Process for the production of purine derivatives

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

2000-11-01

2002-08-20

Berch, Mark L (Department: 1624)

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

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

C544S229000, C544S244000, C544S264000, C544S265000, C544S267000, C544S273000, C544S277000

Reexamination Certificate

active

06437125

ABSTRACT:

This application is the §371 national stage entry of PCT/EP99/02309, filed Mar. 30, 1999.
The present invention relates to a novel process for the production of N-9 alkylated purine derivatives. In particular the present invention relates to a rearrangement reaction of N-7 alkylated to N-9 alkylated purine derivatives.
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28404 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 ‘bromotriester’ 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-carbethoxymalonate. 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.
Co-pending application GB 9807114.5 discloses a method of making purine derivatives which comprises reacting 2-amino-6-chloropurine with an allyl derivative in the presence of a palladium(0) catalyst and a suitable ligand. This reaction effects N-alkylation of the purine, which proceeds with reasonable regioselectivity in favour of the N-9 isomer, however, it is still desirable to optimise the selectivity of the alkylation in favour of the N-9 isomer over the N-7 isomer.
We have now discovered experimental conditions which greatly enhance this selectivity. In particular, we have found a method of procuring the rearrangement of N-7 alkylated purine derivatives to the N-9 alkylated analogues.
According to the invention therefore there is provided a method of rearranging a compound of formula (I):
wherein R and R′ are selected independently from hydrogen and C
1-12
alkyl; and R
1
and R
2
are selected independently from hydrogen, hydroxy, halo, C
1-12
alkyl- or arylcarbonate, amino, mono- or di-C
1-12
alkylamino, C
1-12
alkyl or arylamido, C
1-12
alkyl- or arylcarbonyl, C
1-12
alkyl- or arylcarboxy, C
1-12
alkyl- or arylcarbamoyl, C
1-12
alkyl, C
2-12
alkenyl, C
2-12
alkynyl, aryl, heteroaryl, C
1-12
alkoxy, aryloxy, azido, C
1-12
alkyl- or arylthio, C
1-12
alkyl- or arylsulfonyl, C
1-12
alkyl- or arylsilyl, C
1-12
alkyl- or arylphosphoryl, and phosphato;
to form a compound of formula (II):
wherein R, R′, R
1
and R
2
are as as defined for formula (I);
said method comprising treating the compound of formula (I) with a palladium (0) catalyst and a (diphenylphosphino)
n
C
1-6
alkane, wherein n is an integer of from 1-6.
Any of R, R′, R
1
and R
2
, when other than H, may be unsubstituted or substituted by one or more groups selected independently from hydroxy, halo, C
1-12
alkyl- or aryl carbonate, amino, mono- or di- C
1-12
alkylamino, C
1-12
alkyl- or arylamido, C
1-12
alkyl- or arylcarbonyl, C
1-12
alkyl- or arylcarboxy, C
1-12
alkyl- or arylcarbamoyl, C
1-12
alkyl, C
1-12
alkenyl, C
1-12
alkynyl, aryl, heteroaryl, C
1-12
alkoxy, aryloxy, azido, C
1-12
alkyl- or arylthio, C
1-12
alkyl- or arylsulfonyl, C
1-12
alkyl- or arylsilyl, C
1-12
alkyl- or arylphosphoryl, and phosphato.
The palladium (0) catalyst may be a palladium (0) dibenzylidene catalyst. In a preferred embodiment of the invention the catalyst is a tris(dibenzylidene) dipalladium (0) catalyst, e.g. tris(dibenzylidene) dipalladium (0) chloroform.
The palladium (0) catalyst may be formed in situ from a palladium (II) source such as palladium acetate, or may be added to the reaction as another form of palladium (0), e.g. tetrakis(triphenylphosphine) palladium (0).
The (diphenylphosphino)
n
C
1-6
alkane ligand is preferably a bis(diphenylphosphino)C
1-6
alkane such as 1,2-bis(diphenylphosphino)ethane or 1,3-bis(diphenylphosphino)propane.
The rearrangement reaction of the invention may be conducted at a temperature in the range of about 40°-120° C., preferably about 60°-100° C., and typically about 80° C. The reaction may be conducted for a period of 1 to 24 hours, preferably 1-12 hours, typically about 4 hours.
The rearrangement reaction of the invention may be carried out in an inert solvent. The inert solvent may be selected from dimethylformamide (DMF), diethylformamide, dimethylacetamide and aqueous dimethylformamide. DMF is preferred.
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.
R
1
is preferably halo, typically chloro.
R
2
is preferably an amino group. The amino group may be protected throughout using conventional protecting groups such as benzyl, acetyl or a Schiff's base.
R and R′ are preferably CH
2
OR
3
and CH
2
OR
4
respectively, wherein R
3
and R
4
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
3
and R
4
are joined together to form a cyclic acetal or ketal.
Thus the side-chain on N-7 of formula (I) is preferably a 4-alkoxy-3-alkoxymethyl but-2-enyl group of formula (III):
R
3
and R
4
may be selected independently from benzyl and C
1-12
alkyldiphenylsilyl, e.g. t-butyldiphenylsilyl. Preferably however, R
3
and R
4
are linked to form a six membered cyclic acetal or ketal of formula (IV):
wherein R
5
and R
6
are selected independently from H, C
1-12
alkyl, and aryl.
Preferably R
5
and R
6
are both C
1-12
alkyl, more preferably R
5
and R
6
are both methyl.
Thus, in one embodiment of the invention, the rearrangement of the compound of formula (I) to the compound of formula (II) proceeds as follows:
The compound of formula (I) may be introduced as such to the reaction mixture. Alternatively, the compound of formula (I) may be formed in situ by the reaction of a compound of formula (V):
wherein R
1
and R
2
are as defined for formula (I), with a compound of formula (VI):
wherein Y is a leaving group and R and R′ are as defined for formula (I), in the presence of the dipalladium (0) catalyst and (diphenylphosphino)
n
C
1-6
alkane.
Preferably, the reaction between the compound of formula (V) and the compound of formula (VI) is conducted in the presence of a base. The base may be selected from caesium carbonate, sodium carbonate, potassium 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. Preferably however the base is caesium carbonate.
Various of the compounds of formula (VI) are novel, thus according to a further aspect of the invention there is provided a compound of formula (VI):
wherein Y

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