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WO2007004028A2 - Procedes de preparation de penemes et de leurs intermediaires - Google Patents

Procedes de preparation de penemes et de leurs intermediaires Download PDF

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Publication number
WO2007004028A2
WO2007004028A2 PCT/IB2006/001821 IB2006001821W WO2007004028A2 WO 2007004028 A2 WO2007004028 A2 WO 2007004028A2 IB 2006001821 W IB2006001821 W IB 2006001821W WO 2007004028 A2 WO2007004028 A2 WO 2007004028A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
azetidinone
group
protecting group
hydroxy
Prior art date
Application number
PCT/IB2006/001821
Other languages
English (en)
Other versions
WO2007004028A3 (fr
Inventor
Parendu Dhirajlal Rathod
Kiran Kumar Ganagakhedkar
Ram Chander Aryan
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2007004028A2 publication Critical patent/WO2007004028A2/fr
Publication of WO2007004028A3 publication Critical patent/WO2007004028A3/fr

Links

Classifications

    • 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
    • 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 field of the invention relates to a process for the preparation of 4-acetoxy azetidinone of Formula I,
  • the compounds of Formula I are important synthetic intermediates of ⁇ -lactam antibiotics that possess the carbapenem and penem ring systems such as imipenem, ertapenem, faroperem, doripenem, meropenem, and the like.
  • the ⁇ -lactam antibiotics are commonly prescribed antimicrobial agents with activity against a wide range of both Gram- positive and Gram-negative bacteria.
  • Ri represents a C 1 . 4 alkyl group and R 2 Js a protective group for ⁇ -lactam ring such as aryl or substituted aryl, particularly 4-methoxyphenyl or 2,4-dimethoxybenzyl.
  • R 2 is p-methoxyphenyl
  • Ri and R' each independently represent Ci -4 alkyl group, by a series of react: ons involving hydrolysis of the ester group at 4- ⁇ osition to carboxyl group followed by oxidation of the carboxyl group to acetoxy group and finally deprotection of the azetidinone ring nirrogen using ozone.
  • R 2 is hydrogen or a suitable amino protecting group and P is suitable hydroxy protecting group.
  • Ri is Ci -4 alkyl group and R 2 is hydrogen or a suitable amino protecting group.
  • Ri is CM alkyl group and R 2 is hydrogen or a suitable amino protecting group.
  • Ri is Ci - 4 alkyl group
  • R 2 is hydrogen or a suitable amino protecting group
  • Ri is CM alkyl
  • P is a hydroxy protecting group
  • R 2 is hydrogen or a suitable amino projecting group
  • R 7 and Rs are same or different and are hydrogen, Q -S alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a first aspect of the present invention provides a process for the preparation of 4- acetoxy azetidinone of Formula I,
  • tie process comprising: a) stirring a basified reaction mixture comprising L-threonine of Formula H,
  • Suitable hydroxy and amino protecting groups include, but are not limited to, lowertrialkylsilyl groups, lowerdialkylhalosilyl groups, nitrogen containing silyl groups, lower alkoxymethjl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups, aryl or substituted aryl group for example, 4-methoxyphenyl or 2,4-dimethoxybenzyl.
  • the silyl groups described above can be introduced using silylating agents.
  • Examples include trimethylchlorosilane, tert- butyldimethylchloiosilane, 1 , 1 ,1 ,3,3,3,-hexamethyl disilazane, ⁇ -trimethylsilylacetamide, tetramethyldisilazane, bis(trimethylsilyl)acetamide, vinyltriacetoxysilane. dimethylchlorosilaie, bromomethyldimethylchlorosilane, diCchloromethy ⁇ te-jamethyldisilazane, vinyltriethoxysilane, and the like.
  • Suitable condensing agents include 1,3-dicyclohexylcarbodiimide (DCC), 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), and the like.
  • DCC 1,3-dicyclohexylcarbodiimide
  • DBU 1,8- diazabicyclo(5.4.0)undec-7-ene
  • a second aspect of the present invention provides a process for the preparation of (2R,3R)-epoxybutyric acid of Formula III,
  • Formula III the pTocess comprising stirring a basifled reaction mixture comprising L-threonine of Formula I, an acid and an alkali metal nitrite, which is acidified with an acid at a temperature less than 20 0 C.
  • the reaction mixture containing the (2R,3R)-epoxybutyric acid of Formula III may be extracted with an organic solvent comprising one or more of C ⁇ g ethers; Ci -4 alcohols; C$.% ketones; halogenat ⁇ d solvents; polar aprotic solvents, hydrocarbons, or a mixture thereof,' with a proviso that the organic solvent is not an ester.
