Smithkline Beecham Corporation

Beecham Group Plc

Novartis International Pharmaceutical, Ltd.

Graham R Geen

Richard Lewis Jarvest

Vance J Novack

Inderjit S Mann

Andrew Colin Share

Neil Smith

Graham Johnson

Trevor J Grinter

Thomas Weir Ramsay

Richard Freer

Neil Michael Smith

Michael R Harnden

Martin J Parratt

John C Hanson

Stephen Moore

Intermediates such as methyl 2,2-dimethyl-5-ethenyl-1,3-dioxane-5-carbonate useful to prepare antiviral compounds such as penciclovir and famciclovir are disclosed.

Process for the production of purine derivatives and intermediates therefor

The invention provides a method of rearranging a compound of formula (I), wherein R and R&prime; are selected independently from hydrogen and C alkyl; and R and R are selected independently from hydrogen, hydroxy, halo, C alkyl- or aryl carbonate, amino, mono- or di-C alkylamino, C alkyl or arylamido, C alkyl- or arylcarbonyl, C alkyl- or arylcarboxy, C alkyl- or arylcarbamoyl, C alkyl, C alkenyl, C alkynyl, aryl, heteroaryl, C alkoxy, aryloxy, azido, C alkyl- or arylthio, C alkyl- or arylsulfonyl, C alkyl- or arylsilyl, C alkyl- or arylphosphoryl, and phosphato; to form a compound of formula (II), wherein R, R&prime;, R and R are as defined for formula (I); said method comprising treating the compound of formula (I) with a palladium (0) catalyst and a (diphenylphosphino) C alkane, wherein n is an integer of 1-6. The invention also provides methods of R making penciclovir and famciclovir using this rearrangement reaction.

Process for the production of purine derivatives

The present invention provides a process for the synthesis of penciclovir and famciclovir by 9-substituting 2-amino-6-chloropurine (ACP) with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxy moiety (i.e. to form a guanine) or hydrogen (to form a 2-aminopurine), respectively.

Process for the preparation of purine derivatives

The present invention provides for the compound and synthesis of 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine, which compound is an intermediate involved in the synthesis of penciclovir and famciclovir.

The present invention provides a process for the synthesis of penciclovir and famciclovir by 9-substituting 2-amino-6-chloropurine (ACP) with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxy moiety (i.e. to form a guanine) or hydrogen (to form a 2-aminopurine), respectively; and 2-acetoxymethyl-4-halo-butyl-1-yl acetates.

2-acetoxymethyl-4-halo-butyl-1-yl acetates

The present invention provides a process for the synthesis of penciclovir and famciclovir by 9-substituting the compound 2-amino-6-chloropurine (ACP) with 2-acetoxymethyl-4-(leaving group)-but-1-yl acetate, followed by displacement of the 6-chloro moiety with a hydroxy moiety (i.e. to form a guanine derivative) or with hydrogen (to form the 2-aminopurine derivative), respectively.

Process for preparing benzopyran compounds

This invention comprises a process for preparing benzopyran derivatives represented by formula (I) ##STR1## in which, R.sup.1 is C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, or a group of structure (i), (ii) or (iii). ##STR2##

A process for preparing substituted benzopyran derivatives which comprises a final step cyclisation of the corresponding open-chain intermediates.

Process for preparing tetrazol-5-yl substituted benzopyran compounds

A process for the preparation of a compound of formula (A): ##STR1## wherein X is hydrogen, hydroxy, chloro, C.sub.1-6 alkoxy or phenyl C.sub.1-6 alkoxy and R.sub.a and R.sub.b are hydrogen, including acyl and phosphate derivatives thereof; which process comprises:

Process for the preparation of purine derivatives as antiviral agents

A process for preparing pharmaceutically active compounds of formula (A): ##STR1## wherein X is hydrogen, hydroxy, chloro, C.sub.1-6 alkoxy or phenyl C.sub.1-6 alkoxy; and R.sub.a and R.sub.b are hydrogen, or acyl or phosphate derivatives thereof, which process comprises the preparation of an intermediate of formula (I): ##STR2## wherein R.sub.1 is C.sub.1-6 alkyl, or phenyl C.sub.1-6 alkyl in which the phenyl group is optionally substituted; R.sub.2 is hydrogen, hydroxy, chlorine, C.sub.1-6 alkoxy, phenyl C.sub.1-6 alkoxy or amino; and R.sub.3 is halogen, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphonyl, azido, an amino group or a protected amino group, via the reaction of a compound of formula (II): ##STR3## wherein R.sub.2 and R.sub.3 are as defined for formula (I) with: (a) a compound of formula (III): ##STR4## wherein R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1-6 alkyl, or phenyl, or R.sub.4 and R.sub.5 together are C.sub.5-7 cycloalkyl; or

Process for preparing purine derivatives and intermediates thereof

A process for the preparation of a compound of formula (I) ##STR1## which process comprises reacting a compound of formula (II): ##STR2## wherein the amino group is optionally protected, with a side chain intermediate of formula (III): ##STR3## wherein Q is a leaving group, R.sub.x and R.sub.y are protected hydroxymethyl or acyloxymethyl, or group(s) convertible to hydroxymethyl or acyloxymethyl; and R.sub.z is hydrogen or a group convertible thereto; and thereafter converting the 6- and 8- chloro substituents to hydrogen by means of reduction; converting R.sub.x and R.sub.y when other than hydroxymethyl or acyloxymethyl, to hydroxymethyl or acyloxymethyl, optionally converting R.sub.x /R.sub.y hydroxymethyl to acyloxymethyl or vice versa, deprotecting the 2-amino group where necessary and converting R.sub.z, (when other than hydrogen) to hydrogen; and optionally forming a pharmaceutically acceptable salt thereof.

Chemical process for the preparation of purine derivatives

A crystalline monohydrate of the compound of formula (A) or a crystalline sodium salt monohydrate of the compound of formula (A): ##STR1## having antiviral activity, processes for their preparation and their use as pharmaceuticals.

Growing community of inventors

Stansted Mountfitchet, United Kingdom

Graham R Geen