WO2014097257A1 - Méthode de préparation du composé (1'r,3r,4r)-4-acétoxy-3-(1'-(tert-butyldiméthylsilyloxy)éthyl)-2-azétidinone, précurseur de synthèse d'antibiotiques de carbapénème - Google Patents

Méthode de préparation du composé (1'r,3r,4r)-4-acétoxy-3-(1'-(tert-butyldiméthylsilyloxy)éthyl)-2-azétidinone, précurseur de synthèse d'antibiotiques de carbapénème Download PDF

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WO2014097257A1
WO2014097257A1 PCT/IB2013/061211 IB2013061211W WO2014097257A1 WO 2014097257 A1 WO2014097257 A1 WO 2014097257A1 IB 2013061211 W IB2013061211 W IB 2013061211W WO 2014097257 A1 WO2014097257 A1 WO 2014097257A1
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formula
group
copper
compound defined
reaction
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PCT/IB2013/061211
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Barbara GRZESZCZYK
Sebastian Stecko
Bartłomiej FURMAN
Marek Chmielewski
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Instytut Chemii Organicznej Pan
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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 present invention relates to a method of preparation of (1'R,3R,4R)-4-acetoxy-3-(1'-(tert- butyl-dimethylsilyloxy)ethyl)-2-azetidinone (1) which is a chiral building block in the synthesis of carbapenem antibiotics.
  • Thienamycin (1) is the best known, natural carbapenem antibiotic with a high pharmacological activity.
  • Thienamycin derivatives such as imipenem (2), panipenem (3), doripenem (4), meropenem (5), ertapenem (6), biapenem (7), razupenem (8) are the active ingredients of known pharmaceutical preparations with anti-inflammatory activity, with a high resistance to ⁇ -lactamases, bacterial enzymes that destroy the administered antibiotics.
  • azetidinone 1 The earliest synthesis of azetidinone 1 was reported by group of Sankyo Co., Ltd. Described synthesis involved penicillin ester derivative, obtained from an inexpensive fermentation product of 6- aminopenicillic, as a chiral building block (Scheme 2, Method A) (Oida, S. Recent Advances in Beta Lactam Antibiotics; Royal Society of Chemistry: London, 1981; pp 330-348. (b) Yoshida, A.; Hayashi, T.; Takeda, N.; Oida, S.; Ohki, E. Chem. Pharm. Bull. 1981, 29, 2899-2909). The Sankyo team also devised synthesis of 1 , starting from 6- -bromopenicillin.
  • the subject of the present invention is a method of preparation 2-azetidinone defined by the formula 1,
  • R 1 and R 2 independently of one another denote any substituent selected from among:
  • - benzyl group (-CHkPh), including a benzyl group substituted in the phenyl ring,
  • R 1 and R 2 independently of one another denote any substituent selected from among:
  • - benzyl group (-CHtePh), including a benzyl group arbitrarily substituted in the phenyl ring,
  • R and R 2 independently of one another denote any substituent selected from among:
  • - benzyl group (-CH2Ph), including a benzyl group substituted in the phenyl ring,
  • R 1 and R 2 independently of one another denote any substituent selected from among:
  • - benzyl group (-ChbPh), including a benzyl group arbitrarily substituted in the phenyl ring,
  • the reaction of alkyne 9 with nitrone 10a or 10b is conducted in the temperature range from -60°C to 60°C, most preferably at a temperature of - 40°C to -30°C.
  • the reaction of alkyne 9 with nitrone 10a or 10b is conducted in a solvent selected from a group encompassing: aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, aliphatic ethers, aliphatic nitiriles, aliphatic /V,/v * -di-(Ci-6-alkyl)amides.
  • the method is characterised in that preferably the reaction of alkyne 9 with nitrone 10a or 10b is conducted in the presence of a copper (I) salt selected from a group encompassing CuCI, CuBr, Cul, CuOTf, most preferably Cul, wherein use is made of at most 3 equivalents of a copper (I) salt in relation to the compound defined by the formula 9; preferably from 0.01 to 1 equivalent of a copper (I) salt.
