Penciclovir

• Molecular FormulaC₁₀H₁₅N₅O₃
• Average mass253.258 Da

Cas 39809-25-1
97845-62-0 (Na salt)

Launched – 1996 PERRIGO, Herpes labialis

BRL-39123; penciclovir; BRL 39123A; penciclovir sodium; Denavir; Vectavir; Euraxvir; Fenivir

Penciclovir [USAN:INN:BAN]

• BRL 39123
• BRL-39123
• CCRIS 9213
• Denavir
• HSDB 8123
• Penciclovir
• Penciclovirum
• Penciclovirum [INN-Latin]
• UNII-359HUE8FJC

Penciclovir was approved for medical use in 1996.^[2]

Developed and launched by SmithKline Beecham (SB; now GlaxoSmithKline) and now marketed in the US by Prestium Pharma and ex-US by Novartis, penciclovir (Vectavir; Fenivir; Denavir; Euraxvir) is a 1% topical cream indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age and older

Medical use

In herpes labialis, the duration of healing, pain and detectable virus is reduced by up to one day,^[3] compared with the total duration of 2–3 weeks of disease presentation.

Mechanism of action

Penciclovir is inactive in its initial form. Within a virally infected cell a viral thymidine kinase adds a phosphate group to the penciclovir molecule; this is the rate-limiting step in the activation of penciclovir. Cellular (human) kinases then add two more phosphate groups, producing the active penciclovir triphosphate. This activated form inhibits viral DNA polymerase, thus impairing the ability of the virus to replicate within the cell.

The selectivity of penciclovir may be attributed to two factors. First, cellular thymidine kinases phosphorylate the parent form significantly less rapidly than does the viral thymidine kinase, so the active triphosphate is present at much higher concentrations in virally infected cells than in uninfected cells. Second, the activated drug binds to viral DNA polymerase with a much higher affinity than to human DNA polymerases. As a result, penciclovir exhibits negligible cytotoxicity to healthy cells.

The structure and mode of action of penciclovir are very similar to that of other nucleoside analogues, such as the more widely used aciclovir. A difference between aciclovir and penciclovir is that the active triphosphate form of penciclovir persists within the cell for a much longer time than the activated form of aciclovir, so the concentration within the cell of penciclovir will be higher given equivalent cellular doses.

SYN

Choudary, B.M.; Geen, G.R.; Grinter, T.J.; MacBeath, F.S.; Parratt, M.J.
Influence of remote structure upon regioselectivity in the N-alkylation of 2-amino-6-chloropurine: Application to the synthesis of penciclovir
Nucleosides Nucleotides 1994, 13(4): 979

PATENT

US 6573378

PATENT

CN 102070636

PAPER

https://www.tandfonline.com/doi/abs/10.1081/SCC-120026312?journalCode=lsyc20Selective and Practical Synthesis of Penciclovir

• https://doi.org/10.1081/SCC-120026312

 

9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine
(Penciclovir)[3a,b] (1)
………………………as a colorless crystalline solid: m.p. 268.4–269.2C [Lit.[3a,b]
275–277C]. UV (H2O) max 252 and 273 (sh) nm [Lit[3a,b] 253 and 270
(sh) nm].

1HNMR (DMSO-d6)
1.42 (pseudo septet, 1H, J¼7 Hz, H-30),
1.69 (pseudo q, 2H, J¼7 Hz, H-20), 3.37 (ddd, 2H, J¼11, 7 and 7 Hz)
and 3.41 (ddd, 2H, J¼11, 7 and 7 Hz) (CH2OH), 3.98 (t, 2H, J¼7 Hz,
H-10), 4.42 (t, 2H, J¼7 Hz, OH), 6.42 (br s, 2H, NH2), 7.67 (s, 1H, H-8),
10.50 (br s, 1H, H-1).

