Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

• This invention relates to a process for the preparation of a compound useful as an intermediate in the preparation of pharmaceutical compounds.
• nucleoside analogue antiviral agents such as penciclovir and famciclovir, described in EP-A-141927 (Example 1) and EP-A-182024 (Example 2).
• the intermediate is 9-substituted with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen (a 2-aminopurine).
• EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing a compound of formula (I) as hereinbefore defined, which process comprises reacting guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions.
• EP-A-433846 (Hoechst Aktiengesellschaft) describes a corresponding process for preparing the 2-acylated derivative, involving chlorination of 2,9-diacylguanine and subsequent removal of the 9- acyl group by hydrolysis.
• phase transfer catalysts include tetrasubstituted ammonium chlorides.
• ammonium substituents include C2-12 aik i, usually C2-4 alkyl, or phenyl or benzyl.
• Other possible phase transfer catalysts include tetra-substituted phosphonium chlorides wherein examples of the substitutents are as defined above for ammonium chlorides.
• the phase transfer catalyst is tetraethylammonium chloride.
• phase-transfer catalyst is preferably present in an amount of from 1 to 3 equivalents of the compound of formula (II) and preferably from 1 to 2 equivalents.
• a preferred chlorinating agent is phosphorus oxychloride.
• the chlorinating agent is present in an amount of from 2-10 preferably from 3-6 molar equivalents of the guanine derivative.
• the reaction may be effected in the presence of a weak base, such as a tertiary amine, for example N,N-dimethylanili ⁇ e or diethylaniline or triethylamine-
• a weak base such as a tertiary amine, for example N,N-dimethylanili ⁇ e or diethylaniline or triethylamine-
• the base is usually present in an approximately molar equivalent amount with respect to the guanine derivative.
• a catalytic amount of water may be added to the reaction mixture.
• added base may not be necessary, but is preferred.
• the reaction is preferably carried out at an elevated temperature of from 30-100°C, most preferably under reflux and/or with ultrasonication at 50-70°C.
• reaction is allowed to proceed for a period of greater than half an hour, usually less than 30 hours.
• the compound of formula (I) may be prepared from 2,9-diacylguanine. Accordingly, the present invention provides a process for preparing 2-amino- 6-chloropurine, which process comprises reacting a 2,9-diacylated derivative of guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions, and thereafter removing the 9-acyl group and the 2-acyl group by hydrolysis.
• Aqueous sodium hydroxide is a suitable basic medium for the hydrolysis.
• Diacetyl guanine (8.0g, 0.034 moles), triethyimethylammonium chloride (15.45g, 0.102 moles), and triethylamine (4.74 mis, 0.034 moles) were heated together with stirring in acetonitrile (70mls) to 50°C.
• Phosphorus oxychioride (6.34 mis, 0.068 moles) was then added and stirring continued for 4 hours.
• the reaction mixture was cooled and then added to aqueous sodium hydroxide solution (20g in 300mls water).
• the reaction mixture was heated to 80°C for 2 hours and then the volume made up to 300 mis with water.
• the mixture was cooled to 25°C and the pH adjuster to 7 using 10% hydrochloric acid.
• the resulting slurry was stirred for fifteen minutes and the product filtered off and washed with water 30 mis and then dried at 80°C under vacuum to give a cream/off white coloured product.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

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Family Applications (1)

Country Status (10)

Families Citing this family (7)

Family Cites Families (6)

• 1992
  • 1992-01-30 GB GB929201961A patent/GB9201961D0/en active Pending
• 1993
  • 1993-01-28 AU AU33654/93A patent/AU669874B2/en not_active Ceased
  • 1993-01-28 CA CA002117435A patent/CA2117435A1/en not_active Abandoned
  • 1993-01-28 NZ NZ246677A patent/NZ246677A/en unknown
  • 1993-01-28 ZA ZA93615A patent/ZA93615B/xx unknown
  • 1993-01-28 WO PCT/GB1993/000185 patent/WO1993015075A1/en not_active Application Discontinuation
  • 1993-01-28 KR KR1019940702650A patent/KR950700299A/ko not_active Application Discontinuation
  • 1993-01-28 MX MX9300482A patent/MX9300482A/es unknown
  • 1993-01-28 JP JP5513055A patent/JPH07503246A/ja active Pending
  • 1993-01-28 EP EP93902481A patent/EP0625154A1/en not_active Withdrawn

Non-Patent Citations (1)

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