  • a copper (I) salt selected from a group encompassing CuCI, CuBr, Cul, CuOTf, most preferably Cul, wherein use is made of at most 3 equivalents of a copper (I) salt in relation to the compound defined by the formula 9; preferably from 0.01 to 1 equivalent of a copper (I) salt.
  • the method is characterised in that preferably the reaction of alkyne 9 with nitrone 10a or 10b is conducted in the presence of a copper (II) salt, and possibly a reducing compound, preferably selected from a group encompassing copper (II) sulphate, copper (II) chloride, copper (II) triflate, copper (II) acetate; preferably, the reducer used is sodium ascorbate, wherein use is made of at most 3 equivalents of a copper (II) salt in relation to 9.
  • a copper (II) salt preferably a reducing compound, preferably selected from a group encompassing copper (II) sulphate, copper (II) chloride, copper (II) triflate, copper (II) acetate
  • the reducer used is sodium ascorbate, wherein use is made of at most 3 equivalents of a copper (II) salt in relation to 9.
  • the method is characterised in that preferably the reaction of alkyne 9 with nitrone 10a or 10b is conducted in the presence of a base selected from a group encompassing secondary and tertiary amines, in particular an amine selected from a group encompassing trialkylamines, such as triethylamine or /V.N-diisopropylethylamine, alkyldi(cycloalkyl)amines, such as W-methyldicyclohexylamine, tetramethylguanidine, dialkylamines with branched alkyl sybstituents, such as diisopropylamine, di(cycloalkyl)amines, such as dicyclohexylamine, and heterocyclic amines, such as pyridine; most preferably diisopropylethylamine; wherein the base is used in the amount of at least 3 equivalents in relation to the compound defined by the formula 9.
  • a base selected from a group
  • the method is characterised in that preferably the reaction of alkyne 9 with nitrone 10a or 10b is conducted in the presence of a base selected from a group encompassing carbonates of an alkali metal or alkali earth metals, in particular from a group encompassing potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.
  • a base selected from a group encompassing carbonates of an alkali metal or alkali earth metals, in particular from a group encompassing potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.
  • the next subject of the present invention is a method of preparation of the compound defined by the formula 12: characterised in that in compound defined by the formula 11, where R 1 and R 2 independently of one another denote any substituent selected from among:
  • - benzyl group (-ChkPh), including a benzyl group arbitrarily substituted in the phenyl ring,
  • the alkali metal is selected from a group encompassing: lithium, sodium, potassium, calcium, most preferably lithium or sodium.
  • the method is characterised in that preferably the transformation is conducted in the temperature range from -70°C to -30°C, most preferably at a temperature of -40°C to -35°C.
  • the subject of the present invention is a method of preparation of azetidinone 1 , and its precursors, according to the reaction sequence shown in Scheme 8.
  • R 1 and R 2 independently of one another denote any substituent selected from among:
  • -CHfePh a benzyl group (-CHfePh), including a benzyl group arbitrarily substituted in the phenyl ring,
  • R 1 and R 2 have the above defined meaning.
  • the compound 9 is reacted with nitrone 10a or 10b in the presence of a copper (I) salt selected from a group encompassing CuCI, CuBr, Cul, CuOTf.
  • a copper (I) salt selected from a group encompassing CuCI, CuBr, Cul, CuOTf.
  • the copper (I) salt used is Cul.
  • At most 3 equivalents of the copper (I) salt are used in relation to 9; preferably use is made of 0.01 to 1 equivalent of a copper (I) salt.
  • the compound 9 is reacted with nitrone 10a or 10b in the presence of a copper (II) salt and possibly a reducing compound, preferably selected from a group encompassing copper (II) sulphate, copper (II) chloride, copper (II) inflate, copper (II) acetate.
  • a copper (II) salt and possibly a reducing compound preferably selected from a group encompassing copper (II) sulphate, copper (II) chloride, copper (II) inflate, copper (II) acetate.
  • the reducer used is sodium ascorbate.
  • Use is made of at most 3 equivalents of a copper (II) salt in relation to 9.
  • the compound 9 is reacted with nitrone 10a or 10b in the presence of a base selected from a group encompassing secondary and tertiary amines.
  • a base selected from a group encompassing secondary and tertiary amines.
