EP0836607A1 - Procede ameliore de synthese d'intermediaires du carbapeneme - Google Patents

Procede ameliore de synthese d'intermediaires du carbapeneme

Info

Publication number
EP0836607A1
EP0836607A1 EP96923404A EP96923404A EP0836607A1 EP 0836607 A1 EP0836607 A1 EP 0836607A1 EP 96923404 A EP96923404 A EP 96923404A EP 96923404 A EP96923404 A EP 96923404A EP 0836607 A1 EP0836607 A1 EP 0836607A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
substantially non
base
reactive solvent
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Withdrawn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
EP96923404A
Other languages
German (de)
English (en)
Inventor
Chunhua Yang
Nobuyoshi Yasuda
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 GBGB9602921.0A external-priority patent/GB9602921D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0836607A1 publication Critical patent/EP0836607A1/fr
Withdrawn legal-status Critical Current

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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • 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
    • 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
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages

Definitions

  • the present invention is related to an improved synthesis of carbapenem intermediates, and in particular, the following compounds:
  • the present invention overcomes these disadvantages, providing a scheme which avoids unstable intermediates, and in many instances, producing intermediates which are in crystalline form, requiring little or no purification before futher use.
  • R represents H or methyl and P represents triethylsilyl or trimethylsilyl.
  • the process comprises treating a compound of the formula:
  • the 1 - ⁇ methyl isomer of the final product is more resistant to deactivation than the IH or the 1- ⁇ methyl isomer.
  • the bicyclic ketoester 2 can be further reacted at the 2- position to establish a leaving group, e.g., L, which represents diphenyl phosphate, triflate, tosylate, mesylate, fluorosulfonate, chloride and the like, to form the appropriate activated carbapenem intermediate.
  • the activated carbapenem intermediate is suitable for coupling to a substituent at position 2, for example, through the use of a palladium catalyst, e.g., Pd2(dba)3*CHCl3, and tris(2, 4, 6- trimethoxyphenyl)phosphine in a suitable solvent. Further details regarding coupling reactions can be obtained from U.S. Patent No. 5,034,384.
  • a compound of formula 3 wherein R represents H or methyl is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 1 :
  • a compound of formula 3 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula la:
  • a compound of formula 3 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula lb:
  • a compound of formula 4 wherein R represents H or methyl is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 2:
  • a compound of formula 4 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula 2a:
  • a compound of formula 4 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula 2b:
  • the substituted azetidinone is cyclized before protection of the hydroxyethyl side chain. After cyclization, the side chain is protected with P.
  • PNB refers to the protecting group para- nitrobenzyl.
  • THF tetrahydrofuran
  • OAc refers to acetate, CH3C(0)0-.
  • EtOAc solvent ethyl acetate
  • iPrOAc isopropyl acetate
  • TES refers to the group triethylsilyl.
  • TMS refers to the group trimethylsilyl.
  • Et3N refers to triethylamine.
  • dba refers to dibenzylideneacetone.
  • the objects of the present invention are to utilize crystalline intermediates and to avoid unstable intermediates. Additionally, stereospecificity and regiospecific reactions are favored. The following schemes are representative.
  • the anhydride L2O or the halide L-Cl can be combined with the bicyclic ketoester in the presence of a nitrogen containing base and in a substantially non-reactive solvent to produce the activated carbapenem 5.
  • the activated carbapenem 5, with the appropriate group L at position 2 can then be coupled to an appropriate substituent according to the procedures set forth in U. S. Pat. No. 5,034,384.
  • Carbapenems which can be synthesized in accordance with the process described herein are disclosed, and the groups which are appropriate for such attachment, can be found, e.g., in U.S. Pat. No. 5,034,384.
  • the preferred substantially non-reactive solvents used herein are dimethylformamide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate and methylene chloride. Most preferably, mixtures thereof are used.
  • the preferred base used in the processes described herein is imidazole.
  • the nitrogen containing bases for use in the activating reaction with L2O or L-Cl include triethylamine, diisopropylethylamine and diisopropylamine.
  • L examples include the sulfonate leaving groups, such as trifluoromethanesulfonate (triflate), methanesulfonate (mesylate), toluenesulfonate (tosylate) and fluorosulfonate, the phosphonic acid residues, such as diphenylphosphonate and the halide leaving groups, such as chloride, bromide or iodide.
  • triflate OTf
  • OSO2F flurorosulfonate
  • OMs mesylate
  • the batch was aged at 20 °C for 2 hr.
  • the reaction mixture was assayed by HPLC.
  • the starting material should be less than 0.15 area % at 245 nm.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur un procédé de synthèse d'un composé de formule (1) ou (2), dans lesquelles R représente H ou méthyle et P représente triéthylsilyle ou triméthylsilyle. Un composé de formule (3) ou (4) est amené à réagir avec P-C1, P étant défini comme ci-dessus, en présence d'une base et d'un solvant sensiblement non réactif de façon à donner (1) ou (2).
EP96923404A 1995-06-28 1996-06-24 Procede ameliore de synthese d'intermediaires du carbapeneme Withdrawn EP0836607A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US58595P 1995-06-28 1995-06-28
US585P 1995-06-28
GBGB9602921.0A GB9602921D0 (en) 1996-02-13 1996-02-13 Improved process for synthesizing carbapenem intermediates
GB9602921 1996-02-13
PCT/US1996/010783 WO1997001564A1 (fr) 1995-06-28 1996-06-24 Procede ameliore de synthese d'intermediaires du carbapeneme