The 1HNMR spectrum is in good agreement with
the literature data.[3a,b]

3 (a) Harnden, M.R.; Jarvest, R.L.Tetrahedron Lett. 1985, 26, 4265–4268;

(b) Harnden, M.R.;Jarvest, R.L.; Bacon, T.H.; Boyd, M.R. J. Med. Chem. 1987, 30,1636–1642;

PAPER

Nucleosides Nucleotides Nucleic Acids. 2006;25(4-6):625-34.

Improved industrial syntheses of penciclovir and famciclovir using N2-acetyl-7-benzylguanine and a cyclic side chain precursor.

Torii T¹, Yamashita K, Kojima M, Suzuki Y, Hijiya T, Izawa K.

The synthesis of penciclovir by two related ways has been reported: 1) The reaction of 2-(hydroxymethyl)butane-1,4-diol (I) with formaldehyde (or an aldehyde such as trimethylacetaldehyde) (II) by means of H2SO4 (or p-toluenesulfonic acid, TsOH) gives the dioxane (III), which by reaction first with methanesulfonyl chloride and triethylamine and then with NaI in acetone affords the corresponding 5-(2-iodoethyl)-1,3-dioxane (IV). The reaction of (IV) with 2-amino-6-chloropurine (V) by means of K2CO3 in DMF gives the corresponding condensation product (VI), which is finally hydrolyzed and deprotected with refluxing 2M aqueous HCl. 2) The reaction of triol (I) with 2,2-dimethoxypropane (VII) by means of TsOH gives the corresponding 1,3-dioxane (VIII), which by reaction with triphenylphosphine and CBr4 is converted to the 5-(2-bromoethyl) derivative (IX). The reaction of (IX) with the purine (V) by means of K2CO3 as before affords the corresponding condensation product (X), which is hydrolyzed and deprotected with 2M HCl as before.

AND

This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.

AND

A synthesis of famciclovir that corresponds to that previously published and studies on its oral bioavailability in rats and mice, identifying famciclovir as the preferred prodrug of BRL-39123 (penciclovir), have been published.

AND

The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (II) by means ofK2CO3 in DMF gives the expected condensation product (III), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (V), which is finally converted into famciclovir by reductive dechlorination with H2 over Pd/C in ethyl acetate/triethylamine.

PAPER

Synth Commun 1972,2345-351

This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.

PAPER

Tetrahedron Lett 1985,264265-68

This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.

PAPER

J Med Chem 1987,301636-42

PAPER

http://www.jzus.zju.edu.cn/article.php?doi=10.1631/jzus.A1300238

Journal of Zhejiang University SCIENCE A 2013 Vol.14 No.10 P.760-766 10.1631/jzus.A1300238

Accelerated effect on Mitsunobu reaction via bis-N-tert-butoxycarbonylation protection of 2-amino-6-chloropurine and its application in a novel synthesis of penciclovir

Author(s):  Li-yan Dai, Qiu-long Shi, Jing Zhang, Xiao-zhong Wang, Ying-qi Chen

Affiliation(s):  . Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China

Corresponding email(s):   dailiyan@zju.edu.cn

Key Words:  2-amino-6-chloropurine, Mitsunobu reaction, bis-Boc protection, Penciclovir (PCV)

Fig.1
Purine derivatives

To synthesize 3 and 4, 2-amino-6-chloropurine (ACP) is commonly used as a starting material, coupling with alkyl halide side chains (Geen et al., 1990; Geen et al., 1992; Kim et al., 1998; Brand et al., 1999; Toyokuni et al., 2003). However, considering its isomerization at N7 and N9 positions under acidic or alkaline conditions, the most challengeable issue is the selectivity of a N-alkylation at the N7 or N9 position of ACP. Normally, alkylation takes place at the N9 position as well as at the N7 position of the purine moiety, and the N9/N7 ratio is usually less than 6:1 (Kim et al., 1998). Accordingly, to improve this ratio, several approaches have been reported, mainly involving changing the structure of the side chains (Geen et al., 1992) and modification of the ACP (Brand et al., 1999). For example, as reported by Zheng et al. (2004) (Fig. 2), a side chain 6 was synthesized and separated readily at 0 °C. After coupling 6 with 2-amino-6-chloropurine 7, the ratio of the product 9-isomer purine (8a) and the 7-isomer purine (8b) could reach about 10:1. However, the reaction temperature must be strictly controlled as 6 decomposes easily even at room temperature and then an extra careful column chromatography separation procedure would be required to obtain pure 8a. Thus, finding a more practical and efficient method, which could avoid the formation of N7-alkylated compound and shorten the synthetic steps to obtain ACP, becomes attractive.