  • the (2R,3F)-epoxybutyric acid of Formula III can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the present invention.
  • the inventors have found that the yield of (2R,3R)-epoxybutyric acid obtained by stirring the reaction mixture for less than 10 hours at 25 0 C after addition of 40% w/v sodium hydroxide is comparable to the yield obtained by practicing Example 1 of WO 98/07691.
  • Examples cf suitable acids include hydrochloric acid, hydrobromic acid, nitric acid, p- toluene sulphonic acid, and the like.
  • suitable alkali metal nitrites include sodium nitrite, potassium citrite, and the like.
  • suitable bases include alkali metal amides, hydrides, hydroxides, metal ulkyls, tertiary amines and bicyclic amines.
  • the tertiary amines may include triethylamitie, pyridine, 4-N,N-dimethylamino pyridine, N-methylmorpholine, and the like.
  • the bicyclic amines may include l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo(5.4.0'undec-7-ene (DBU) 3 and the like.
  • Suitable solvents include C 4 - 8 ethers; Ci -4 alcohols; C 3-8 ketones; halogenated solvents; polar aprotic solvents; and hydrocarbon solvents.
  • halogenated solvents include dichloromethane, cichloroethane, chloroform, carbon tetrachloride, ethylene bromide, and the like.
  • a suitable polar aprotic solvent includes one or more of tetrahydrofuran, dimethylformamid2 ) dimethylacetamide, and the like.
  • Suitable hydrocarbon solvents include benzene, toluene, xylene, and the like. Mixtures of all of these solvents are also contemplated. The solvents described above do not cause undesired side reactions and also can be recovered and reused in the present process without purification.
  • a third aspect of the present invention provides a process for the preparation of glycine ester of formula IV,
  • R] is C M ⁇ lkyl group and R 2 is hydrogen or a suitable amino protecting group, the process comprising reacting a compound of Formula A,
  • X is a leavir g group and Rj is as described above, in the presence of a base at about 80- 100 0 C.
  • the glycine ester of Formula IV can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention.
  • Suitable bases include alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines.
  • the tertiary amines may include triethylamine, pyridine, 4-NjN-dimethylamino pyridine, N-methylmorpholine, and the like.
  • the bicyclic amines may include l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo(5.4.0)u ⁇ dec-7-ene (DBU), and the like.
  • Suitable leaving groups represented by X in Formula B above can be chlorine, bromine, iodine, mesyl, tosyl, and the like.
  • the present inventors have found that the process for the preparation of glycine derivative of Formula IV reported in Example 7 of WO 98/07691 failed to initiate at ths reported temperature of 50 0 C leading to consumption of a large amount of ethylchloroacetate. The reaction suddenly got initiated whereby the high exothermicity led to a runaway condition and consequently resulted in low yield of the glycine derivative of Formula IV.
  • a fourth aspect of the present invention provides a process for the preparation of epoxyatnide of Formula V,
  • Ri is C] -4 alkyl group and R 2 is hydrogen or a suitable amino protecting group, the process comprising condensing (2R,3R)-epoxybutyric acid of Formula III with glycine ester of Formula IV in the presence of a condensing agent in a halogenated solvent.
  • Epoxyamide Formula V can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention.
  • Epoxybutyric acid of Formula III and glycine ester of Formula TV can be prepared by methods known in the art or according to the processes disclosed in the present invention.
  • halogenated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethylene bromide, and the like.
  • the process of the present invention does not require tedious column chromatography for isolation of the final product and provides good yield of the epoxyamide.
  • the product can be used as such in the subsequent reaction step and the halogenated solvent used can be recovered and reused without purification.
  • a fifth aspect of the present invention provides a process for the preparation of hydroxy azetidinor.e ester of Formula VIa 5
  • R[ and R 2 are as described above, with a base.
  • the hydroxy azetidinone ester of Formula Via can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention.
  • the epoxyamide of Formula V can be prepared by methods known in the art or according to the processes described in the present invention.
