EP1019411A4 - Verfahren zur herstellung von zwischenprodukten für carbapenem-seitenketten - Google Patents

Verfahren zur herstellung von zwischenprodukten für carbapenem-seitenketten

Info

Publication number
EP1019411A4
EP1019411A4 EP98933069A EP98933069A EP1019411A4 EP 1019411 A4 EP1019411 A4 EP 1019411A4 EP 98933069 A EP98933069 A EP 98933069A EP 98933069 A EP98933069 A EP 98933069A EP 1019411 A4 EP1019411 A4 EP 1019411A4
Authority
EP
European Patent Office
Prior art keywords
compound
accordance
formula
produce
reacted
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98933069A
Other languages
English (en)
French (fr)
Other versions
EP1019411A1 (de
Inventor
Karel M J Brands
John M Williams
Ulf H Dolling
Ronald B Jobson
Anthony J Davies
Ian F Cottrell
Mark Cameron
Michael S Ashwood
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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
Priority claimed from GBGB9810184.3A external-priority patent/GB9810184D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1019411A1 publication Critical patent/EP1019411A1/de
Publication of EP1019411A4 publication Critical patent/EP1019411A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention relates to the synthesis of carbapenem side chains, and in particular, to side chains or portions thereof containing a pyrrolidine group, which is bonded to the carbapenem nucleus through a thioether linkage.
  • the pyrrolidine is a portion of the side chain, and is substituted at the two position with any of a variety of substituents.
  • EP 551 993 Al published on July 21, 1993 relates to a synthesis which utilizes active esterifying agents and base, followed by treatment with hydrogen sulfide, or an alkali metal salt of hydrogen sulfide, and base.
  • the present invention is an improvement over these other processes, utilizing a sulfide source which surprisingly improves the process when commercial quantities are synthesized.
  • R! and R2 are independently selected from hydrogen, aryl and heteroaryl, said aryl and heteroaryl groups being unsubstituted or substituted with from 1-3 groups selected from the group consisting of: Cl-4 alkyl, Cl_4 alkoxy, Cl-4 alkyl thio, halo, hydroxy, CO2H, CO2CI-4 alkyl, NH 2 , NHCl-4 alkyl, N(Ci-4 alkyl)2, SO3H, CN, NHC(0)C M alkyl, S0 2 NH 2 , SO2C1-4 alkyl, aryl and heteroaryl;
  • Alkyl and the alkyl portions of substituent groups include monovalent hydrocarbon chains containing from 1-4 carbon atoms which are straight or branched as appropriate.
  • Aryl refers to 6-10 membered mono- and bicyclic ring systems, containing carbon atoms with alternating (resonating) double bonds.
  • Preferred aryl groups are phenyl and naphthyl.
  • Heteroaryl refers to aromatic 5-10 membered mono- and bicyclic ring systems, containing from 1-4 heteroatoms, O, S or N.
  • Preferred nitrogen containing monocyclic heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl and 1, 2, 4-triazolyl.
  • Preferred heteroaryl groups containing oxygen as the only heterotom include furanyl.
  • Preferred heteroaryl groups containing sulfur as the only heterotom include thienyl.
  • Preferred bicyclic heteroaryl groups include benzthiazolyl, benzimidazolyl, quinolinyl and isoquinolinyl, indolyl and isoindolyl.
  • the aryl and heteroaryl groups may be substituted with 1-3 groups selected from the group consisting of: Ci-4 alkyl, Ci-4 alkoxy, C1.4 alkylthio, halo, hydroxy, CO2H, CO2C1-4 alkyl, NH 2 , NHC1-4 alkyl, N(C ⁇ _ 4 alkyl) 2 , NHC(0)Ci- 4 alkyl, SO3H, CN, SO2NH2, SO2C1-4 alkyl, aryl and heteroaryl.
  • Suitable protecting groups include the following without limitation: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyl- oxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2- trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethyl- silyl)ethyl,
  • Preferred silyl protecting groups are trimethylsilyl and triethylsilyl.
  • Preferred carboxyl protecting groups are p-nitrobenzyl and allyl.
  • Preferred phosphoryl based protecting groups include diisopropylphosphoryl.
  • P represents a protecting group on the proline nitrogen atom.
  • P represents a member selected from the group consisting of: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitro- benzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2-trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl) ethyl, phen
  • P represents a protecting group which is selected from the group consisting of: t-BOC, diisopropylphosphoryl and p-nitrobenzyloxycarbonyl.
  • P represents diisopropylphosphoryl.
  • Compound 2 used herein as a starting material is N protected trans-4-hydroxy-L-proline.
  • the 2-carboxyl group is activated using the compound diphenylphosphinic chloride, which is reacted with compound II in a solvent in the presence of excess base.