Fig.2
Synthesis of penciclovir (PCV) with conventional method

The Mitsunobu reaction might be an alternative (potential) approach (Mitsunobu, 1981; Swamy et al., 2009). This reaction has become a very popular chemical transformation due to its mildness, occurring under essentially neutral conditions, and its stereospecificity, proceeding with complete Walden inversion of stereochemistry (Mitsunobu, 1981). Moreover, it permits C-O, C-S, C-N, or C-C bonds formed by the condensation of an acidic component with a primary or a secondary alcohol. Actually, some literature has already reported successful Mitsunobu coupling of ACP and adenine with allylic and benzylic alcohol, showing a good N9 selectivity (Yang et al., 2005; Kitade et al., 2006; Yin et al., 2006). However, a poor to modest yield (20%–50%) and a limited substrate scope were observed. In order to improve these yields, Lu et al. (2007) developed a modified Mitsunobu method to couple purine with alcohols in a higher temperature (70 °C), along with two rounds of the Mitsunobu reaction; yet its long reaction procedure and poor atom economy weaken its potential. The poor solubility of ACP or its derivatives in THF, the preferred solvent for Mitsunobu reactions, is likely the primary reason for these defects being observed.

A possible process to improve the solubility of ACP is to make use of the tert-butoxycarbonyl group (Boc), which can serve as the protection of the exocylic amino groups functionality and increase the lipophilicity of the base portion of the purine. Another advantage of the Boc protection group is that its acidolytic removal is less sensitive to steric factors and can also be removed under neutral conditions (Hwu et al., 1996; Siro et al., 1998). In contrast, a few studies have recently been reported that apply the Boc group in the protection of nucleobase (Sikchi and Hultin, 2006; Porcheddu et al., 2008). As described by Porcheddu et al. (2008), solubility of nucleobases, including guanine, was increased in some organic solvents after protected by Boc groups. In addition, some results in our previous study (Yang et al., 2011) demonstrated a very good improvement in coupling purine derivatives under Mitsunobu conditions. Thus, it could be safer to presume that protecting amino groups of ACP with Boc would be an ideal way for its application in the synthesis of PCV 3 and offer similar results as shown under Mitsunobu conditions.

In this study, we firstly synthesized a bis-Boc protected ACP, namely, bis-Boc-2-amino-6-chloropurine 9 (Fig. 3) and investigated its solubility in several different Mitsunobu solvents, then coupling bis-Boc-2-amino-6-chloropurine 9 with a large scope of alcohols confirmed its good reactivity for a Mitsunobu reaction and successfully developed a new and efficient method for the preparation of PCV using Mitsunobu coupling reaction as the key step.

Fig.3
Synthesis of bis-Boc-6-chloropurine 9
a: 2-amino-6-chloropurine, 4,4-dimethylaminopyridine (DMAP), THF and Boc₂O, 25 °C, N₂; b: MeOH, NaHCO₃, 55 °C

