WO2008127070A1 - Procédé de préparation stéréosélective de 4-bma utilisant un auxiliaire chiral - Google Patents

Procédé de préparation stéréosélective de 4-bma utilisant un auxiliaire chiral Download PDF

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Publication number
WO2008127070A1
WO2008127070A1 PCT/KR2008/002142 KR2008002142W WO2008127070A1 WO 2008127070 A1 WO2008127070 A1 WO 2008127070A1 KR 2008002142 W KR2008002142 W KR 2008002142W WO 2008127070 A1 WO2008127070 A1 WO 2008127070A1
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WIPO (PCT)
Prior art keywords
formula
compound
preparing
chloride
bma
Prior art date
Application number
PCT/KR2008/002142
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English (en)
Inventor
Dong Gyun Shin
Myeng Chan Hong
Won Koo Lee
Hyun Joon Ha
Seong Cheol Moon
Chung Hyun Song
Kyung Ho Lee
Chang Woan Han
Jong Hyek Kim
Byung Goo Lee
Yoon Seok Song
Original Assignee
Daewoong Pharmaceutical Co., Ltd.
Daewoong Chemical Co., Ltd.
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Application filed by Daewoong Pharmaceutical Co., Ltd., Daewoong Chemical Co., Ltd. filed Critical Daewoong Pharmaceutical Co., Ltd.
Priority to CN2008800124172A priority Critical patent/CN101675031B/zh
Priority to JP2010503970A priority patent/JP5180289B2/ja
Publication of WO2008127070A1 publication Critical patent/WO2008127070A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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 present invention relates to a new process for stereoselectively preparing a compound of the following formula (6):
  • R represents hydrogen or a hydroxy-protecting group, particularly, (3R,4S)-3- [ [[R] - 1' -t-butyldimethylsilyloxy] ethyl] -A- [(R)- 1 "-carboxyethyl] -2-azetidinone (beta- methylazetidin-2-one; 4-BMA), which is useful as an intermediate for the synthesis of penems or carbapenems.
  • the present invention also relates to a new process for preparing a compound of the following formula (3):
  • the compound of formula (7) whose common name is Meropenem, exhibits a broad spectrum of antibacterial activity against gram-positive and gram-negative strains. In particular, it has an excellent antimicrobial effect in controlling gram-negative strains and metalactamase-producing strains. Also, the presence of the beta-methyl group makes Meropenem to have better stability against dehydropeptidase-1 (DHP-I) in the kidney compared to the existing carbapenem antibacterial agent of Imipenem (Antimicrobial Agents and Chemotheraphym 33, 215-222 (1989)). Thus, in contrast to Imipenem, Meropenem does not have to be administered along with cilastatin to maintain stability in the body, and can be administered alone.
  • DHP-I dehydropeptidase-1
  • propionyl group is introduced as an acyl group.
  • a halide compound, which is not easy to handle such as propionyl bromide, is used for introducing propionyl group, and a metal catalyst, such as n-butyllithium, is used for the coupling reaction (JP2789190, DE3632916, US5104984, KR940008748).
  • the present inventors have extensively studied to resolve the demerits of the earlier methods for the synthesis of 4-BMA of formula (6). As a result, they succeeded in preparing a chiral auxiliary from cheap starting material in high yield under mild conditions, and in obtaining good quality 4-BMA of ⁇ / ⁇ ratio being 99.5/0.5 or more and a high yield of 70% or more by coupling the chiral auxiliary with the 4- AA also under mild conditions, and then completed the present invention.
  • one of the objects of the present invention is to provide a new process for preparing the 4-BMA of formula (6) that can be effectively used as an intermediate for preparing carbapenem or penem antibiotics.
  • Another object of the present invention is to provide a new process for preparing the chiral auxiliary of formula (3) that is effectively used for stereoselectively preparing the compound of formula (6).
  • the present invention relates to a process for preparing the 4-BMA compound of formula (6):
  • R represents hydrogen or a hydroxy-protecting group, preferable one of which is the organic silyl group, such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, trimethylsilyl, etc. and particularly preferable is t-butyldimethylsilyl, which comprises the steps of coupling the chiral auxiliary of formula (3):
  • TMSCl trimethylchlorosilane
  • LDA lithium diisopropylamide
  • Tin 2 BOTf diethylborotriflate
  • ZnBr 2 zinc bromide
  • TDMSOTf tert- butyldimethylsilyltriflate
  • the process of the present invention uses titanium chloride that is comparatively cheap, and the reaction is carried out in a conventional organic base and solvent at 0 ° C to room temperature.