  • Solvents which are useful herein include dichloromethane, acetonitrile, toluene, fluorobenzene, tetrahydrofuran, or mixtures thereof.
  • Bases which are useful for this reaction include trialkylamines.
  • Preferred trialkylamines include diisopropylethylamine (DIPEA) and triethylamine.
  • diphenylphosphinic chloride which is about equimolar to the starting compound
  • the reaction between compound 2 and diphenylphosphinic chloride is typically run at reduced temperature, below about 0°C to as low as about -40°C.
  • the reaction temperature is maintained at about -10°C.
  • Compound 3, with the diphenylphosphinyloxycarbonyl group at position two is reacted with methanesulfonyl chloride (MsCl) to produce compound 4.
  • MsCl methanesulfonyl chloride
  • This reaction is conducted in a solvent, in the presence of a slight molar excess of pyridine, collidine, lutidine and the like, using a slight molar excess of MsCl.
  • This mesylation reaction may be conducted over about 1-4 hours, at a reduced temperature, e.g., about 0°C to as low as about -40°C.
  • the reaction temperature is maintained at about -10°C.
  • Compound 4 is thereafter combined with an alkali metal sulfide or non-alkali metal sulfide and water to form the thiolactone 1.
  • the reaction can be conducted at about -10°C to about room temperature.
  • the sulfide and water are added quickly, and the reaction is aged for several hours at ambient temperature.
  • alkali metal sulfide refers to the group I metal sulfides, such as the sulfides of sodium and potassium.
  • the alkali metal sulfide is Na 2 S.
  • non-alkali metal sulfides and “alkaline earth metals” are used interchangeably to include the group II alkaline earth metal sulfides selected from the group consisting of: magnesium, calcium and barium. Preferred are calcium and barium.
  • the preferred non-alkali metal sulfide most notably CaS, provides an unexpected advantage in that side products of the reaction have low solubility in water, and thus can be removed as a precipitate.
  • the amine HNR'R 2 is m-aminobenzoic acid.
  • the compound of formula 5 is reacted with an acid to produce a compound of formula 6:
  • compound 4' is reacted with a member selected from the group consisting of: Na 2 S, K 2 S, CaS and BaS to produce a compound of formula 1':
  • the thiolactone compound 1 is reacted with the amine HNR'R 2 in the presence of an organic acid to produce compound 5.
  • organic acids include formic acid, acetic acid and propionic acid. Most preferably, the reaction is conducted in the presence of acetic acid.
  • compound 4' After the conversion of compound 4' to compound 1', the latter is combined with ammonia or a primary or secondary amine to form compounds of formula 5', which can be deprotected to give compound 6' or salt thereof.
  • solvents such as C,_ 5 alcohols, C j . 3 alkanoic acids, toluene, acetonitrile, ethyl acetate and others may be added to improve crystallization, or otherwise facilitate isolation.
  • addition of a trialkyl or triaryl phosphine, e.g., tri-n-butylphosphine, at this stage may be useful in reducing the formation of disulfides corresponding to compound 6' and/or improving the rejection of other impurities.
  • HNR*R 2 wherein R 1 and/or R 2 represent H, aryl or heteroaryl react with compound 1 upon slight heating. Generally, the reaction proceeds from about RT to about 100°C over a few minutes to several hours.
  • the acid that is used to convert compound 5' to compound 6' can be varied within wide limits.
  • concentrated HCl can be used and is preferred.
  • the invention described herein can be conducted in essentially a single reaction vessel, thus allowing for economical production of compounds 6' from compound 2.
  • the mesylate mixed anhydride was formed according to WO 97/06154 published on February 20, 1997, incorporated herein by reference, and stirred with cooling at -15°C for 15 min.
  • Example One Part B
  • the compounds of column one are reacted with methanesulfonyl chloride to produce the compounds in column two.
  • Example Three Using the procedures set forth in Example Three, the compounds of column one are reacted with the amine in column two to produce the compounds in column three.
  • Tri-n-butylphosphine may be added.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
EP98933069A 1997-07-09 1998-07-02 Verfahren zur herstellung von zwischenprodukten für carbapenem-seitenketten Withdrawn EP1019411A4 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US5203297P 1997-07-09 1997-07-09
US52032P 1997-07-09
GBGB9810184.3A GB9810184D0 (en) 1998-05-13 1998-05-13 Process for synthisizing carbapenem side chain intermediates
GB9810184 1998-05-13
PCT/US1998/013738 WO1999002531A1 (en) 1997-07-09 1998-07-02 Process for synthesizing carbapenem side chain intermediates

