A new method to synthesize famciclovir

Article abstract of DOI:10.3987/COM-08-11435

A new and efficient method has been reported for the synthesis of 2-amino-9-[4-acetoxy-3-(acetoxymethyl)butyl-1-yl]purine(famciclovir)starting from guanine. The route involves chlorination of guanine, optimized Mitsunobu reaction, coupling with diethyl malonate, hydrogenation, reduction and esterification,and the overall yield is about 29%. This method does not require any form of chromatographic purification to give pure famciclovir, and it is an industrially viable manufacturing process for this drug. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11435

HETEROCYCLES, Vol. 75, No. 11, 2008
2803
HETEROCYCLES, Vol. 75, No. 11, 2008, pp. 2803 - 2808. © The Japan Institute of Heterocyclic Chemistry
Received, 11th May, 2008, Accepted, 20th June, 2008, Published online, 23rd June, 2008. COM-08-11435
A NEW METHOD TO SYNTHESIZE FAMCICLOVIR
Lei Luo,1 Guorong Chen,1 and Yuanchao Li2*
1Laboratory for Advanced Materials, Institute of Fine Chemicals, East China
University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, P.R.
China
2Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555
Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai, 201203, P. R. China
*Corresponding author. Tel.: +86 21 50806600 3502; fax: +86 21 50807288
E-mail: ycli@mail.shcnc.ac.cn
Abstract - A new and efficient method has been reported for the synthesis of
2-amino-9-[4-acetoxy-3-(acetoxymethyl)butyl-1-yl]purine (famciclovir) starting
from guanine. The route involves chlorination of guanine, optimized Mitsunobu
reaction, coupling with diethyl malonate, hydrogenation, reduction and
esterification, and the overall yield is about 29%. This method does not require
any form of chromatographic purification to give pure famciclovir, and it is an
industrially viable manufacturing process for this drug.
INTRODUCTION
Acyclic analogues of nucleosides (acyclonucleosides) have remained major biomedical research targets
since the discovery of the potent antiviral activity of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir,1,
Figure 1),1 the standard drug for the treatment of herpes viral infections. Additional acylonucleosides,
including 2-amino-9-(4-hydroxybutyl)purine(2),2 famciclovir(3),3 and 2-amino-9-[4-hydroxyl-3-
(hydroxylmethyl)butyl]purine (penciclovir, 4),4 have been prepared and found to have such activities.
Most of these nucleoside analogues have the structure of N-9-alkylation which is probably necessary for
the antiviral activities.

2804
HETEROCYCLES, Vol. 75, No. 11, 2008
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
HN
HN
H2N
HN
H2N
H2N
N
H2N
O
AcOH2C
CH2OAc
HOH2C
CH2OH
CH2OH
CH2OH
4
1
3
2
Figure 1
Famciclovir is a prodrug of penciclovir (4, Figure 1), and it has been approved by FDA for treatment of
herpes zoster (shingles) and acute recurrent genital herpes. Four methods have been reported for
preparation of purine derivatives such as famciclovir: (a) construction of purines and pyrimidines from
respective aminoalkanes,5 but this route usually involves more steps and gives low overall yield; (b)
palladium- catalyzed displacement of an allylic ester or carbonate,6 however, it is limited to use for the
application of heavy metals; (c) direct nucleophilic displacement of halides or activated alcohols,7 while
the ratios of the regionisomers are not usually ideal when using this method; (d) Mitsunobu coupling.8
Although the Mitsunobu reaction can afford good regioselectivities at N-9, the protected-deportected
process is needed and the route is long generally. Considering the above methods, we wish to report a
new and efficient method for the preparation of famciclovir using the optimized Mitsunobu coupling
reaction.8c
RESULTS AND DISCUSSION
Guanine (5, Scheme 1) was converted into 2-amino-6-chloropurine (6) according to the reported
procedures,9 and the yield was 70%. As the starting material, guanine is quite cheap and commercially
available. The key intermediate product 7 was obtained from compound 6 via the optimized Mitsunobu
coupling reaction in 81% yield. Although it has been noted that the yield of the N-9 alkylation was
influenced significantly by the size of the substituent at C-6 on purine rings,7b the protected- deportected
process was omitted in this progress, and the route was shorter. Coupling of compound 7 with
diethylmalonate afford 8 in 84%. Catalytic hydrogenation of 8 affected the C-Cl bond to provide 9 in a
yield of 87%. Diester reduction and O-acetylation were achieved without isolation of the intermediate
diol to give 72% of famciclovir 3. The overall yield was about 29%, and this method did not require any
form of chromatographic purification to give pure famciclovir, and it was an industrially viable
manufacturing process for this drug.