  • the chiral auxiliary is dissolved in a solvent and cooled to 0 ° C , titanium chloride is added in drops, and then an organic base is added in drops.
  • the 4- AA is added, and the reaction is carried out at room temperature to produce the desired compound of formula (5).
  • the solvent methylene chloride, dichloroethane, chloroform, etc., preferably methylene chloride can be used.
  • the solvent is used in an amount which is 5-50 times, preferably 15-25 times, greater with respect to the 4- AA compound of formula (4).
  • the organic base includes triethylamine (TEA), diisopropylethylamine (DIPEA), diethylamine
  • DEA butylamine, etc., preferably diisopropylethylamine
  • DIPEA diisopropylethylamine
  • the organic base is used in the amount of 0.8-5 eq., preferably 1-2 eq., with respect to the 4-AA compound of formula (4).
  • Titanium chloride is used in the amount of 1-3 eq., preferably 1.3-1.7 eq., with respect to the 4-AA compound of formula (4). If small amounts of titanium chloride are used, the reaction cannot be completed.
  • the suitable temperature when the organic base and titanium chloride are added should be between -20-10 ° C, preferably -5-5 ° C .
  • the chiral auxiliary is used in the amount of 1-2 eq., preferably 1.2-1.4 eq., with respect to the 4-AA compound of formula (4).
  • the suitable reaction temperature after adding even the 4-AA compound of formula (4) should be between 15-25 ° C .
  • the reaction proceeds very slowly when the temperature falls below this range, and the amount of impurities produced increases when the temperature is 25 ° C or higher.
  • the appropriate reaction time should be within 3 h, and the reaction should be completed within 2 h, if possible. The longer the reaction time, the more impurities produced, and therefore, it is preferable that the reaction be completed within 2 h.
  • the compound of formula (5) is hydrolyzed according to a method known in the art to produce the 4-BMA compound (see J Am. Chem. Soc, 1986, 108, 4675).
  • the desired 4-BMA compound is obtained by the hydrolysis using hydrogen peroxide and lithium hydroxide.
  • the present invention also relates to a new process for preparing the compound of formula (3) used as a chiral auxiliary in the above process for preparing the 4-BMA compound.
  • the chiral auxiliary of formula (3) can be prepared by a process comprising the steps of reacting the compound of formula ( 1 ) (L- Valinol) :
  • the compound of formula (2) can be easily synthesized by reacting the L-Valinol of formula (1) with a base and diethylcarbonate at a high temperature.
  • the reaction time may be shortened by controlling the amount of base under the same conditions.
  • the amount of base used should be 0.1-2 eq., preferably 0.5-1 eq., with respect to L-Valinol.
  • the bases that can be used include potassium carbonate, sodium hydride, potassium hydride, sodium carbonate, sodium bicarbonate, etc., preferably potassium carbonate and sodium carbonate.
  • the reaction temperature is 80-150 ° C , preferably 110 ⁇ 130 ° C or the reflux temperature of the solvent. Usually, 4-24 h, preferably 10-14 h, is required for completing the reaction.
  • the earlier methods for preparing the compound of formula (3) from the compound of formula (2) usually used an acyl halide, such as propionyl chloride, and the coupling reaction of propionyl chloride with the compound of formula (2) was performed using a strong base, such as n-butyllithium or sodium hydride.
  • a strong base such as n-butyllithium or sodium hydride.
  • the disadvantage of having to use a strong base is that the reaction had to be performed under an extremely low temperature (-78 ° C).
  • the earlier methods are not desirable to be applied industrially due to the risk of explosion of the metal reagents and the instability of propionyl chloride in the presence of moisture.
  • the compound of formula (3) is prepared under mild conditions. Specifically, conventional organic bases are used instead of the explosive metal reagents. And, the stable propionic acid anhydride is used instead of the acyl halides, such as propionyl chloride, that are not stable in air and moisture.
  • reaction can be carried out at room temperature.
  • tetrahydrofuran THF
  • dimethylformamide DMF
  • dimethylsulfoxide DMSO
  • dimethylacetamide DMAc
  • acetonitrile AN
  • the amount of solvent used is 2 ⁇ 10 times, preferably 3 ⁇ 5 times, greater than the compound of formula (2).
