Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

• the present invention is directed to a method of preparing bromoisoquinoline derivatives, in particular 5- or 8-bromoisoquinoline derivatives.
• Bromoisoquinoline derivatives, and in particular 5-bromoisoquinoline and 5-bromo-8-nitroisoquinoline derivatives, are key intermediates in the synthesis of pharmaceutical compounds.
• Bromoisoquinoline derivatives and in particular 5-bromoisoquinoline and 5-bromo-8- nitroisoquinoline derivatives, are key intermediates in the synthesis of pharmaceutical compounds.
• the direct bromination procedure tends to give mixtures of brominated products and in unsatisfactory yield, and none of the methods described are well suited for large scale work.
• the indirect method is not very suitable for large scale work especially due to the diazotation step.
• the method of the invention is particularly well suited for large scale work operation and for accomplishing "one- pot” synthesis.
• the present invention provides a method of preparing bromoisoquinoline and its derivatives. More particularly, the invention provides a high yielding method for the synthesis of 5- or 8-bromoisoquinoline and its derivatives, in particular 5-bromo-8-nitroisoquinoline. Accordingly, in its most general aspect, the invention provides a process for the preparation of 5- or 8-bromoisoisoquinoline, or a derivative thereof, which process comprises the step of reacting isoquinoline, or a derivative thereof, with a brominating agent in the presence of a catalyst.
• the brominating Agent used according to the present invention may be any suitable brominating agent. However, in a preferred embodiment, a suitable brominating agent is an agent of the general formula Z-Br, wherein Z represents a suitable leaving group.
• the leaving group may be a secondary amino group of the general formula R 2 N-Br, wherein R is alkyl, aryl, acyl or sulfonyl, or R 2 N-Br describes a cyclic structure [e.g. /V-bromosuccinimide (NBS), ⁇ /, ⁇ /'-dibromoisocyanuric acid (DBI) or N,N'- dibromohydantoin (DBH)]:
• NSS V-bromosuccinimide
• DBI ⁇ /, ⁇ /'-dibromoisocyanuric acid
• DBH N,N'- dibromohydantoin
• the catalyst contemplated in the method of the invention may be any suitable H + or a Lewis acid.
• the Lewis acid may in particular be a compound of the formula M' m X n ,, where M' represents a metal, and X represents halogen.
• Preferred Lewis acids are e.g. BF 3 , AIX 3 , TiX 4 , ZnX 2 , MnX 2 , FeX 3 , FeX 2 , SnX 2 , PbX 2 , SbX 3 , and SbX 5 .
• the solvent is an acid with or without H 2 O, e.g. FSO 3 H, CISO 3 H, CF 3 SO 3 H, H 2 SO 4 ,
• the solvent is an acid with or without H2O i.e. HCI (0.1 N to cone), CF3SO3H, H 2 SO 4 , CH3SO3H, CF3COOH or CH3COOH.
• the solvent functions as a catalyst.
• MNO3 is a nitrating reagent as known in the art, wherein M represents a metal or H + .
• the active component being NO 2 + formed in situ in the reaction mixture.
• the method of the invention may be conducted at temperatures ranging from -50 °C to 200 °C with the temperature range between -30 °C to -15 °C being the preferred for the preparation of the 5- or 8-bromoisoquinolines.
• the method of the invention may be conducted from 0.1 g to 500 kg scale with the preferred scale being 1 g to 50 kg. Finally, the reaction may be conducted at 0.1 M to 5 M concentration with a preferred concentration of 0.5-1 M.
• the method of the invention may be quenched after bromination giving 5-bromo or 8- bromoisoquinoline or continued by addition of metal nitrate, whereby 5-bromo-8- nitroisoquinoline or 8-bromo-5-nitroisoquinoline may be isolated from a "ONE POT" reaction.
• 5-bromoisoquinoline and 5-bromo-8-nitroisoquinoline may in broad terms be described as a transformation of isoquinoline to 5-bromoisoquinoline using strong acid, preferably cone. H2SO4, and a brominating agent, preferably NBS.
• the bromination is preferably conducted at 0.5-1 M scale at a temperature of -30 °C to -15°C.
• 5- Bromoisoquinoline may be worked up and isolated as pure material or it may be further transformed, without prior isolation into 5-bromo-8-nitroisoquinoline by addition of potassium nitrate to the reaction mixture. Workup and recrystalization gives pure 5-bromo-8- nitroisoquinoline. Examples
• NBS NBS > DBH.
• NBS and DBH are commercially available and DBI is very easy to make from elemental bromine, lithium hydroxide and cyanuric acid according to the procedure of Gottardi.
• the reaction temperature is very important in order to achieve a high 5- vs. 8-selectivity and should not be above -15 °C during the bromination. 5.
• the crude product was typically of the following composition: 5-Bromo-8-nitroisoquinolin/5,8-dibromoisoquinoline/5-nitroisoquinoline/8-bromo-5- nitroisoquinoline:
• the purified product was typically of the following composition: 5-Bromo-8-nitroisoquinolin/5,8-dibromoisoquinoline/5-nitroisoquinoline/8-bromo-5- nitroisoquinoline: >97%/ ⁇ 1 %/ ⁇ 1 %/ ⁇ 1 %.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Quinoline Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 1999
  • 1999-06-22 DK DK99927733T patent/DK1089976T3/da active
  • 1999-06-22 EP EP99927733A patent/EP1089976B1/en not_active Expired - Lifetime
  • 1999-06-22 WO PCT/DK1999/000347 patent/WO1999067218A2/en not_active Ceased
  • 1999-06-22 JP JP2000555872A patent/JP2002518480A/ja active Pending
  • 1999-06-22 DE DE69911603T patent/DE69911603T2/de not_active Expired - Lifetime
  • 1999-06-22 AT AT99927733T patent/ATE250584T1/de not_active IP Right Cessation
  • 1999-06-22 AU AU44987/99A patent/AU4498799A/en not_active Abandoned
• 2000
  • 2000-10-10 US US09/685,025 patent/US6500954B1/en not_active Expired - Fee Related

Non-Patent Citations (5)

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