone (I) (here-in-after, abbreviated as "4- acetoxyazetidinone”) which is a useful intermediate for preparing carbapenem and penem type ⁇ -lactam antibiotics.
  • Ri represents a lower alkyl group
  • OAc represents acetoxy group
  • the 4-acetoxyazetidinones represented by general formula (I), a useful intermediate for carbapenem and penem type antibiotics, are known compounds which are produced by three Japanese companies (Kanega Fuchi, Suntory-Nippon Soda and Takasago) in a beautiful amount every year.
  • the synthetic processes are illustrated in short by the following reaction schemes.
  • TBDMS represents t-butyldimethylsilyl group
  • TMS represents trimethylsilyl group
  • R 2 represents a CM lower alkyl group
  • R 3 represents aryl group, or substituted benzyl group, particularly 4- methoxyphenyl group or 2,4-dimethoxybenzyl, as a ⁇ -lactam protective group.
  • the compound (V) can be prepared by a process developed by the present inventors et al. First, L-threonine is converted to (2R,3R)- epoxybutyric acid (VII) by the use of a known procedure [Tae-sub Hwang et al., Korean Patent Laid-Open No.
  • R 2 and R 3 are defined as above.
  • the object of the present invention is to provide a process for economically preparing the compound represented by general formula (I) with a high yield.
  • a process for preparing the compound (I) through a 5-step process starting from the compound represented by general formula (V) is provided, as illustrated in Scheme 3.
  • an epoxyamide (V) is reacted with an alkali metallic strong base, and the product, without further purification, is treated with t- butyldimethylchlorosilane to give silyl ester azetidinone (IV) in a one-pot reaction.
  • the alkyl ester group of silyl ester azetidinone (IV) thus obtained is hydrolyzed and treated with an acid to obtain (3S,4S)-3- ⁇ [(l'R)- -t- butyldimethylsilyloxy ] ethyl ⁇ - 4 - carboxy - 1 - aryl - 2 - azetidinone represented by general formula (III) (here-in-after, abbreviated as "4-carboxyazetidinone”) as a free acid form.
  • general formula (III) here-in-after, abbreviated as "4-carboxyazetidinone
  • the free acid group of the 4-carboxyazetidinone (III) is stereoselectiveiy acetoxylated to synthesize (3R,4R)-4- acetoxy-3- ⁇ [( rR)-l '-t- butyldimethylsilyloxy]ethyl ⁇ -l-aryl-2-azetidinone of general formula (II) (here-in-after, abbreviated as "aryl-4-acetoxyazetidinone".
  • the protective group for ⁇ -lactam ring, the aryl group is then selectively deprotected by ozonolysis to give 4-acetoxyazetidinone represented by general formula (I).
  • R 1 , R 2 , R 3 and OAc arc defined as above.
  • Step 1 and Step 2 are a process performed in a one-pot reaction.
  • the present invention provides a more economic and simple process as the reactions are carried out in an one-pot reaction in the present invention, while the reactions have been performed in two steps in the known process. Thus, the overall yield is greatly increased in the invention.
  • the alkali metallic strong bases which may be used in the step include lower alkyl lithiums such as methyl lithium and n-butyl lithium; alkali metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal amides such as lithium amide, sodium amide, lithium hexamethyldisilazide, lithium diisopropylamide and lithium dicyclohexylamide; alkali metal hydride such as sodium hydride and potassium hydride; and mixtures of alkali metal and DMSO such as sodium Dimsylate and lithium Dimsylate.
  • lower alkyl lithiums such as methyl lithium and n-butyl lithium
  • alkali metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide
  • alkali metal amides such as lithium
  • lithium hexamethyldisilazide in an amount of 1 to 3 equivalents is used.
  • the reaction temperature is selected between -30 ° C to room temperature in order to inhibit the production of diastereomers as far as possible.
  • dichloromethane or tetrahydrofuran may be preferably used.
  • the step 2 is performed in situ by adding trialkylhalosilane derivative to the product of step 1 , to obtain the silyl ester azetidinone of general formula (IV).
  • Trialkylhalosilane derivatives are fully described in the literature ["Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons: New York, USA( 1991 )].
