PROCESS FOR THE PREPARATION OF 2-AMINO-6-CHLOROPURINE

Abstract: A process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of 2,4,5-triamino-6-chloropyrimidine.

Description: PROCESS FOR THE PREPARATION OF 2-AMIN0-6-CHL0R0PURINE This invention relates to a process for the preparation of a compound useful as an intermediate in the preparation of pharmaceutical compounds. The compound 2-amino-6-chloropurine (ACP) of formula (I): (I) is a useful intermediate in the preparation of 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. A new process has now been discovered, which obviates the need for using guanine as an intermediate, and avoids other possible routes from pyrimidines which react irreversibly with ACP, which new process utilises a condensation reaction to form the purine from a 2,4,5-triaminopyrimidine. Accordingly, the present invention provides a process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of 2,4,5-triamino-6-chloropyrimidine. Appropriate reagents for imidazole ring closure include suitable carbanion generating condensation agents, such as diethoxymethylacetate and triethyl orthoformate. The reaction preferably takes place at elevated temperature, above 80°C, in the absence of any additional solvent or in the presence of a suitable inert solvent. 2,4,5-Triamino-6-chloropyrimidine is a known compound which may be prepared as described in EP-A-335355, or from 2,5-diamino-4,6-dichloropyrimidine or 2,4,5-triamino-6-hydroxypyrimidine. The invention may be illustrated with reference to the following scheme and examples. Scheme Examples of 2-Amino-6-chloropurine (ACP) Preparation 2,4,5-Triamino-6-chloropyrimidine intermediate A. 2,5-Diamino 4,6-dichloropyrimidine (prepared as in WO 91/01310) (10.8g) and concentrated aqueous ammonia (30 ml) were heated together in a sealed vessel at 105°C for 18 hrs., then cooled. 2.34g NaOH in water (10 ml) was added and the excess ammonia striped out by concentrating to a low volume - 25 ml at 20°C. Dilute HC1 2N 35 ml and water 10 ml were added and heated to dissolve, charcoaled with carbon, filtered hot, cooled to crystallize, then filtered to give 2,4,5-triamino-6- chloropyrimidine hydrochloride 8.93g and a second crop on concentrating of 1.28g total 87% yield. [Higher acid concentration gives the dihydrochloride monohydrate.] B. 2,4,5-Triamino-6-hydroxypyrimidine free base (2.82g), triethylmethylammonium chloride (20g) and phosphorus oxychloride (25 ml) (41g) were stirred and heated to 105° for 24-48 hrs. The reaction was shown by h.p.l.c. to be almost complete. Some excess phosphorus oxychloride was distilled out at a temperature of 130°C over a period of one hour. The reaction mixture was poured into water ice to maintain a temperature of approx. 60°C to complete hydrolysis. Some water/HCl was stripped off and KOH added to cause crystallisation of either monohydrochloride or free base at different pH's. ACP Preparation A. 2,4,5-Triamino-6-chloropyrimidine hydrochloride (3.92g, 0.02M) and diethoxymethyl acetate (32g) were heated for 10 hrs. at 95°C, allowing the ethanol to distill off. Two products were formed, ACP and formyl ACP. After checking that the reaction was complete by h.p.l.c, the reaction mixture was cooled to (20°C) and 2N HC1 20ml added to give a solution which slowly crystallised. After stirring for 2 hrs., the mixture was filtered to give 2-amino-6-chloropurine hydrochloride (2.16g). A second crop was obtained from the concentration of the liquors (0.5g). Total yield 64%. Ig of hydrochloride was suspended in water (20 ml), 0.38g NaOH added to pH 12 and the solution warmed to 50°C. The solution was filtered over charcoal, acetone (8 ml) added and the pH adjusted to 7.5 (while hot) to give 2-amino-6-chloropurine (0.84g 98%). B. 2,4,5-Triamino-6-chloropurine hydrochloride and triethyl orthoformate (26 ml) were heated overnight at 105°C allowing the ethanol produced to distill off. After checking the reaction was complete by h.p.l.c, it was cooled and 2N Hydrochloric acid (20 ml) added to give a solution which crystallised slowly. The solid and liquors were made basic to pH 11.8 charcoaled with carbon 0.4g at 50°C in 80 ml (total solution filtered), acetone 8 ml added and the pH adjusted with 4N HC1 to 7.5 (while hot), allowing the product to crystallise. The product was filtered, washed and dried. Yield 2.12g ACP 62.5% 13 C n.m.r., δ = 159.8, 155.2, 148.9, 141.2, 123.0 ppm in D6DMSO, identical to ACP. ACP may also be prepared directly from 2,4,5-triamino-6-hydroxypyrimidine by treatment with POCI3 in dimethylformamide.

Claims: Claims 1. A process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of 2,4,5-triamino-6-chloropyrimidine. 2. A process according to claim 1 wherein the carbanion generating condensation agent for imidazole ring closure is diethoxymethylacetate or triethyl orthoformate. 3. A process according to claim lor 2 wherein the reaction takes place at elevated temperature, above 80°C, in the absence of any additional solvent or in the presence of a suitable inert solvent. 4. A process for the preparation of a nucleoside analogue antiviral agent which process comprises the preparation of 2-amino-6-chloropurine according to the process of any one of claims 1 to 3, and thereafter reacting 2-amino-6-chloropurine with a side chain precursor at the 9-position of the purine and optionally converting the 6-chloro substituent. 5. A process according to claim 4, for the preparation of famciclovir. 6. A process according to claim 4, for the preparation of penciclovir.

Inventors: HANSON JOHN CHRISTOPHER, HANSON, JOHN, CHRISTOPHER
Applicants: HANSON JOHN CHRISTOPHER, SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: C07D473
IPC codes: A61K31, A61P31, C07D239, C07D473