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.

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

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Citations (4)

• 1996
  • 1996-06-18 AR ARP960103190A patent/AR002507A1/es unknown
  • 1996-06-24 CN CN96196325A patent/CN1193322A/zh active Pending
  • 1996-06-24 CA CA002224439A patent/CA2224439A1/en not_active Abandoned
  • 1996-06-24 EP EP96923404A patent/EP0836607A1/en not_active Withdrawn
  • 1996-06-24 SK SK1765-97A patent/SK176597A3/sk unknown
  • 1996-06-24 CZ CZ974190A patent/CZ419097A3/cs unknown
  • 1996-06-24 KR KR1019970709722A patent/KR19990028406A/ko not_active Withdrawn
  • 1996-06-24 WO PCT/US1996/010783 patent/WO1997001564A1/en not_active Ceased
  • 1996-06-24 JP JP9504502A patent/JPH11513979A/ja active Pending
  • 1996-06-24 AU AU63921/96A patent/AU696543B2/en not_active Ceased
  • 1996-06-24 EA EA199800096A patent/EA199800096A1/ru unknown
  • 1996-06-24 BR BR9609338A patent/BR9609338A/pt unknown
  • 1996-06-24 HU HU9903016A patent/HUP9903016A3/hu unknown

Patent Citations (4)

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