  • t- butyldimethylchlorosilane was preferably used so as to minimize the side reactions and to improve the yield and stability of the product.
  • the epoxyamide (V) is treated with a strong base such as lithium amide or the like to produce an anion at a -carbon position adjacent to the ester group, and the anion attacks C2-position of the epoxide by SN2 mode to form an azetidinone ring.
  • diastereomers are usually produced, however, the inventors confirmed by using 300 MHz 'H-NMR and high performance liquid chromatography, that only the desirable stereoisomer having trans configuration is produced according to the present invention.
  • Step 3 the silyl ester azetidinone of general formula (IV) is treated by means of saponifi cation in the presence of alkali metal hydroxide and then acidification to obtain the 4-carboxyazetidinone of general formula (III) as free acid form.
  • alkali metal hydroxide sodium hydroxide or potassium hydroxide (KOH) may be used. It is preferable to use sodium hydroxide in an amount of 1 to 2 equivalents, with an economic viewpoint.
  • the reaction temperature may be selected between room temperature and reflux temperature unless there occurs particular side reactions.
  • the Step 4 is a process to introduce an acetoxy group at C4- position by a stereoselective acetoxylation of the 4-carboxyazetidinone of general formula (III).
  • an oxidant which can oxidize the free acid at C4-position and introduce an acetoxy group thereto, lead oxide (Pb3 ⁇ ), lead tetraacetate [Pb(OAc)4], mercuric acetate [Hg(OAc)2], cupric acetate [Cu(OAc)2] or thallium acetate [Tl(OAc). ] may be used.
  • acetic acid in an amount of 1 to 3 equivalents in the presence of acetic acid, or lead tetraacetate of 1 to 3 equivalents.
  • acetonitrile dimethylformamide, methanol, dimethyl sulfoxide, acetic acid or acetic anhydride may be employed.
  • acetic acid may be preferably used alone or with dimethylformamide.
  • the reaction is preferably performed at a temperature range between 0 ° C and 80 ° C .
  • the Step 5 is to effectively remove the aryl group, particularly p- methoxyphenyl group among the protective groups, in order to prepare 4- acetoxyazetidinone of general formula (I).
  • a variety of oxidation processes are applied on the aryl-4-azetidinone of general formula (II) to remove aryl group so as to obtain desired 4- acetoxyazetidinone (I).
  • the oxidation process included in the step is a known technique from the literature written by Green et al. ["Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons: New York, USA( 1991 )] on page 400.
  • the conventional deprotecting techniques described in the literature may be usually applied.
  • the protective groups are usually removed in the final reactive step, they are sometimes needless from the viewpoint of the overall synthetic steps. However, they must be considered carefully because they can avoid the possibility of side reactions to increase the total reaction yield.
  • the properties of the protective group to be used depend upon the properties of the functional groups thereof. As the common knowledge concerning the protective groups is essential to any organic chemists, it is not necessary to explain or define protective groups and deprotection thereof in the specification. However, described herein is the deprotection process, in connection with Step 5, in which the aryl group, particularly p- methoxyphenyl group (a protective group for ⁇ -lactam ring) from aryl- 4-acetoxyazetidinone of general formula (II) is removed.
  • the removal of p-methoxyphenyl group, the protective group for ⁇ -lactam, in Step 5 is mainly performed through an oxidation reaction by generating oxygen.
  • an oxidant ceric ammonium nitrate, potassium permanganate, sodium bichromate, 2,3-dichloro-5,6- dicyano- l ,4-benzoquinone (DDQ) or ozone may be used. Good results could be also obtained by modifying the electrochemical oxidation developed by the present inventors et al.
  • Preferable oxidants used in Step 5 include ceric ammonium nitrate or ozone.
  • Preferable solvents include dioxane, tetrahydrofuran, hexane, ethyl acetate, acetonitrile, dimethyl formamide, dichloromethane, chloroform, carbon tetrachloride, acetic acid, methanol and ethanol.
  • ceric ammonium nitrate as an oxidant
  • best result could be obtained by using a mixed solvent of acetonitrile and water.
  • the reaction was preferably performed by using methanol as a single solvent, at a relatively low temperature at -40 to 10 ° C .