To a 250 ml N₂-flushed flask with dry THF (100 ml), equipped with a magnetic stir bar, 2-amino-6-chloropurine (2.0 g, 11.8 mmol) and DMAP (0.14 g, 1.18 mmol) were added. Boc₂O (10.3 g, 47.2 mmol) was added to the stirred suspension under an N₂atmosphere, then the reaction mixture was stirred for 6 h at room temperature (TLC analysis indicated the disappearance of 2-mino-6-chloropurine). The excess amount of THF was removed, and the crude product was dissolved in AcOEt (400 ml), washed with HCl aqueous (2 mol/L, 1×30 ml) and brine (2×50 ml), dried with Na₂SO₄ and concentrated in vacuo to give a white solid (5.2 g, 94.5%). mp 51–52 °C; ¹H NMR (500 MHz, CDCl₃): δ=1.47 (s, 18H, C(CH₃)₃), 1.69 (s, 9H, C(CH₃)₃), 8.58 (s, 1H, CH); ¹³C NMR (125 MHz, CDCl₃) δ=153.8, 152.0, 151.8, 150.6, 145.5, 144.7, 130.8, 88.0, 83.9, 28.0.

2. Bis-Boc-2-amino-6-chloropurine (9)

A solution of the white solid obtained above (14 g, 30 mmol) in MeOH (400 ml) was added to saturated NaHCO₃ aqueous (200 ml), then the turbid solution was stirred at 55 °C for 2 h, at which point clean conversion to bis-Boc protected adenine was observed by TLC. After evaporation of MeOH, the residue mixture was cooled, added 5 mol/L hydrochloric acid to get pH=7 (approximate). A large amount of white solid formed, the reaction mixture was filtrated and then dried under a vacuum to give a white solid 9 (10.5 g, 95.5%). mp 101.3–103.3 °C; ¹H NMR (500 MHz, CDCl₃): δ=1.50 (s, 18H, C(CH₃)₃), 8.41 (s, 1H, CH); ¹³C NMR (125 MHz, CDCl₃) δ=153.5, 151.9, 151.6, 151.3, 145.6, 128.5, 82.7, 28.5.

2.3.  5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxane (5)

2-hydroxymethyl-1,4-butanediol 11 (8.10 g, 67.4 mmol) and 2,2-dimethoxypropane (13 ml, 105.7 mmol) were dissolved in dry THF (20 ml). The mixture was stirred and p-toluenesulfonic acid monohydrate (0.64 g, 3.4 mmol) was added, the clear solution was stirred at room temperature for 12 h, triethylamine (10 ml) was added to quench the reaction, and the solution was stirred for 30 min. Then solvents were removed to leave a colorless liquid, the residue was subject to column chromatography on silica gel eluted with 2:1 EtOAc/hexane to give a colorless liquid 5 (6.2 g, 61.5%), R _f=0.46 (2:1 EtOAc/hexane). ¹H NMR (500 MHz, CDCl₃): δ=3.99 (dd, 2H, Heq. J ₁=11.80 Hz, J ₂=4.45 Hz, CH₂); 3.80 (t, 2H, J=6.71 Hz, CH₂), 3.34 (dd, 2H, Hax. J ₁=11.80 Hz, J ₂=8.11 Hz, CH₂), 1.90–1.98 (m, 2H, CH and OH), 1.62 (q, 2H, J=6.85 Hz, CH₂ ); ¹³C NMR (125 MHz, CDCl₃): δ=100.5, 69.8, 60.4, 31.9, 30.3, 21.2.

2.4.  Bis-Boc-2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl] purine (12)

Bis-Boc-2-amino-6-chloropurine 9 (1.0 equivalent) was added to a solution of the side chain 5 (1.1 equivalent) and phosphine reagent (1.1 equivalent) in anhydrous THF under N₂ atmosphere at 0 °C, the resulting solution was treated with di-p-nitrobenzyl azocarboxylate (DNAD) (1.1 equivalent) dropwise and the reaction mixture was continued at room temperature for 8 h, then the solvent was evaporated and the residue dissolved in cyclohexane. The triphenylphosphane oxide precipitated and was filtered off and then the filtrate evaporated under reduced pressure. The product was purified by a column chromatography on silica gel to obtain the pure products as a white solid. mp>280 °C (dec); ¹H NMR (500 MHz, CDCl₃): δ=8.36 (s, 1H, CH), 4.02 (t, 2H, J=7.23 Hz, CH₂), 3.79 (dd, 2H, Heq. J ₁=11.57 Hz, J ₂=4.46 Hz, CH₂), 3.56 (dd, 2H, Hax. J ₁=11.57 Hz, J ₂=8.77 Hz, CH₂), 1.67 (q, 2H, J=7.22 Hz, CH₂), 1.53–1.61 (m, 1H, CH), 1.47 (s, 18H, C(CH₃)₃), 1.39 (s, 3H, CH₃), 1.36 (s, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃): δ=154.3, 151.7, 151.5, 151.1, 128.0, 104.8, 81.7, 71.5, 50.8, 33.7, 28.6, 26.2, 25.7.

