Organic Process Research & Development
-Amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
Communication
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4
(2) (a) Sorm, F.; Vesely, J. Neoplasma 1968, 15, 339−343.
b) Momparler, R. L.; Momparler, L. F.; Samson, J. Leuk. Res. 1984,
(
8
(
1, Crude). A mixture of 5-azacytosine (4, 4.0 kg, 38.74 mol),
, 1043−1049. (c) Leone, G.; Voso, M. T.; Teofili, L.; Lubbert, M.
Clin. Immunol. 2003, 109, 89−102. (d) Beisler, J. A. J . Med. Chem.
978, 21, 204−208.
hexamethyldisilazane (HMDS) (8.64 kg, 53.57 mol), ammo-
nium sulfate (200 g, 1.51 mol), and acetonitrile (12.0 L) were
charged into GLR through isolator, and the resultant mixture
was heated to reflux for 4−8 h. After observing the clear
solution, the reaction mixture was concentrated to obtain the
residue. Ethyl acetate (8 L) was co-distilled in two lots to
remove HMDS completely to obtain the 5, then dissolved in
ethyl acetate (40 L), and cooled to 0−10 °C. To the above
mixture was added 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose, and
then triflic acid (6.42 kg, 42.82 mol) was added, and the
resulting mixture was heated to 40−50 °C and stirred for 30
min. Then the reaction mixture was concentrated to obtain
residue, the residue was dissolved in dichloromethane (40 L).
Then 0.24 N hydrochloric acid (40 L) was added, and after 45
min stirring, 10% sodium carbonate solution (60 L) was added
in 30 min. The organic layer was separated and transferred to
SSR and then concentrated. Methanol (8 L) was co-distilled in
two lots to obtain a foamy residue, 8. The foamy residue was
dissolved in methanol (140 L), and then n-butylamine (1.6 L,
1
(
3) (a) Cihak, A. Oncology 1974, 30 (5), 405−422. (b) Kaminskas,
E.; Farrell, A. T.; Wang, Y. C.; Sridhara, R.; Pazdur., R. FDA Drug
Approval Summary: 5-Azacytidine. Oncologist 2005, 10 (3), 176−182.
4) (a) Gregoire, V.; Hittelman, W. N.; Rosier, J. F.; Milas, L. Oncol.
(
Rep. 1999, 6, 949−1006. (b) Sacchi, S.; Kantarjian, H. M.; O’Brien, S.;
Cortes, J.; Rios, M. B.; Giles, F. J.; Beran, M.; Koller, C. A.; Keating, M.
J.; Talpaz, M. Cancer 1999, 86, 2632−2641. (c) Poplin, E.; Roberts, J.;
Tombs, M.; Grant, S.; Rubin, E. Invest. New Drugs 1999, 17, 57−61.
̌
5) (a) Piskala, A.; Sorm, F. Collect. Czech. Chem. Commun. 1964, 29,
(
̌
2
060−2076. (b) Piskala, A.; Sorm, F. U.S. Pat. 3,350,388, 1967.
(
6) (a) Winkley, M. W.; Robins, R. K. J. Org. Chem. 1970, 35, 491−
̌
95. (b) Piskala, A.; Sorm, F. Nucleic Acid Chem. 1978, 1, 435−441.
4
(
1
3
̌
c) Piskala, A.; Fiedler, P.; Sorm, F. Nucleic Acids Res., Spec. Publ. 1975,
, 17−18. (d) Niedballa, U.; Vorbru
̈
ggen, H. J. Org. Chem. 1974, 39,
672−3674. (e) Vorbruggen, H.; Ruh-Polenz, C. Org. React. 2000, 55,
̈
̈
1−630. (f) Vorbruggen, H.; Bennua, B. Chem. Ber. 1981, 114, 1279−
1286. (g) Argemi, A.; Saurina, J. Talanta 2007, 74, 176−182.
(h) Ionescu, D.; Blumbergs, P. U.S. Pat. 7,038,038, 2006.