  • the environmental pollution resulted from the prior art can be avoided by performing the removal of p-methoxyphenyl group, a protective group for azetidinone ring, by the use of ozone, and the acetoxylation using electrochemical oxidation reaction also is an advanced synthetic technique to minimize the pollution, although this reaction can be carried out with known oxidation agent.
  • the present invention provides economic advantages as well as high synthetic yield.
  • Lithium amide (2.5 g, 0.1 mol) was suspended in THF (40 ml) under nitrogen atmosphere, and hexamethyldisilazane (12.5 ml, 0.15 mol) was added thereto. After heating under reflux for 3 hours, the reaction mixture was chilled to -10 ° C .
  • Epoxyamide (V) (20.5 g, 0.07 mol) was dissolved in THF (200 ml) and the solution chilled to -30 ° C .
  • the Lithium hexamethyldisilazide solution prepared above was added thereto under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at the same temperature.
  • Example 3 (3R,4R)-4-Acetoxy-3- ⁇ ((l'R) -l'-t-butyldimethyl silyloxy]ethyl ⁇ -l-p-methoxyphenyl-2-azetidinone (Method A) To a mixed solution of dimethylformamide and acetic acid (3/1 , 300 ml), 4-carboxyazetidinone (III) (15 g, 39.5 mmol) was added. Tetravalent lead acetate (24.5 g, 55.3 mmol) was then added thereto, and the reaction mixture was stirred for 2 hours while maintaining the reaction temperature at 60 ° C .
  • Aryl-4-acetoxyazetidinone (II) (26 g, 66 mmol) was dissolved in methanol (500 ml). The internal temperature of the reactor was lowered to -20 ° C , and the reaction was performed for 3 hours with slowly incorporating ozone. After the reaction was completed, 10% solution of Na2S2 ⁇ 3 and thiourea were added sequentially, and the resultant mixture was vigorously stirred for 30 minutes at room temperature. Then, the reaction mixture was concentrated to have a volume of 1/3 of the initial volume of the mixture. The concentrate was chilled to -10 ° C to produce white crystalline powder. The powder was filtered, dried and recrystallized from n-hexane to obtain pure 4-acetoxyazetidinone (I) ( 18.1 1 g, 85%) as white crystals.
  • aryl-4-acetoxyazetidinone (II) (349 mg, 1 mmol) was added and dissolved.
  • the mixture was poured in a non-dividable electrolysis vessel with connecting an amorphous carbon anode and an cathode plate, and a Ag/Ag" reference electrode to a Potentiostat (EG & G 273). Under 1.8 V constant voltage, the mixture was electrolysed until all the starting material disappeared. After removing the organic solvent by evaporation under reduced pressure, the residue was dissolved in ethyl acetate.
  • Aryl-4-acetoxyazetidinone (II) (5 g, 12.7 mmol) was dissolved in acetonitrile (100 ml). After chilling the solution to -15 ° C , a solution of ceric ammonium nitrate (34.8 g, 63.5 mmol) dissolved in water (150 ml) was added dropwise. The resultant mixture was stirred for 30 minutes. After the completion of the reaction, the mixture was extracted from ethyl acetate (300 ml), and the organic layer was washed with each 200 ml of water, 10% Na2S ⁇ 3 solution, 10% NaHC ⁇ 3 solution and saturated brine, sequentially, and then concentrated under reduced pressure. The obtained brown residue was recrystallized from n-hexane to give 4- acetoxyazetidinone (I) (3.1 g, 89%) as white crystalline powder.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation stéréosélective de (3R,4R)-4-acétoxy-3-{[(1'R)-1'-t-butyldiméthylsilyloxy]éthyl}-2-azétidinone (I), constituant un intermédiaire utile dans la préparation des antibiotiques β-lactame de type carbapénem et pénem. Selon l'invention, le composé en étant l'objet peut être synthétisé avec des avantages économiques et un bon rendement de synthèse.