2.5.  2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl) ethyl]purine (8a)

A mixture of compound 12 (2.56 g, 5.0 mmol), 2,6-dimethyl pyridine (1.18 ml, 10 mmol) and dry DCM (20 ml) was stirred at 0 °C, then TBTMS-OTf was added dropwise; after the addition, the reaction mixture was stirred at room temperature until TLC showed that compound 12 had completely disappeared. Then 30 ml saturated ammonium chloride solution was added, separated the organic layer, extracted with DCM (2×20 ml), combined and washed by saturated NaCl (2×40 ml), dried with anhydrous sodium sulfate and evaporated to give a white solid (1.21 g, 78%). mp 125–126 °C; ¹H NMR (500 MHz, CDCl₃): δ=8.07 (s, 1H, CH) , 6.99 (s, 2H, NH₂), 4.12 (t, 2H, J=7.31 Hz, CH₂), 3.82 (dd, 2H, 4′-Heq, J ₁=11.79 Hz, J ₂=4.50 Hz, CH₂), 3.53 (dd, 2H, 4′-Hax, J ₁=11.79 Hz, J ₂=8.80 Hz, CH₂), 1.74 (q, 2H, J=7.30 Hz, CH₂), 1.53–1.65 (m, 1H, CH), 1.36 (s, 3H, CH₃), 1.31 (s, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃): δ=159.94, 150.31, 150.26, 141.84, 132.11, 100.52, 68.14, 52.90, 31.32, 26.84, 26.05.

2.6.  9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine (PCV 3)

Compound 12 (5.12 g, 10 mmol) was dissolved in THF (20 ml) hydrochloric acid (2 mol/L, 20 ml). The mixture was stirred for 2 h at 70 °C, and then slowly warmed to reflux for 2 h. After evaporation of the THF under reduced vacuum, 10% aqueous NaOH solution was added to neutralize the residual liquid, and a large amount of off-white solid formed, filtered, washed with acetone and then water, and dried under vacuum to give an off-white solid 3 (2.07 g, 82%). mp 274.6–276.9 °C.

Fig.4
Synthesis of penciclovir (PCV) with new method
a: 2,2-dimethoxypropane, p-toluenesulfonic acid, THF; b: 1.1 equivalent of the side chain 5, 1.1 equivalent of PPh₃, and 1.1 equivalent of azodicarboxylate reagent at rt. in THF; c: TBDMS-OTf, DCM; d: aqueous hydrochloric acid (2 mol/L), THF; e: aqueous hydrochloric acid (2 mol/L)

Our next objective was the synthesis of PCV. As was expected, bis-Boc-2-amino-6-chloropurine 9 combined with the side chain 5(1.1 equivalent) under normal Mitsunobu conditions successfully obtained the desired N9-alkylated compound 12 in 92% yield without the undesired N7 alkylation by-product being formed. Importantly, the reaction conditions were significantly milder than those reported in recent studies (Geen et al., 1990; 1992; Kim et al., 1998; Brand et al., 1999; Toyokuni et al., 2003), requiring only 1.1 equivalent of each of the alcohol, PPh₃ and DNAD, and proceeding to completion within 60 min at room temperature. This is mainly due to the enhanced solubility of the compound 9 as mentioned above. By process c in Fig. 4, compound 8a was obtained under neutral conditions. It is ¹H and ¹³C NMR spectra further indicated that no 7-isomer purine (8b) was formed. Subsequently, we could obtain PCV 3 in an acid condition as procedure e; or directly starting from 12, where hydrolytic dechlorination and deprotection step(s) were accomplished in one pot under mild acid conditions (2mol/L, hydrochloric acid in THF at room temperature) to afford the target PCV 3 in 80%–85% yield (process d). The overall yield of PCV from 11 was 44.5% higher than that in previous study (16%) (Zheng et al., 2004).