  • the preseni inventors have found that the above cyclization of epoxyamide of Formula V when carried out under reduced quantities of tetrahydrofuran proceeds with nearly 100% conversion ⁇ .s determined by Thin Layer Chromatography.
  • the process of the present invention does not require tedious column chromatography purification, provides good yield of the hydroxy azeiidinone of Formula Via, which can be used as such in the subsequent reaction step.
  • a sixth aspect of the present invention provides a process for the preparation of azetidinone ester or ' Formula VIb,
  • the hydroxy azetidinone ester of Formula Via wherein Ri and R 2 are as described above, can be prep ared by methods known in the art or according to the process disclosed in the present invention.
  • the hydroxy azetidinone ester of Formula Via described above was treated with a hydroxy protecting agent for example, a silylating agent in the absence of a reaction solvent, to obtain O-silyl protected azetidinone ester which can be converted to 4- acetoxy azetidinons of Formula I, by the process of the present invention.
  • a hydroxy protecting agent for example, a silylating agent in the absence of a reaction solvent
  • the present inventors have surprisingly found that the silyl protection of side chain hydroxy group in azetidinone ester of Formula Via, wherein R 1 and R 2 are as described above, can be carried out without solvent with good yield and the product can be used as such in the subsequent reaction step. Further, the present inventors have found that the reaction times are greatly reduced when solvent is not used and the process of the present invention does not require tedious coluir.n chromatography for isolation of the product.
  • 4-acetoxy gwetidinone of Formula I prepared by the process of the present invention can be further converted to ⁇ -lactam compounds of Formula VIII,
  • Formula VHI wherein P] is hydrogen or a cafboxyl protecting group, R$ is hydrogen or C1.5 alkyl and X is C OT S 5 Y is a tetrahydrofuran ring connected via C 2 or Y represents a substituted thiol of Formula S-A wherein A is selected from the group consisting of a)
  • compound of Formula I can be converted to compound of Formula VIII by processes disclosed in U.S. Patent Nos. 4,943,569; 5,478,820; 5,317,016; 5,652,233; 5,856,321; 4,997,829; and 5,998,612.
  • 4- acetoxy azetidinone of Formula I can be converted to ⁇ -lactam compounds of Formula VIII by the following steps: a) reacting 4-acetoxy azetidinone of Formula I
  • Ring B is a benzene ring which may be substituted by one to four group(s) selected from halogen, C ]-6 -alkyl, C 1-6 -alkoxy and phenyl which maybe substituted with Ci-e-alkyl, Ci -6 -alkoxy, halogen or optionally protected amino;
  • X' is O or S;
  • Y' is O, S, CH 2 or an imino group which may be substituted by Ci- 6 -alkyl or an acyl group selected from C 2 .
  • Z is a methylene group which may be substituted by one to two group(s)
  • Fo ⁇ nula XIII wherein P, Pi, R 6 are as described above and OE is an esterified hydroxy group; and d) reacting the compound of Formula XIII with a thiol of Fo ⁇ nula,
  • Tetrahydrofuran was recovered from the combined extracts under vacuum at less than 15°C.
  • dichloromethane 700 ml was added followed by the addition of anhydrous sodium sulfate (100 g). The reaction mixture was stirred for 0.5 to 1 hour and filtered to remove the solids.
  • Dichloromethane (100 ml) washings were added to the above filtrate.; This combined filtrate wa; concentrated under vacuum at less than 15 0 C to obtain the product. Alternatively, the filtrate was concentrated to half its volume and the solution was used as such for the next step.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé de préparation de 4-acétoxy-azétidinone de formule (I), dans laquelle R2 est hydrogène ou un groupe amino-protecteur approprié et P est un groupe hydroxy-protecteur approprié, ainsi que l'utilisation de ces composés comme intermédiaires pour la préparation d'antibiotiques de β-lactame renfermant les systèmes cycliques carbapénème et pénème. La 4-acétoxy-azétidinone de formule (I) est un intermédiaire clé dans la synthèse d'antibiotiques de β-lactame, lesquels sont des agents antimicrobiens communément prescrits dont l'activité est dirigée contre un large éventail de bactéries gram-positives et gram-négatives.
PCT/IB2006/001821 2005-06-30 2006-06-30 Procedes de preparation de penemes et de leurs intermediaires WO2007004028A2 (fr)