PCT/KR1997/000071 1996-08-24 1997-04-30 Procede de preparation stereoselective de 4-acetoxyazetidinones WO1998007690A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU27131/97A AU2713197A (en) 1996-08-24 1997-04-30 Process for stereoselective preparation of 4-acetoxyazetidinones
JP51060498A JP4108130B2 (ja) 1996-08-24 1997-04-30 ４―アセトキシアゼチジノンの立体選択的な製造方法

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KR1019960035355A KR100205768B1 (en) 1996-08-24 1996-08-24 Stereo-selective composition of 4-acetoxyazetidinone
KR1996/35355 1996-08-24

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PCT/KR1997/000072 WO1998007691A1 (fr) 1996-08-24 1997-04-30 Procede de preparation stereoselective de trans-azetidinones

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WO2007004028A2 (fr) * 2005-06-30 2007-01-11 Ranbaxy Laboratories Limited Procedes de preparation de penemes et de leurs intermediaires
CN102002066A (zh) * 2010-11-01 2011-04-06 山东鑫泉医药中间体有限公司 一种4―乙酰氧基―2―氮杂环丁酮的合成方法
CN102336696A (zh) * 2011-07-15 2012-02-01 浙江海翔川南药业有限公司 合成4-aa的中间体及其制备方法和用途
CN102432632A (zh) * 2011-09-16 2012-05-02 上海悦昂化学有限公司 一种（3r，4r）-3-[（1r）叔丁基二甲基硅氧乙基]-4-乙酰氧基-2-氮杂环丁酮的制备方法
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US10858385B2 (en) 2017-10-11 2020-12-08 Greenlight Biosciences, Inc. Methods and compositions for nucleoside triphosphate and ribonucleic acid production
US10954541B2 (en) 2016-04-06 2021-03-23 Greenlight Biosciences, Inc. Cell-free production of ribonucleic acid
CN113549102A (zh) * 2021-09-22 2021-10-26 凯莱英医药集团（天津）股份有限公司 脱除酰胺基团上的对甲氧基苯基保护基的方法
US11274284B2 (en) 2015-03-30 2022-03-15 Greenlight Biosciences, Inc. Cell-free production of ribonucleic acid
CN115385950A (zh) * 2022-10-27 2022-11-25 天津凯莱英医药科技发展有限公司 连续臭氧氧化制备4-乙酰氧基氮杂环丁酮的系统及方法

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CN101684110B (zh) * 2008-09-22 2014-02-12 浙江九洲药业股份有限公司 一种氮杂环丁酮衍生物的制备方法
KR101314955B1 (ko) 2011-02-21 2013-10-04 강원대학교산학협력단 페넴계 항생제 중간체의 제조방법
CN105153075A (zh) * 2015-08-31 2015-12-16 江苏瑞克医药科技有限公司 一种提高亚胺培南关键中间体2，3-环氧丁酸纯度的后处理方法

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WO2007004028A3 (fr) * 2005-06-30 2007-03-29 Ranbaxy Lab Ltd Procedes de preparation de penemes et de leurs intermediaires
WO2007004028A2 (fr) * 2005-06-30 2007-01-11 Ranbaxy Laboratories Limited Procedes de preparation de penemes et de leurs intermediaires
US9637746B2 (en) 2008-12-15 2017-05-02 Greenlight Biosciences, Inc. Methods for control of flux in metabolic pathways
US8956833B2 (en) 2010-05-07 2015-02-17 Greenlight Biosciences, Inc. Methods for control of flux in metabolic pathways through enzyme relocation
US10006062B2 (en) 2010-05-07 2018-06-26 The Board Of Trustees Of The Leland Stanford Junior University Methods for control of flux in metabolic pathways through enzyme relocation
US10036001B2 (en) 2010-08-31 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Recombinant cellular iysate system for producing a product of interest
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CN102002066B (zh) * 2010-11-01 2013-10-02 山东鑫泉医药中间体有限公司 一种4―乙酰氧基―2―氮杂环丁酮的合成方法
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JP2000516934A (ja) 2000-12-19
KR100205769B1 (ko) 1999-07-01
WO1998007691A1 (fr) 1998-02-26
KR19980018088A (ko) 1998-06-05
AU2713197A (en) 1998-03-06
KR19980018089A (ko) 1998-06-05
JP2000516628A (ja) 2000-12-12
JP4108130B2 (ja) 2008-06-25
KR100205768B1 (en) 1999-07-01
AU2713297A (en) 1998-03-06

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