  • an amine selected from a group encompassing trialkylamines, such as triethylamine or A/./V-diisopropylethylamine, alkyldi(cycloalkyl)amines, such as N- methyldicyclohexylamine, tetramethylguanidine, dialkylamines with branched alkyl sybstituents, such as diisopropylamine, di(cycloalkyl)amines, such as dicyclohexylamine, and heterocyclic amines, such as pyridine.
  • diisopropylethylamine in the amount of at least 3 equivalents in relation to 9.
  • acetylene 9 with the nitrone 10a or 10b use is made of carbonates of an alkali metal or alkali earth metals as the base.
  • a base selected from a group encompassing potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate.
  • the compound 9 is reacted with nitrone 10a or 10b in a solvent selected from a group encompassing aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, aliphatic ethers, aliphatic nitiriles, aliphatic N,/V-di-(Ci-6-alkyl)amides.
  • a solvent selected from a group encompassing acetonitrile, toluene, benzene, N,N- dimethylformamide, ty/V-dimethylacetamide, tetramethylguanidine, HMPA, /V-methylpyrrolidone.
  • acetonitrile acetonitrile.
  • reaction of the compound 9 with nitrone 10a or 10b can occur at a broad range of temperatures and the precise reaction temperature is not significant.
  • a preferable reaction temperature for the reaction is dependent on such factors as the type of solvent, the initial materials used or reagents. However, it is generally preferable to conduct the reaction at temperature range between - 60°C and 60°C, more preferably between -40°C and 30°C.
  • compound 11 where R 1 and R 2 have the above defined meaning, is transformed into compound 12.
  • compound 11 is treated with an alkali metal in liquid ammonia.
  • the alkali metal use is made of a metal selected from a group encompassing lithium, sodium, potassium, calcium. Particularly preferably, the metal uses is lithium.
  • the transformation of a compound defined by the general formula 11 to compound 12 is conducted in the temperature range from -70 to -30°C, most preferably at a temperature of -40 to -
  • a compound defined by the general formula 11 is transformed into in compound 12 through hydrogenation in the presence of heterogenic or homogenic metallic catalysts according to the art of organic synthesis.
  • Compound 12 is transformed into in 2-azetidynone 1 as a result of the reaction with lead tetraacetate in accordance withe known synthesis procedures.
  • the method disclosed herein is faster and simpler. It encompasses only three reaction steps that occur with a high efficiency.
  • the key step the copper-catalyzed reaction of nitrones defined by the general formula 10a and 10b with acetylene 9 which is performed under mild conditions and proceeds with a high stereoselectivity.
  • Reagents used in this step catalysts and solvents, are inexpensive and easily available.
  • substrates 9 and 10a,b are characterised by a much greater stability and shelf-life.
  • Benzyl glyoxalate (7.34 g, 56.9 mmol) was dissolved in MeOH (60 mL) and anhydr. AcONa (6.07 g, 74.0 mmol) was added at room temperature. Next, a solution of /V-benzylhydroxylamine hydrochloride (9.08 g, 56.9 mmol) in MeOH (20 mL) was added dropwise. After 2 h MeOH was removed and the residue was partitioned between CH2CI2 (100 mL) and water (30 mL). The organic phase was dried over gS0 and then the solvent was removed to give nitrone (14.5 g) as a white solid.
  • Triethylamine (0.56 mL, 4.0 mmol) was added to a suspension of Cul (190 mg, 1.0 mmol) in degassed MeCN (4 mL). Subsequently, mixture was cooled to 0°C and acetylene 9 (184 mg, 1.0 mmol) in MeCN (1 mL) was added. After 15 min, a solution of nitrone 10a/b (404 mg, 1.5 mmol) in MeCN (5 mL) was added slowly. The mixture was kept at 0°C for an additional 15 min. After removal of the cooling bath, the mixture was stirred at ambient temperature under an inert atmosphere for 24 h. The progress of the reaction was monitored by TLC.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une méthode de préparation du composé (1'R,3R,4R)-4-acétoxy-3-(1'- (tert-butyl-diméthylsilyloxy)éthyl)-2-azétidinone de formule (1), qui est constituant chiral basique, dans la synthèse des antibiotiques de carbapénème.