HETEROCYCLES, Vol. 75, No. 11, 2008
2805
O
Cl
Cl
N
BrCH2CH2OH
DMF, POCl3
N
N
N
N
HN
N
PPh3, DEAD
ClCH2CH2Cl
reflux, 5 h,
N
THF, 81 %
70 %
N
H
H2N
N
H
H2N
N
N
H2N
7
6
5
Br
CH2(CO2Et)2,
K2CO3, DMSO, 4 h,
84 %
Cl
N
1. NaBH4, MeOH,
CH2Cl2, 2.5 h
H2, Pd/C,
TEA,
MeOH, 7 h,
N
N
N
N
N
N
N
N
2. Ac2O, TEA,
N
H2N
N
DMAP,
CH2Cl2, 12 h
H2N
N
87 %
H2N
72 % for two steps
AcOH2C
CH2OAc
EtO2C
CO2Et
EtO2C
CO2Et
3
9
8
Scheme 1
EXPERIMENTAL
Melting points were determined on a Büchi 510 melting point apparatus and were uncorrected. Mass
spectra were measured on a Finnigan MAT-95 mass spectrometer operating at an ionization potential of
70eV. 1H and 13C NMR spectra were run on a Bruker AM-400 spectrometer using tetramethylsilane as the
internal standard (chemical shifts in parts per million). Splitting patterns were designated as ‘s, d, t, q, and
m’, these symbols indicated ‘singlet, doublet, triplet, quartet, and multiplet’, respectively. All reactions
were monitored by TLC (Yantai Marine Chemical Co. Ltd, China).
2-Amino-6-chloropurine (6)
To a solution of 5 (10 g, 66.2 mmol) in dry DMF (20 mL) and CH2Cl2 (100 mL) was added phosphorus
oxychloride (12.3 mL, 132.4 mmol) at the temperature of 0 ℃. The mixture was stirred for 1 h at the
same temperature, and then refluxed for 5 h. After the completion of the reaction, the mixture was poured
into cold water (150 mL) and the organic layer was recovered. The pH value of the aqueous phase was
adjusted to 7-8 by 10% NaOH aq and the precipitate was filtered off. The compound was dissolved in
12% AcOH aq (50 mL), and stirred for 1 h at 70 ℃. Cooled to rt, the precipitate was filtered off and

