1004
R. Paramashi6appa et al. / Tetrahedron Letters 44 (2003) 1003–1005
In summary, we report an inexpensive, two step
method, which can be conveniently applied to the large-
scale synthesis of d4T.
atures leads to decomposition of d4T to give thymine as
an undesired product thereby decreasing the overall
yield and purity of the product. To overcome these
drawbacks, Starret et al.,8c made an attempt to improve
the process for the synthesis of d4T. In this method,
3%,5%-anhydrothymidine was subjected to an elimination
reaction using a strong base (t-BuO−K+) in polar sol-
vents like DMSO/DMF similar to Horwitz et al.10
After completion of the reaction, the potassium salt of
d4T was precipitated by adding solvents such as tolu-
ene, ethyl acetate, and acetone. The resultant salt was
redissolved in the minimum quantity of water, neu-
tralised with an acid and the precipitated d4T was
recrystallised from acetone. Although this method is
considered an improved method, it retains a few draw-
backs. Isolation of the potassium salt is very tedious, as
it is highly hygroscopic and usually it should be used
immediately in the next step. The neutralisation of the
potassium salt is an exothermic process, which leads to
decomposition of the d4T to thymine as an undesired
side product.
Typical procedure:
Preparation of 3%,5%-anhydrothymidine 2:
To a stirred solution of b-thymidine 1 (200 g, 0.82 mol)
in acetone, triethylamine was added. To this solution
distilled methanesulfonyl chloride (198.2 g, 1.73 mol)
was added in portions, while maintaining the tempera-
ture of reaction between 30 and 35°C. After the addi-
tion was complete the reaction was slowly brought to
40–45°C and stirred for about 5 h. The solvent was
concentrated and the residue was cooled to room tem-
perature. 20% Sodium hydroxide was added until a pH
of 10 was attained and the solution was heated to
45–50°C for 2 h. After completion of the reaction, it
was cooled to 5°C and neutralised with acetic acid. The
precipitated solid was filtered and washed with water to
give 108 g (58%) of 3%,5%-anhydrothymidine. mp 189–
192°C; lit8c 188–190°C.
1H NMR (200 MHz, DMSO-d6): 11.34 (s, 1H, NH), 8.0
(s, 1H, H-6), 6.53 (t, 1H, J=5.4 Hz, H-1%), 5.48 (m, 1H,
H-3%), 4.89 and 4.68 (m, 2H, H-5%), 4.02 (d, 1H, J=8.0
Hz, H-4%), 2.47 (m, 2H, H-21), 1.77 (s, 3H, CH3).
Here, we report a two-step method (Scheme 1) involv-
ing inexpensive reagents and non-hazardous solvents,
which can be conveniently applied for industrial scale
synthesis. In the first step, thymidine was converted to
the intermediate dimesylated thymidine by reacting
with 2 equiv. of methane sulfonyl chloride in acetone,
in the presence of triethylamine. After concentrating the
solvent, the reaction mass was treated with aqueous
sodium hydroxide to obtain the reactive intermediate
3%,5%-anhydrothymidine (an oxetane). In the second
step, the oxetane was subjected to an elimination reac-
tion by treatment with potassium hydroxide in t-
butanol. After completion of the reaction, methanol
was added, the mixture was neutralised with HCl gas in
isopropyl alcohol, and the precipitated potassium chlo-
ride was filtered. Upon concentration of the solvent, the
product was recrystallised from acetone to yield
stavudine. In the first step, thymidine was directly
converted to the oxetane using acetone instead of haz-
ardous pyridine as reported for earlier processes.8c,9,10
During the second step, the reaction time was reduced
from 18–20 h to 2–3 h. This step involves the use of the
relatively mild base KOH and t-BuOH as solvent com-
pared to earlier processes,8c,9,10 which use t-BuO−K+ as
base and DMSO or DMF as solvent.
Preparation of 2%,3%-didehydro-3%-deoxythymidine 3:
To a stirred solution of 3%,5%-anhydrothymidine 2 (100
g, 0.44 mol) in t-BuOH (600 mL), potassium hydroxide
(80 g, 1.42 mol) was added in portions over a period of
20–30 min. The solution was heated to 55–60°C and
maintained at this temperature for 2 h. After comple-
tion of the reaction, it was cooled to room temperature
and methanol (400 mL) was added slowly to give a
clear solution. This was then neutralised with hydro-
chloric acid (HCl gas in IPA). Precipitated potassium
chloride was filtered and the clear filtrate was concen-
trated under vacuum to give crude d4T, which was
recrystallised from acetone to yield a colourless solid
(85 g, 85%). mp 165–166°C; lit10 165–166°C, [h]D25 −44
(c 0.7, water); lit10 [h]2D5 −42 (c 0.69, water).
IR (KBr): 3463, 3159, 3033, 1691, 1496, 1116, 1093
cm−1.
1H NMR (200 MHz, DMSO-d6): 11.28 (s, 1H, NH),
7.64 (s, 1H, H-6), 6.82 (d, 1H, J=1.4 Hz, H-1%), 6.40 (d,
1H, J=1.5 Hz, H-3%), 5.92 (dd, 1H, J=1.1, 3.8 Hz,
H-2%), 5.03 (m, 1H, OH), 4.76 (s, 1H, H-4%), 3.62 (m,
2H, H-5%), 1.72 (s, 3H, CH3).
In the above process, the first step involves preparation
of 3%,5%-anhydrothymidine intermediate 2 starting from
thymidine 1. This was obtained by the reaction of
thymidine with 2 equiv. of methanesulfonyl chloride,
followed by reaction with aqueous sodium hydroxide.
During the conversion of dimesylthymidine to 3%,5%-
anhydrothymidine, the primary mesylate undergoes
hydrolysis by the action of the base, and subsequently
displaces the secondary mesylate through intramolecu-
lar nucleophilic substitution. The second step involves
abstraction of the proton (C1-2) from the oxetane in the
presence of potassium hydroxide, followed by ring
opening to obtain d4T via an E2 mechanism.
Acknowledgements
We thank Dr. M. Srinivas and Mr. M. N. Manoj for
technical assistance. P.P.K. thanks the Council of Sci-
entific and Industrial Research (India) for a research
fellowship.
Paramashivappa