Publications (1)

Publication Number Publication Date
EP0836607A1 true EP0836607A1 (fr) 1998-04-22

Family

ID=26308678

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96923404A Withdrawn EP0836607A1 (fr) 1995-06-28 1996-06-24 Procede ameliore de synthese d'intermediaires du carbapeneme

Country Status (13)

Country Link
EP (1) EP0836607A1 (fr)
JP (1) JPH11513979A (fr)
KR (1) KR19990028406A (fr)
CN (1) CN1193322A (fr)
AR (1) AR002507A1 (fr)
AU (1) AU696543B2 (fr)
BR (1) BR9609338A (fr)
CA (1) CA2224439A1 (fr)
CZ (1) CZ419097A3 (fr)
EA (1) EA199800096A1 (fr)
HU (1) HUP9903016A3 (fr)
SK (1) SK176597A3 (fr)
WO (1) WO1997001564A1 (fr)

Cited By (2)

* 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
US8841444B2 (en) 2008-07-30 2014-09-23 Ranbaxy Laboratories Limited Process for the preparation of carbapenem compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4683301A (en) * 1982-04-08 1987-07-28 Bristol-Myers Company Carbapenem antibiotics
JP2675625B2 (ja) * 1989-01-12 1997-11-12 鐘淵化学工業株式会社 エノールシリルエーテル化合物の製造方法
NZ234411A (en) * 1989-07-18 1991-05-28 Merck & Co Inc Preparation of 2-diazo-3-silyloxy-3-butenoate esters
DE3934100A1 (de) * 1989-10-12 1991-04-18 Bayer Ag Verfahren zur herstellung von 0-silylierten hydroxylverbindungen und ihre verwendung zur herstellung von estergruppen aufweisenden isocyanaten

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9701564A1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841444B2 (en) 2008-07-30 2014-09-23 Ranbaxy Laboratories Limited Process for the preparation of carbapenem compounds
WO2011048583A1 (fr) 2009-10-23 2011-04-28 Ranbaxy Laboratories Limited Procédé pour la préparation de composés de carbapénème

Also Published As

Publication number Publication date
SK176597A3 (en) 1998-07-08
AU6392196A (en) 1997-01-30
CA2224439A1 (fr) 1997-01-16
CZ419097A3 (cs) 1998-07-15
HUP9903016A2 (hu) 2000-03-28
AU696543B2 (en) 1998-09-10
AR002507A1 (es) 1998-03-25
JPH11513979A (ja) 1999-11-30
WO1997001564A1 (fr) 1997-01-16
MX9800041A (es) 1998-08-30
KR19990028406A (ko) 1999-04-15
EA199800096A1 (ru) 1998-08-27
HUP9903016A3 (en) 2000-04-28
CN1193322A (zh) 1998-09-16
BR9609338A (pt) 1999-05-11

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