  • the organic base used includes triethylamine (TEA), diisopropylethylamine (DIPEA), t- butylamine, diethylamine (DEA), etc., preferably triethylamine (TEA), and should be used in the amount of 1 ⁇ 3 eq., preferably 1-1.3 eq., with respect to the compound of formula (2).
  • TAA triethylamine
  • DIPEA diisopropylethylamine
  • DEA diethylamine
  • TEA triethylamine
  • lithium chloride (LiCl), aluminum chloride (AlCl 4 ), aluminum bromide (AlBr 4 ), iron tetrachloride (FeCl 4 ), zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), trifluoroborane (BF 3 ), magnesium bromide (MgBr 2 ), preferably lithium chloride (LiCl) can be used.
  • the amount of Lewis acid used should be 0.5-3 eq., preferably 1-1.5 eq., with respect to the compound of formula (2).
  • reaction After adding all the reactants, the reaction is carried out for 1-10 h, preferably 1-2 h.
  • the reaction temperature is between 0 ⁇ 50 ° C , preferably 20-30 ° C .
  • the chiral auxiliary of formula (3) obtained according to the above improved process produced a high yield of about 99% with respect to the compound of formula (2).
  • the starting material L-Valinol (15Og) was added to diethylcarbonate (227m#), and potassium carbonate (2Og) was then added while the mixture was stirred at room temperature.
  • the reaction solution was refluxed for 5 h at 120 ⁇ 130 ° C .
  • the reaction solution was cooled to 0 ° C, 1.5N hydrochloric acid (450m#) and ethyl acetate (450m#) were added, and the resulting two phases were separated.
  • the aqueous phase was extracted twice with ethyl acetate (450m£), and the organic phase was washed with aqueous sodium chloride solution (450m#), phase-separated, dried, filtered and distilled.
  • Example 2 The compound (2) prepared in Example 1 (10Og) was dissolved in tetrahydrofuran (300m#), and cooled to 0 ° C . Lithium chloride (36g) was added, triethylamine (10Ig) was then slowly added, and the resulting mixture was stirred for 30 min. Propionic acid anhydride (106g) was slowly added over a 30 min. time period. The reaction mixture was slowly warmed to room temperature, and stirred for 1-1.5 h. The reaction solution was cooled, IN aqueous sodium chloride solution (300m#) was added, and the mixture was stirred for 30 min.
  • Example 2 The compound (3) prepared in Example 2 (44g) was dissolved in methylene chloride (890ml), and cooled to 0 ° C . Titanium chloride (55g) was slowly added. After 1 h, diisopropylethylamine (4Og) was added and then 4-AA (50g) was added. The resulting mixture was reacted for 3 h at room temperature and cooled. Water (890ml) was added to separate the phases. 1.5N hydrochloric acid (500ml) was added thereto.
  • Example 3 The compound (5) prepared in Example 3 (95g) was dissolved in acetone (350ml) and water (200ml). Hydrogen peroxide (50ml) was added thereto, and the mixture was stirred at 0 ° C . Lithium hydroxide dihydrate (2Og) was dissolved in water (150ml), which was then added over a 30 min. time period. The reaction solution was stirred for 1 h, water (500ml) and methylene chloride (500ml) were added, and the phases were separated. The organic phase was distilled to produce the compound of formula (2) (2Og). The aqueous phase was adjusted to pH 2.5 using 6 N hydrochloric acid to produce a crystal. This crystal was filtered to produce the title compound having ⁇ / ⁇ ratio of 99.5/0.5 (37g, Yield 70% that was calculated from the 4- A A compound).
  • the compound of formula (6) particularly, (5i?, ⁇ 5)-3-[[[R]-l'-t-butyldimethylsilyloxy]ethyl]-4-[(/?)-l"-carboxyethyl]-2- azetidinone (4-BMA), which is a key intermediate for the synthesis of carbapenem and penem antibiotics, can be prepared in high yield and high selectivity under industrially mild conditions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention porte sur du (3R,4S)-3-[[[R]-V-t- butyldiméthylsilyloxy] éthyl] -4- [(/?)- l'-carboxyéthyl]-2-azétidinone] 4-BMA, de formule (6), intermédiaire de synthèse des antibiotiques carbapénem et pénem, et spécifiquement, sur un procédé consistant d'abord, à préparer un auxiliaire chiral du L-Valinol bon marché, puis à préparer le 4-BMA avec un fort rendement et une haute sélectivité, dans des conditions industrielles douces.
PCT/KR2008/002142 2007-04-16 2008-04-16 Procédé de préparation stéréosélective de 4-bma utilisant un auxiliaire chiral WO2008127070A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN2008800124172A CN101675031B (zh) 2007-04-16 2008-04-16 使用手性助剂立体选择性制备4-bma的方法
JP2010503970A JP5180289B2 (ja) 2007-04-16 2008-04-16 キラル補助剤を用いた４−ｂｍａの立体選択的製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020070037108A KR100886347B1 (ko) 2007-04-16 2007-04-16 키랄 보조제를 이용한 4-비엠에이의 입체선택적 제조방법
KR10-2007-0037108 2007-04-16