2806
HETEROCYCLES, Vol. 75, No. 11, 2008
again dissolved in 10% NaOH aq (75 mL). After stirred for 3 h at rt, the pH of the solution was adjusted
to 7.5 by 6M HCl aq. The precipitate was filtered off and washed with cold water (45 mL). After the
residue was dried, compound 6 (8 g, 70%) was obtained as light yellow powder: mp 300 ℃(lit.,9 300 ℃);
1H NMR (400 MHz, DMSO-d6) δ: 3.795 (2H, s), 7.181 (1H, s), 8.516 (1H, s). The other spectral data for
this compound were identical to those reported previously.9
2-Amino-6-chloro-9-(2-bromoethyl)purine (7)
Compound 6 (3.392 g, 20 mmol) was added to a solution of 2-bromoethanol (1.5 mL, 21 mmol) and PPh3
(5.508 g, 21 mmol) in anhydrous THF under an N2 atmosphere. The resulting suspension was treated with
diethyl azodicarboxylate (DEAD, 3.3 mL, 21 mmol) and the reaction mixture was then stirred at 70 ℃
for 6 h. Then the second portions of 2-bromoethanol (1.5 mL, 21 mmol), PPh3 (5.508 g, 21 mmol), and
DEAD (3.3 mL, 21 mmol) were added to the reaction mixture sequentially. The mixture was stirred for
another 6 h at the same temperature. The mixture was cooled, treated with saturated brine, and extracted
with CH2Cl2. The combined organic layer was then washed with water and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure. The resulting syrup was recrystallized from mixture of
CHCl3 and MeOH (5:2), and the key intermediate product 7 was obtained as a colorless crystals in 81%
yield: mp 181-182 ℃ (lit.,10 182-183 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 3.909 (2H, t, J = 6.3 Hz),
13
4.472 (2H, t, J = 6.2 Hz), 6.984 (2H, s), 8.171 (1H, s); C NMR (DMSO-d6) δ: 159.793, 154.030,
149.402, 143.103, 123.206, 44.567, 30.883; MS (70eV) m/z (%): 277 (M+, 42)，275(32), 171(36),
169(100), 134(39), 133(7). The other spectral data for this compound were identical to those reported
previously.10
2-Amino-6-chloro-9-(ethyl 2-carboethoxybutanoate-4-yl)purine (8)
Intermediate compound 7 (2.105 g, 7.6 mmol) was completely dissolved in DMSO (14 mL). To the
solution, diethyl malonate (3.5 mL, 22.8 mmol) and potassium carbonate (3.151 g, 22.8 mmol) were
added, followed by stirring for 4 h at a temperature of 40-50 ℃. After completion of the reaction, the
product was cooled to rt, and water (30 mL) was added. The resulting solution was extracted three times
with portions of CH2Cl2 (60 mL). The organic layer was collected, and dried with anhydrous Na2SO4,
followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure and
crystallized from butanol, thereby giving compound 8 as light yellow-colored solid in 84% yield: mp
121-123 ℃ (lit.,11 123-124 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 1.148 (6H, t, J = 7.2 Hz), 2.325 (2H,
q, J = 6.9 Hz), 3.481 (1H, t, J = 7.0 Hz), 3.996- 4.100 (4H, m), 4.135 (2H, t, J = 3.4 Hz), 6.911 (2H, s),
8.075 (1H, s). The other spectral data for this compound were identical to those reported previously.11

