Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

• the present invention relates to a new process for the preparation of the chiral nucleoside analogue (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H purin-9-yl]-2- cyclopentene-1-methanol (compound of Formula (I)).
• the compound of formula (I) is described as having potent activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) in EPO34450.
• WO91/15490 discloses a single step process for the formation of the (1S, 4R)- 4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1- methanol intermediate by reacting (1S, 4R)-4-hydroxy-2-cyclopentene-1 -methanol, in which the allylic hydroxyl group has been activated as an ester or carbonate and the other hydroxyl group has a blocking group attached (for example 1 ,4- bis- methylcarbonate) with 2-amino-6-chloropurine.
• This process offers significant cost savings compared to previous processes described and represents the first aspect of the present invention.
• the major commercial advantages are the length of time to manufacture the compound of formula (I) is significantly reduced using the process of the invention compared to earlier processes described, and wastage is significantly reduced.
• X is H or a blocking group and Y is H or an activating group, with 2- amino-6-(cyclopropylamino) purine in the presence of a catalyst.
• X is H or a blocking group and Y is H or an activating group, with 2-amino- 6-(cyclopropylamino) purine.
• An optional further step is resolving the product of the invention to a compound of formula (I) substantially free of the corresponding enantiomer.
• 2-Amino-6-cyclopropylamino-9H-purine can be prepared by treating 2-amino-6- chloropurine with cyclopropylamine, or in accordance with the methods described in US5420115.
• (1S, 4R)- 4-Hydroxy-2-cyclopentene-1 -methanol and the activated and/or blocked version of (1S, 4R)-4-hydroxy-2-cyclopentene-1-methanol may be prepared in accordance with reactions described in WO91/15490 or Hodgson et al. in J.Chem. Soc. Perkin Trans. 1 1994; 3373-3378..
• the preferred catalyst is a transition metal catalyst, preferably a palladium compound but may also be a derivative of other transition metals (such as nickel, molybdenum, tungsten), preferably in the presence of a ligand such as a phosphine.
• a transition metal catalyst preferably a palladium compound but may also be a derivative of other transition metals (such as nickel, molybdenum, tungsten), preferably in the presence of a ligand such as a phosphine.
• Preferred transition metal catalyst are tetrakis (triphenylphosphine) palladium, or tris(dibenzylideneacetone) dipalladium, in the presence of triphenylphosphine
• Suitable activated derivatives of the allylic alcohol group of the compound of formula (II) or (III) include esters (such as acetate); carbonates (such as methylcarbonate); carbamates, preferably RR 'NOC wherein R and R 1 independently selected from C1-6alkyl, aryl or heteroaryl; or phosphates, preferably (RO) 2 OP wherein each R is independently selected from C1-6alkyl, aryl and heteroaryl.
• the allylic alcohol may be activated in situ by the addition of a metal salt, for example stannous chloride (see, for example, Y. Masuyama et al, Chem.Lett. 1995 p. 1121 and references contained therein).
• a metal salt for example stannous chloride (see, for example, Y. Masuyama et al, Chem.Lett. 1995 p. 1121 and references contained therein).
• a base such as sodium hydride or cesium carbonate may optionally be added, particularly where the activated derivative is a simple ester such as acetate.
• a preferred activng blocking groups are cylic carbonates (such as used for the compound of formula (IV).
• Suitable blocking groups may be any such groups recognised in the art of organic chemistry as suitable for protecting primary hydroxymethyl groups, suitable blocking groups include those reported by T W Green in Protecting Groups in Organic Synthesis, Chapter 7, page 10. J. Wiley and sons, New York, 1981 , and include esters, ethers and carbonates (such as methyl carbonate).
• Suitable solvents include, for example, dimethylsulphoxide, N.N- dimethylformamide, N.N-dimethylacetamide or tetrahydrofuran preferably at temperatures between 0° and 150°C.
• Triphenylphosphine 14mg was added, under nitrogen, to a mixture of (1S.4R)- 4-hydroxy-2-cyclopentene -1 -methanol bis(methylcarbonate) (91 mg), 2-amino-6- (cyclopropylamino) purine (90mg), tris(dibenzylideneacetone)dipalladium (12mg) and dry DMF (2ml) and the resulting solution stirred at room temperature for 40 min.
• the DMF was removed at 60° in vacuo and the residue partitioned between ethyl acetate (25ml.) and 20% sodium chloride solution (10ml.).
• the ethyl acetate solution was washed with 20% sodium chloride (2x12ml.) and with saturated sodium chloride solution, then dried (MgSO ) and the solvent removed in vacuo.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (1)

Publications (1)

Family

ID=8166798

Family Applications (1)

Country Status (4)

Citations (4)

• 1997
  • 1997-11-12 WO PCT/EP1997/006379 patent/WO1999024431A1/en not_active Application Discontinuation
  • 1997-11-12 AU AU56534/98A patent/AU5653498A/en not_active Abandoned
  • 1997-11-12 JP JP2000520442A patent/JP2001522850A/ja active Pending
  • 1997-11-12 EP EP97952769A patent/EP1032573A1/de not_active Withdrawn

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events