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WO2008127070A1 true WO2008127070A1 (fr) 2008-10-23

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CN (1) CN101675031B (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2345645A1 (fr) * 2009-12-22 2011-07-20 Savior Lifetec Corporation Procédé de fabrication de préparation stéréosélective du 4-bma utilisant un auxiliaire chiral et auxiliaire chiral

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102491992A (zh) * 2011-11-24 2012-06-13 山东润泽制药有限公司 一种碳青霉烯类抗生素关键中间体4-bma的制备方法
CN102977134A (zh) * 2012-12-13 2013-03-20 凯莱英医药集团（天津）股份有限公司 碳青霉烯中间体β-甲基-ADC-8的制备方法

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DE3632916A1 (de) * 1986-09-27 1988-03-31 Bayer Ag Enantiomerenreine 2-azetidinone, verfahren zu ihrer herstellung und ihre verwendung
US5104984A (en) * 1985-03-29 1992-04-14 Merck & Co., Inc. Enantioselective process for producing 1-beta-methyl carbapenem antibiotic intermediates
US5231179A (en) * 1986-01-27 1993-07-27 Sumitomo Pharmaceuticals Company, Limited Heterocyclic compounds and their production
EP0974582A1 (fr) * 1998-07-24 2000-01-26 Takasago International Corporation Procédé de préparation de dérivés 4-substitués de l'azétidinone

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ATE202087T1 (de) * 1991-12-26 2001-06-15 Nippon Soda Co Verfahren zur herstellung von 4-substituierten azetidinon-derivaten
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US5231179A (en) * 1986-01-27 1993-07-27 Sumitomo Pharmaceuticals Company, Limited Heterocyclic compounds and their production
DE3632916A1 (de) * 1986-09-27 1988-03-31 Bayer Ag Enantiomerenreine 2-azetidinone, verfahren zu ihrer herstellung und ihre verwendung
EP0974582A1 (fr) * 1998-07-24 2000-01-26 Takasago International Corporation Procédé de préparation de dérivés 4-substitués de l'azétidinone

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GUERLAVAIS V. ET AL.: "Progress towards the total synthesis of callipeltin A. Asymmetric synthesis of (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid", TETRAHEDRON ASYMMETRY, vol. 13, no. 7, 2002, pages 675 - 680, XP004354857 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2345645A1 (fr) * 2009-12-22 2011-07-20 Savior Lifetec Corporation Procédé de fabrication de préparation stéréosélective du 4-bma utilisant un auxiliaire chiral et auxiliaire chiral

Also Published As

Publication number Publication date
JP5180289B2 (ja) 2013-04-10
CN101675031A (zh) 2010-03-17
KR20080093315A (ko) 2008-10-21
JP2010524923A (ja) 2010-07-22
CN101675031B (zh) 2013-12-11
KR100886347B1 (ko) 2009-03-03

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