References

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[2] Brand, B., Reese, C.B., Song, Q., Visintin, C., 1999. Convenient syntheses of 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine (penciclovir) and 9-[4-acetoxy-3-(acetoxymethyl) butyl]-2-amino-9H-purine (famciclovir). Tetrahedron, 55(16):5239-5252.

[3] De Clercq, E., 1991. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and pyrimidines. Biochemical Pharmacology, 42(5):963-972.

[4] Dey, S., Garner, P., 2000. Synthesis of tert-butoxycarbonyl (Boc)-protected purines. The Journal of Organic Chemistry, 65(22):7697-7699.

[5] Geen, G.R., Grinter, T.J., Kincey, P.M., Jarvest, R.L., 1990. The effect of the C-6 substituent on the regioselectivity of N-alkylation of 2-aminopurines. Tetrahedron, 46(19):6903-6914.

[6] Geen, G.R., Kincey, P.M., Choudary, B.M., 1992. Regiospecific Michael additions with 2-aminopurines. Tetrahedron Letters, 33(32):4609-4612.

[7] Harnden, M.R., Jarvest, R.L., 1985. An improved synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine. Tetrahedron Letters, 26(35):4265-4268.

[8] Harnden, M.R., Jarvest, R.L., Bacon, T.H., Boyd, M.R., 1987. Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl) but-1-yl] purines. Journal of Medicinal Chemistry, 30(9):1636-1642.

[9] Hwu, J.R., Jain, M.L., Tsay, S.C., Hakimelahi, G.H., 1996. Ceric ammonium nitrate in the deprotection of tert-butoxycarbonyl group. Tetrahedron Letters, 37(12):2035-2038.

[10] Kim, D.K., Lee, N., Kim, Y.W., Chang, K.Y., Kim, J.S., Im, G.J., Choi, W.S., Jung, I.H., Kim, T.S., Hwang, Y.Y., 1998. Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonylo-xybut-1-yl) purines as potential prodrugs of penciclovir. Journal of Medicinal Chemistry, 41(18):3435-3441.

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PAPER

https://www.sciencedirect.com/science/article/pii/S004040200600500X

SYN

EP 0141927; ES 8602791; ES 8603887; ES 8603888; JP 1994293764; US 5075445

This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.

References

Penciclovir

Clinical data
Pronunciation	/ˌpɛnˈsaɪkloʊˌvɪər/[1]
Trade names	Denavir
AHFS/Drugs.com	Monograph
MedlinePlus	a697027
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Routes of administration	Topical
ATC code	D06BB06 (WHO) J05AB13 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy only) US: ℞-only
Pharmacokinetic data
Bioavailability	1.5% (oral), negligible (topical)
Protein binding	<20%
Metabolism	Viral thymidine kinase
Elimination half-life	2.2–2.3 hours
Excretion	Renal
Identifiers
IUPAC name[show]
CAS Number	39809-25-1
PubChem CID	4725
DrugBank	DB00299
ChemSpider	4563
UNII	359HUE8FJC
KEGG	D05407
ChEBI	CHEBI:7956
ChEMBL	CHEMBL1540
ECHA InfoCard	100.189.687
Chemical and physical data
Formula	C10H15N5O3
Molar mass	253.258 g/mol
3D model (JSmol)	Interactive image

/////////////Penciclovir, BRL-39123,  BRL 39123A, penciclovir sodium, Denavir, Vectavir, Euraxvir, Fenivir,

C1=NC2=C(N1CCC(CO)CO)NC(=NC2=O)N