PCT/IB2013/061211 2012-12-21 2013-12-20 Méthode de préparation du composé (1'r,3r,4r)-4-acétoxy-3-(1'-(tert-butyldiméthylsilyloxy)éthyl)-2-azétidinone, précurseur de synthèse d'antibiotiques de carbapénème WO2014097257A1 (fr)

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PLP.402199 2012-12-21
PL402199A PL227494B1 (pl) 2012-12-21 2012-12-21 Sposób wytwarzania pochodnej 2-azetydynonowej i sposób wytwarzania związków pośrednich

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US4395418A (en) 1980-06-06 1983-07-26 Sankyo Company Limited Penem-3-carboxylic acid derivatives
GB2144419A (en) 1983-08-04 1985-03-06 Erba Farmitalia Azetidinones
EP0167154A1 (fr) 1984-07-05 1986-01-08 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procédé pour la préparation de dérivés de 4-acétoxy-3-hydroxyéthylazetizin-2-one
GB2162840A (en) 1984-06-23 1986-02-12 Consiglio Nazionale Ricerche Sterospecific process for preparing azetidinones
JPS6284057A (ja) 1985-10-07 1987-04-17 Kanegafuchi Chem Ind Co Ltd ４−アセトキシ−３−ヒドロキシエチルアゼチジン−２−オン誘導体の製造法
EP0230248A1 (fr) 1986-01-14 1987-07-29 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Dérivés de bêta-lactame et procédé de préparation
JPS62195359A (ja) 1986-02-22 1987-08-28 Kanegafuchi Chem Ind Co Ltd ４−アセトキシ−３−ヒドロキシエチルアゼチジン−２−オン誘導体の製造方法
EP0247378A1 (fr) 1986-04-30 1987-12-02 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procédé pour la préparation de dérivés de l'acétoxy-4-hydroxyéthyl-3 azétidinone-2
EP0271586A1 (fr) 1986-06-09 1988-06-22 Sagami Chemical Research Center COMPOSES DE $g(b)-LACTAME ET LEUR PROCEDE DE PREPARATION
EP0280962A1 (fr) 1987-02-20 1988-09-07 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procédé pour la préparation de dérivés de 4-acétoxy-3-hydroxyéthylazétin-2-one
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JPS6421698A (en) 1987-07-17 1989-01-25 Fuji Electric Co Ltd Goods replenishing port display device for vending machine
JPH01101084A (ja) 1987-10-14 1989-04-19 Mitsubishi Electric Corp 静止画像伝送装置
US4861877A (en) 1984-07-05 1989-08-29 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives
JPH01216965A (ja) 1988-02-25 1989-08-30 Sagami Chem Res Center ２−アルコキシブロピオン酸アミド誘導体の製造方法
JPH01246255A (ja) 1988-03-26 1989-10-02 Sagami Chem Res Center ４−アシルオキシ−β−ラクタム誘導体の製造方法
JPH0276888A (ja) 1989-08-28 1990-03-16 Kanegafuchi Chem Ind Co Ltd 新規β―ラクタム化合物及びその製造法
JPH02172970A (ja) 1988-12-26 1990-07-04 Sagami Chem Res Center ４―アシルオキシ―２―アゼチジノンの製造方法
JPH02172985A (ja) 1988-12-26 1990-07-04 Sagami Chem Res Center １，３―ジオキサン誘導体
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GB2144419A (en) 1983-08-04 1985-03-06 Erba Farmitalia Azetidinones
GB2162840A (en) 1984-06-23 1986-02-12 Consiglio Nazionale Ricerche Sterospecific process for preparing azetidinones
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US5026844A (en) 1988-10-19 1991-06-25 Suntory Limited Process for the preparation of 4-acyloxy-2-azetidinone derivatives
JPH02172970A (ja) 1988-12-26 1990-07-04 Sagami Chem Res Center ４―アシルオキシ―２―アゼチジノンの製造方法
JPH02172985A (ja) 1988-12-26 1990-07-04 Sagami Chem Res Center １，３―ジオキサン誘導体
JPH0276888A (ja) 1989-08-28 1990-03-16 Kanegafuchi Chem Ind Co Ltd 新規β―ラクタム化合物及びその製造法

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