Publications (2)

Publication Number Publication Date
EP1019411A1 EP1019411A1 (de) 2000-07-19
EP1019411A4 true EP1019411A4 (de) 2003-08-13

Family

ID=26313663

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98933069A Withdrawn EP1019411A4 (de) 1997-07-09 1998-07-02 Verfahren zur herstellung von zwischenprodukten für carbapenem-seitenketten

Country Status (5)

Country Link
EP (1) EP1019411A4 (de)
JP (1) JP2002504156A (de)
AU (1) AU731586B2 (de)
CA (1) CA2294342C (de)
WO (1) WO1999002531A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2294341C (en) * 1997-07-10 2007-09-25 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
AU4723501A (en) * 2000-03-01 2001-09-12 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
KR100825243B1 (ko) * 2000-11-20 2008-04-25 상꾜 가부시키가이샤 카르바페넴계 항균제의 제조방법
CA2576530A1 (en) 2004-08-11 2006-02-23 Donald L. Barbeau Noncardiotoxic pharmaceutical compounds
WO2010073706A1 (ja) * 2008-12-25 2010-07-01 株式会社カネカ カルバペネム側鎖中間体の改良された製造方法
CN106565579A (zh) * 2016-06-26 2017-04-19 宁夏海诚电化信息科技有限公司 一种尔它培南侧链生产工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0472062A1 (de) * 1990-08-10 1992-02-26 Sumitomo Pharmaceuticals Company, Limited Beta-Lactam-Verbindungen sowie ihre Herstellung und Verwendung
EP0551993A1 (de) * 1992-01-10 1993-07-21 Sumitomo Pharmaceuticals Company, Limited Pyrrolidinderivate und Verfahren zur Herstellung solcher Verbindungen
WO1997006154A1 (en) * 1995-08-04 1997-02-20 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4340738A (en) * 1979-06-21 1982-07-20 Janssen Pharmaceutica, N.V. 2,3-Dihydro-imidazo[2,1-b]benzothiazoles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0472062A1 (de) * 1990-08-10 1992-02-26 Sumitomo Pharmaceuticals Company, Limited Beta-Lactam-Verbindungen sowie ihre Herstellung und Verwendung
EP0551993A1 (de) * 1992-01-10 1993-07-21 Sumitomo Pharmaceuticals Company, Limited Pyrrolidinderivate und Verfahren zur Herstellung solcher Verbindungen
WO1997006154A1 (en) * 1995-08-04 1997-02-20 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRANDS K M J ET AL: "An Expedient One-pot Synthesis for Protected 2-Thia-5-azabicyclo[2.2.1]heptan-3-ones. Versatile Intermediates in the Synthesis of Carbapenem Sidechains", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 37, no. 17, 22 April 1996 (1996-04-22), pages 2919 - 2922, XP004029681, ISSN: 0040-4039 *
MATSUMURA H ET AL: "HETEROCYCLES, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL", HETEROCYCLES, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 41, no. 1, 1995, pages 147 - 159, XP002076865, ISSN: 0385-5414 *
See also references of WO9902531A1 *