HETEROCYCLES, Vol. 75, No. 11, 2008
2807
2-Amino-9-(ethyl 2-carboethoxybutanoate-4-yl)purine (9)
A mixture of compound 8 (2.342 g, 6.6 mmol), triethylamine (TEA, 9.5 mL, 66 mmol), and palladium
charcoal (10% Pd/C, 0.150g) in MeOH (300 mL) was stirred under hydrogen for 7 h at 55 ℃. The
mixture was filtered through Celite after cooling down, evaporated in vacuo. The filtrate was dissolved by
addition of CH2Cl2 and water. The separated aqueous layer was extracted with CH2Cl2 (120 mL). The
combined organic solution was dried (Na2SO4), distilled to remove solvent and crystallized from butanol,
giving compound 9 as a light yellow powder with the yield of 87%: mp 99-101 ℃ (lit.,11 102-103 ℃);
1H NMR (400 MHz, DMSO-d6) δ: 1.245 (6H, t, J = 7.2 Hz), 2.450 (2H, q, J = 6.9 Hz), 3.332 (1H, t, J =
7.3 Hz), 4.129- 4.223 (6H, m), 6.500 (2H, s), 8.020 (1H, s), 8.553(1H, s). The other spectral data for this
compound were identical to those reported previously.11
2-Amino-9-[4-acetoxy-3-(acetoxymethyl)butyl-1-yl]purine (3, famciclovir)
Compound 9 (1.650 g, 5.1 mmol) was dissolved in CH2Cl2 (30 mL), and NaBH4 (1.158 g, 30.6 mmol)
and MeOH (1.5 mL) were added. The reaction mixture was stirred at rt for 2.5 h, then diluted with water
(20 mL) and settled. The separated organic layer was removed. The aqueous (along with the precipitated
solid) was cooled down with an ice/water bath, and HCl acid (25-30%) was added slowly till the solution
became neutral. The precipitate was collected by filtration, and then washed with cold brine and water.
The collected diol was dried under vacuum and directly used in the next step without purification.
The intermediate diol, TEA (1.5 mL, 10.5 mmol) and catalytic 4-N,N-dimethylaminopyridine (DMAP,
0.106 g, 0.87 mmol) were dissolved in CH2Cl2 (30 mL). The acetic anhydride (2.0 mL, 21.0 mmol) was
then added dropwise, keeping the solution at rt. The mixture was stirred for 12 h at the same temperature.
Water (45 mL) was added to dilute the reaction mixture, and 5% NaOH aq was added till the solution
turned neutral. The organic layer was washed with water, saturated brine and dried. The CH2Cl2 was
removed under reduced pressure, and the residue was dissolved with boiling MeOH (15 mL). Famciclovir
3 was crystallized out by keeping the methanol solution at 0-4 ℃ for 4 h as white powder: 72%, mp
136-137 ℃ (lit.,12 137-139 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 1.798- 2.012 (9H, m), 4.035 (4H, d,
J = 5.4 Hz), 4.151 (2H, t, J = 6.9 Hz), 6.542 (2H, s), 8.126 (1H, s), 8.588 (1H, s). The other spectral data
for this compound were identical to those reported previously.12
REFERENCES AND NOTES
1.
H. J. Schaeffer, L. Beauchamp, P. De Miranda, G. B. Elion, D. J. Bauer, and P. Collins, Nature,
1978, 272, 583.
2.
P. M. Keller, J. A. Fyfe, L. Beauchamp, C. M. Lubbers, P. A. Furman, H. J. Schaeffer, and G. B.
Elion, Biochem. Pharmacol, 1981, 30, 3071.

2808
HETEROCYCLES, Vol. 75, No. 11, 2008
3.
T. Torii, H. Shiragami, K. Yamashita, Y. Suzuki, T. Hijiya, T. Kashiwagi, and K. Izawa,
Tetrahedron, 2006, 62, 5709.
4.
5.
6.
M. R. Harnden, R. L. Jarvest, T. H. Bacon, and M. R. Boyd, J. Med. Chem., 1987, 30, 1636.
M. J. Barnes, N. Cooper, and R. J. Davenport, Bioorg. Med. Chem. Lett., 2001, 11, 1081.
F. Richard, R. G. Graham, W. R. Thomas, C. S. Andrew, R. S. Graham, and M. S. Neil,
Tetrahedron, 2000, 56, 4589.
7.
8.
9.
(a) H. Chen and S. Li, J. Phys. Chem. A, 2006, 110, 12360. (b) M. J. Robins and M. J. Zhong, J.
Org. Chem., 2006, 71, 8901. (c) W. Chen, M. T. Flavin, R. Filler, and Z. Xu, Nucleosides
Nucleotides, 1996, 15, 1771.
(a) Y. Kitade, T. Ando, T. Yamaguchi, A. Hori, M. Nakanishi, and Y. Ueno, Bioorg. Med. Chem.,
2006, 14, 5578. (b) M. Yang, W. Ye, and S. W. Schneller, J. Org. Chem., 2004, 69, 3993. (c) W. B.
Lu, S. Sengupta, L. P. Jeffrey, G. A. Novruz, and X. D. Shi, J. Org. Chem., 2007, 72, 5012.
W. H. Chen and L. Zhao, Jiangsu Chemical Industry, 2005, 33, 33.
10. C. Paola and T. Maurizio, Tetrahedron, 1998, 54, 11305.
11. B. M. Choudary, G. R. Geen, P. M. Kincey, M. J. Parratt, and J. R. M. Dales, Nucleosides
Nucleotides, 1996, 15, 981.
12. B. Brand, C. B. Reese, Q. L. Song, and C. Visintin, Tetrahedron, 1999, 55, 5239.