(
7) (a) Praveen, C.; Satishkumar, V.; Ganesh, V.; Srinadhacharyulu,
K.; Srinivas, A.; Satyanarayanaraju, T. U.S. Pat. Appl. 2011/0201800,
011. (b) Praveen, C.; Satishkumar, V.; Ganesh, V.; Srinadhacharyulu,
K.; Srinivas, A.; Satyanarayanaraju, T. EP 2011/2321302 A2, 2011.
8) Baker, B. R.; Schaub, R. E.; Kissman, H. M. J. Am. Chem. Soc.
955, 77, 5911−5915.
9) Lin, K. T.; Momparler, R. L.; Rivard, G. E. J. Pharm. Sci. 1981, 70,
228−1232.
(10) (a) Quirke, J. M. E. In Comprehensive Heterocyclic Chemistry;
16.2 mol) was added. The resultant mixture was heated to
reflux and stirred for 60 min; the product was filtered at the
same temperature in ANFD and dried to afford the crude 5-
azacytidine with 49.3% yield (4.3 kg) having HPLC purity of
2
(
>
98%.
-Amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
1). To a stirred solution of 1.5 kg of crude 1 and DMSO (6 L),
1
4
(
(
1
was added 22.5 L of toluene. The resulting mixture was stirred
for 5 h, and then product was filtered and dried to obtain the 5-
Boulton, A. J., McKillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol.
3, pp 457−530 and references therein. (b) Bartholomew, D. In
Comprehensive Heterocyclic Chemistry II; Boulton, A. J., Ed.; Pergamon
Press: Oxford, 1996; Vol. 6, pp 575−636 and references therein.
azacytidine. Yield 1.13 kg (75.3%) with 99.89% HPLC purity.
1
M + 1 = 245.08, H NMR (400 MHz, DMSO-d ): δ 8.58 (s,
6
1
4
4
1
H), 7.52 (bs, 2H, NH ), 5.67 (d, J = 3.6 Hz, 1H), 5.42 (d, J =
2
(
c) Piskala, A. Collect. Czech. Chem. Commun. 1967, 32, 3966−3976.
d) Niedballa, U.; Vorbruggen, H. J. Org. Chem. 1974, 39, 3672−3674.
.8 Hz, 1H), 5.11 (t, J = 4.8 Hz, 1H), 5.02 (d, J = 6.0 Hz, 1H),
.08 (q, J = 4.8 Hz, 1H), 4.01 (d, J = 5.2 Hz, 1H), 3.86 (m,
H), 3.68 (m, 1H), 3.57 (m, 1H). 1 C NMR (100 MHz,
(
̈
3
DMSO-d ): δ 165.9, 156.5, 153.5, 89.5, 84.4, 74.1, 69.1, 60.3;
6
−1
IR (KBr) cm 3404, 2975, 1702, 1497, 1367; Anal. Calcd for
C H N O : C 39.35, H 4.95, N 22.94. Found: C 39.43, H 4.87,
8
12
4
5
N 22.88.
AUTHOR INFORMATION
■
Corresponding Author
Notes
∥
Dr. Reddy’s Communication no. IPDO IPM-00214
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the management of Dr. Reddy’s Laboratories Ltd. for
supporting this work. Co-operation from the project colleagues
of API-Process Research Department, Integrated Product
Development Organization, Dr. Reddy’s Laboratories Ltd. is
highly appreciated.
REFERENCES
■
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1) (a) Cheng, X. Curr. Opin. Struct. Biol. 1995, 5, 4−10. (b) Ahmad,
I.; Rao, D. N. Crit. Rev. Biochem. Mol. Biol. 1996, 31, 361−380.
(
c) Momparler, R. L. Pharmacol. Ther. 1985, 30, 287−299. (d) Jones,
P. A. Cell 1985, 40, 485−486. (e) Momparler, R. L.; Coote, S.;
Eliopoulos, N. Leukemia 1997, 11, 1−6.
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dx.doi.org/10.1021/op300192e | Org. Process Res. Dev. 2013, 17, 303−306