Applications Claiming Priority (2)

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IN1702/DEL/2005 2005-06-30
IN1702DE2005 2005-06-30

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WO2007004028A3 WO2007004028A3 (fr) 2007-03-29

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011048583A1 (fr) 2009-10-23 2011-04-28 Ranbaxy Laboratories Limited Procédé pour la préparation de composés de carbapénème
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
CN101747250B (zh) * 2008-12-16 2012-09-05 上海医药工业研究院 一种制备4-酰氧基氮杂环丁酮类化合物的方法
CN102827199A (zh) * 2012-08-28 2012-12-19 三峡大学 青霉烯和碳青霉烯类抗生素类关键中间体4aa的合成方法
CN102936262A (zh) * 2012-11-07 2013-02-20 凯莱英医药集团（天津）股份有限公司 培南类药物中间体4aa的制备方法
CN101265271B (zh) * 2008-04-30 2013-06-05 寿光富康制药有限公司 培南类药物中间体4aa的合成方法
CN103242361A (zh) * 2013-05-23 2013-08-14 浙江海翔川南药业有限公司 一种培南类抗生素中间体的制备方法
WO2014071565A1 (fr) * 2012-11-07 2014-05-15 凯莱英医药集团（天津）股份有限公司 Procédé de préparation d'un intermédiaire 4aa des médicaments à base d'imipénème
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
CN109721521A (zh) * 2018-11-26 2019-05-07 广东药科大学 一种光学活性黄皮酰胺酮及其衍生物的制备方法
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE034911T2 (hu) 2009-07-27 2018-03-28 Gilead Sciences Inc Fúzionált heterociklusos vegyületek mint ioncsatorna modulátorok

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EP0126587A1 (fr) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Dérivés de carboxyle thio-pyrrolidinyle-bêta-lactame et leur préparation
EP0367722A1 (fr) * 1988-11-04 1990-05-09 Ciba-Geigy Ag Procédé de préparation d'acyloxyazétidinones optiquement actives
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EP0528678A1 (fr) * 1991-08-20 1993-02-24 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Dérivé de pyrrolidylthiocarbapénème
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EP0126587A1 (fr) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Dérivés de carboxyle thio-pyrrolidinyle-bêta-lactame et leur préparation
EP0367722A1 (fr) * 1988-11-04 1990-05-09 Ciba-Geigy Ag Procédé de préparation d'acyloxyazétidinones optiquement actives
EP0371875A2 (fr) * 1988-11-29 1990-06-06 Takasago International Corporation Procédé de préparation d'acétoxy-4-azétidinones
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CAINELLI, GIANFRANCO ET AL: "Stereocontrolled total synthesis of the chiral building block (3S,4R)-3-Ä(R)-1-hydroxyethylÜ-4-acetyloxy -azetidin-2-one: a useful synthon for the synthesis of (+)-thienamycin, carbapenems and penems" TETRAHEDRON LETTERS, vol. 26, no. 7, 1985, pages 937-940, XP002406363 *
COZZI, FRANCO ET AL: "A short, stereoselective synthesis of (3R,4R)-4-acetoxy-3-Ä(R)-1'((t- butyldimethylsilyl)oxy)ethylÜ-2-azetidinon e, key intermediate for the preparation of carbapenem antibiotics" CHIRALITY, vol. 10, no. 1/2, 1998, pages 91-94, XP002406364 *
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LAURENT, MATHIEU ET AL: "Regioselective Baeyer-Villiger Oxidation in 4-Carbonyl-2-azetidinone Series: A Revisited Route toward Carbapenem Precursor" JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 9, 2004, pages 3194-3197, XP002406360 *
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101265271B (zh) * 2008-04-30 2013-06-05 寿光富康制药有限公司 培南类药物中间体4aa的合成方法
CN101747250B (zh) * 2008-12-16 2012-09-05 上海医药工业研究院 一种制备4-酰氧基氮杂环丁酮类化合物的方法
WO2011048583A1 (fr) 2009-10-23 2011-04-28 Ranbaxy Laboratories Limited Procédé pour la préparation de composés de carbapénème
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
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
CN102827199A (zh) * 2012-08-28 2012-12-19 三峡大学 青霉烯和碳青霉烯类抗生素类关键中间体4aa的合成方法
WO2014071565A1 (fr) * 2012-11-07 2014-05-15 凯莱英医药集团（天津）股份有限公司 Procédé de préparation d'un intermédiaire 4aa des médicaments à base d'imipénème
CN102936262A (zh) * 2012-11-07 2013-02-20 凯莱英医药集团（天津）股份有限公司 培南类药物中间体4aa的制备方法
CN103242361A (zh) * 2013-05-23 2013-08-14 浙江海翔川南药业有限公司 一种培南类抗生素中间体的制备方法
CN109721521A (zh) * 2018-11-26 2019-05-07 广东药科大学 一种光学活性黄皮酰胺酮及其衍生物的制备方法
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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