Also Published As

Publication number Publication date
AU8282198A (en) 1999-02-08
WO1999002531A1 (en) 1999-01-21
CA2294342C (en) 2006-03-14
CA2294342A1 (en) 1999-01-21
JP2002504156A (ja) 2002-02-05
EP1019411A1 (de) 2000-07-19
AU731586B2 (en) 2001-04-05

Similar Documents

Publication Publication Date Title
US4631150A (en) Process for the preparation of penems
KR20010086058A (ko) 광범위한 항균 스펙트럼을 갖는이미다조[4,5-ｂ]피리디늄메틸-함유 세펨 화합물
SU856388A3 (ru) Способ получени ненасыщенных производных 7-ациламидо-3-цефем-4-карбоновой кислоты или их сложных эфиров или их солей с щелочными металлами
CA2294342C (en) Process for synthesizing carbapenem side chain intermediates
CA2657930A1 (en) Synthesis of (2s,5r)-5-ethynyl-1-{n-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile
EP0842166B1 (de) Verfahren zur herstellung von zwischenprodukten von carbapenem-seitenketten
US6063931A (en) Process for synthesizing carbapenem side chain intermediates
AU605491B2 (en) Quaternary amine thiol process
EP0557122B1 (de) Verfahren zur Herstellung von Sulfamid
US6060607A (en) Process for synthesizing carbapenem side chain intermediates
KR950013578B1 (ko) 신규 티아(디아)졸 초산의 반응성 티오포스페이트 유도체 및 그의 제조방법
US5648501A (en) Process for synthesizing carbapenem side chain intermediates
GB2257703A (en) Acylation of 7 - amino-cephems
US5721368A (en) Process for synthesizing carbapenem side chain intermediates
US4841043A (en) Stereoselective synthesis of 1-β-alkyl carbapenem antibiotic intermediates
AU661192B2 (en) 4-substituted alkyl carbapenem antibiotics
JP2696807B2 (ja) カルバペネム誘導体の製法
KR20050086548A (ko) 경구 투여용 카르바페넴 화합물의 제조 방법
KR950010083B1 (ko) 세팔로스포린 유도체의 제조방법
KR100650207B1 (ko) 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체와 이의 제조방법
WO1991017995A1 (en) New penem dithiocarbamates, their use and production methods
US20060281918A1 (en) Resolution of enantiomeric mixtures of beta-lactams
KR930001405B1 (ko) 2-(4-치환아미노-3-옥소-이속사졸리디닐)-5-옥소-2-테트라히드로푸란카르복실산 유도체의 제조방법
IE880488L (en) Benzoindazoles
JPS63310890A (ja) ６−アミノ置換−１−メチルカルバペナム誘導体

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000209

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7C 07D 495/08 A, 7C 07D 207/12 B, 7C 07D 207/16 B, 7C 07D 409/12 B, 7C 07F 9/572 B, 7C 07D 495/08 J, 7C 07D 333:00 J, 7C 07D 209:00 J

A4 Supplementary search report drawn up and despatched

Effective date: 20030626

17Q First examination report despatched

Effective date: 20070810

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090526