Process for the production of purine derivatives and...

Details Process for the production of purine derivatives and... Process for the production of purine derivatives and...

2003-02-19

2004-10-19

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S221000

Reexamination Certificate

active

06806375

ABSTRACT:

Nucleosides and Nucleotides,
15(5), 981-994 (1996) and WO 95/28402 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the ‘bromoester’ route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carboxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.
A disadvantage of this route to famciclovir and penciclovir is that the initial alkylation reaction with the bromotriester reagent gives a mixture of the N-9 and N-7 isomers. 2-Amino-6-chloropurine is a fairly expensive starting material, and accordingly the wastage arising from the production of the unwanted N-7 isomer is undesirable.
EP-A-0352953 discloses a process for the production of purine derivatives according to the bromotriester route in which the ratio of N-9 to N-7 products is improved by converting the 2-amino-6-chloropurine to the analogous 6-iodo, 6-benzylthio or 6-(phenacylmethyl)thio compound.
Whilst the process of EP-A-0352953 represents an improvement in the bromotriester process for producing famciclovir, it suffers from the disadvantages that a material quantity of the N-7 isomer still results, and moreover an additional step of converting the 6-chloro substituent to 6-iodo, 6-benzylthio or 6-(phenacylmethyl)thio is required.
Accordingly, there remains a need for an improved process for making purine derivatives such as famciclovir and penciclovir.
According to one aspect of the invention there is provided a process for the production of a compound of formula (I):
wherein X is H, OH or halo; and R
1
and R
2
are selected independently from C
1-12
alkyl, aryl, C
1-12
alkylaryl, C
1-12
alkylsilyl, arylsilyl and C
1-12
alkylarylsilyl, or R
1
and R
2
are joined together to form a cyclic acetal or ketal; which process comprises reacting a compound of formula (II):
wherein X is as defined for formula (I), with a compound of formula (III):
wherein Y is a leaving group and R
1
and R
2
are as defined for formula (I), in the presence of a palladium(0) catalyst and a ligand.
Preferably X is halo, more preferably X is chloro.
R
1
and R
2
may be selected independently from benzyl and C
1-12
alkyldiarylsilyl, such as C
1-6
alkyldiphenylsilyl, e.g. t-butyldiphenylsilyl. Preferably however, R
1
and R
2
are linked to form a cyclic acetal or ketal, preferably a 6-membered cyclic acetal or ketal of formula (IV):
wherein R
3
and R
4
are selected independently from H, C
1-12
alkyl and aryl.
Preferably R
3
and R
4
are both C
1-12
alkyl, more preferably R
3
and R
4
are both methyl.
The palladium (0) catalyst may be selected from tetrakis(triphenylphosphine) palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform or any palladium(0) dibenzylidene catalyst. More generally it is envisaged that any palladium(0) source may be suitable.
Alternatively the palladium(0) catalyst may be formed in situ from a palladium(II) salt. The salt may be selected from palladium acetate, palladium chloride, allyl palladium chloride dimer, bis(triphenylphosphine) palladium chloride and [1,2-bis(diphenylphosphino)ethane]dichloropalladium (II).
The ligand may be selected from the group consisting of triphenylphosphine; tributylphosphine; tricyclohexylphosphine; bis(diphenylphosphino)methane; 1,2-bis(diphenylphosphino)ethane; 1,3-bis(diphenylphosphino)propane; 1,4-bis(diphenylphosphino)butane; 1,2-bis(diphenylphosphino)ferrocene; (R)-(+)-2,2′bis(diphenylphosphino)-1,1′-binaphthyl; 3,3′3″-phosphinidynetris(benzenesulphonic acid) trisodium salt; trimethyl phosphite; triisopropyl phosphite; triphenyl phosphite, trimethylolpropane phosphite, tri-2-furylphosphine and tris(4-methoxyphenyl)phosphine.
Preferably, the ligand is selected from 1,2-bis(diphenylphosphino)ethane [DIPHOS], trimethylolpropane phosphite [TMPP] and 1,3-bis(diphenylphosphino)propane [DPPP].
The reaction between the compound of formula (II) and the compound of formula (III) may additionally be conducted in the presence of a base. The base may selected from caesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, cesium fluoride, lithium hydride, sodium hydride, sodium hydroxide, triethylamine, diazabicyclo[5.4.0]undec-7-ene and 1,1,3,3-tetramethylguanidine. The base is preferably caesium or potassium carbonate.
Where the catalyst is provided in the form of a palladium(II) salt, which is reduced to palladium(0) in situ, the reaction may be effected by the phosphine or phosphite ligand, or by the use of an additional reducing agent. It has been found, for example, that the TMPP ligand is capable of reducing the palladium(II) salt to palladium(0) to give a good N-9 to N-7 ratio. The additional reducing agent may be selected from hydrazine and sodium hypophosphite.
The reaction will usually be conducted in an inert solvent. The inert solvent may be selected from the group consisting of dimethylformamide (DMF), diethylformamide, N-methylpyrrolidinone, dimethylacetamide, dimethylsulphoxide, acetonitrile, tetrahydrofuran, aqueous methanol, aqueous acetonitrile and aqueous dimethylformamide. Preferably the inert solvent comprises DMF.
The reaction may be carried out at a temperature in the range of about 20-120° C., preferably about 60-80° C., for 1-50 hours depending on the reagents used, preferably 1-24 hours.
The reaction may be conducted under an inert atmosphere. Any suitable inert gas may be used, but argon is preferred. Preferably the reaction is carried out under a flow of the inert gas.
Further additives may be included in the reaction mixture, which additives are selected from hydrazine hydrate, benzyltrimethylammonium chloride, tetrabutylammonium chloride, magnesium iodide, Aliquat 336, barium acetate, lithium chloride, 15-Crown-5, ammonium formate, sodium acetate, sodium hypophosphite hydrate and n-butyllithium.
The reaction may be performed by adding the palladium catalyst to a reaction mixture containing the compounds of formulae (II) and (III), the ligand and any additional reagents, such that the ligated catalytic species is formed in situ. However, pre-formation of the ligated catalytic species is preferred. Pre-formation may be achieved by stirring the palladium catalyst and the ligand in the reaction solvent, e.g. for a period of up to 30 min, prior to the addition of the compounds of formulae (II) and (III) and any additional reagents.
It has been found surprisingly that the reaction between compounds of formulae (II) and (III) in accordance with the present invention gives rise to a very high yield of the N-9 isomer over the unwanted N-7 isomer.
In a further aspect of the invention there is provided a compound of formula (I) which is a novel intermediate wherein X, R
1
and R
2
are as defined above.
In another aspect of the invention there is provided a process for the production of a compound of formula (V):
wherein X′ is H or OH; and R
5
and R
6
are independently selected from H and R′CO wherein R′ is phenyl, C
1-12
alkyl or phosphoryl, which process comprises producing a compound of formula (I) according to the process of the invention defined above, hydrogenating the compound of formula (I), converting —OR
1
and —OR
2
to form two hydroxy groups and thereafter if and as necessary:
(i) converting one or both of the hydroxy

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