FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
Process for the preparation of Zidovudine
APPLICANT:
HERBERT BROWN PHARMACEUTICAL & RESEARCH LABORATORIES
W-256/257/258A, M.I.D.C. Phase II, Shivaji Udyog Nagar, Dombivli (E)-421203, District- Thane, Maharashtra, India.
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved, commercially viable and simple process for preparation of Zidovudine of Formula I and its intermediates. The present invention in particular, relates to an improved process for preparation of highly pure Zidovudine of Formula I from 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV.

wherein, Piv represents Pivaloyl group
The present invention further relates to an improved process for preparation of 5'-0-
pivaloyl-2,3'-anhydrothymidine of Formula IV from p-thymidine.
BACKGROUND OF THE INVENTION
Zidovudine (tradename: Retrovir), chemically known as 3'-azido-3'-deoxythymidine is a nucleoside analog reverse-transcriptase inhibitor, widely used as antiretroviral drug for treatment of human immunodeficiency virus (referred to as HIV) or acquired immunodeficiency syndrome (referred to as AIDS) infection. Zidovudine is known to have decreased mortality and opportunistic infections in patients with AIDS infection. Various processes for preparation of Zidovudine are described below
US4937329 discloses a process for preparation of 2,3'-anhydrothymidine, an intermediate in preparation of Zidovudine. The process for preparation of 2,3'-anhydrothymidine comprises of heating p-thymidine in presence of diphenylsulphite and N-methylimidazole in dimethylacetamide at 156°C for 45 mins. The 2,3'-

anhydrothymidine thus obtained, on reaction with lithium azide can be converted into Zidovudine. The disadvantages of the process includes as low as 65% yield of the step wherein β-thymidine is converted to 2.3 '-anhydrothymidine and requirement of column chromatography for purification of Zidovudine.
WO9001492 discloses a process for preparation of Zidovudine by using D-mannitol as starting material. According to the process, the D-mannitol is converted into 2,3-isopropylidene-D-glyceraldehyde and Wittig reaction of latter with carbethoxymethylene triphenyl phosphorane gave (8:1) mixture of α,β- unsaturated esters. The Z-isomer of unsaturated ester is separated by column chromatography. Michael reaction of isomer of α,β- unsaturated ester with lithium azide in glacial acid and water at room temperature gave mixture of (R) and (S)-azido esters. The mixture was separated by chromatography. The azido esters were cyclized in presence of hydrochloric acid to corresponding 4-(R) or (S)-azidolactones. The 5-hydroxy group of azidolactone thus formed, was protected with bulky reagent like t-butylchlorodimethylsilane, t-butylchlorodiphenylsilane or triphenyl methanol in DMF in presence of imidazole to obtain 5-hydroxy protected azidolactone. The carbonyl group of 5-hydroxy protected azidolactone was then reduced using reagents like lithium borohydride or DIBAL followed by protection of 1-hydroxy group to produce a key intermediate l-O-(acetyl)-3-(azido)-2,3-dideoxy-5-0-protected- α,β-D-erythro pentofuranoside. The key intermediate obtained was condensed with silylated thymine in presence of tin (TV) chloride followed by desilylation using n-tetrabutylammonium fluoride in THF to get 31% of Zidovudine. This process involves 10 steps with relatively low yield and poor selectivity in several steps. As a result column chromatography is required to purify several intermediates along the way, thereby making process difficult on industrial scale. The reaction scheme is as in Scheme I.


US5101023 discloses a process for preparation of Zidovudine by reaction of β-thymidine with triphenylphosphine, diethyl azodicarboxylate (DEAD) and benzoic acid in dimethylformide to form an intermediate of Formula A, which on reaction with lithium azide and followed by treatment with sodium methoxide resulted in Zidovudine. This process uses triphenylphosphine which is difficult to remove after completion of reaction thereby affecting purity of final product. Furthermore use of
expensive reagents like diethyl azodicarboxylate makes the process uneconomical on
■I
industrial scale. The reaction scheme can be shown as in Scheme II
Scheme II


Similarly, US5124442 also uses triphenyl phosphine and diethyl azodicarboxylate for preparation of Zidovudine.
Indian Patent No. 234991 discloses a process for preparation of Zidovudine in a single-pot, the reaction comprises of conversion of β-thymidine to 5'-0-trityl-3'-0-mesylthymidine in two steps, the latter on cyclization in presence of sodium hydroxide in dimethylformamide affords 5'-0-trilyl-2,3'-anhydrothymidine, which on azidation using sodium azide in dimethylformamide and on detritylation gives 99% pure Zidovudine. However, the process involves use of multiple solvents like methanol, n-hexane and ethylacetate in order to isolate 99% pure Zidovudine which makes the process uneconomical on industrial scale.
WO93007162 discloses a process for preparation of Zidovudine from p-thymidine. The process comprises of protecting 5'-position of p-thymidine with pivaloyl group and 3'-position with a mesyl group, subjecting the thus formed protected thymidine to base catalyzed intramolecular cyclisation to obtain 5'-0-pivaloyl-2,3'-anhydrothymidine, which on azidation using sodium azide and lithium halide in presence of ammonium chloride in weakly alkaline solvent like dimethylformamide and on deprotection of 5'-position using a base, Zidovudine of Formula I. Various solvents like ethylacetate and dioxane are used for isolation. Furthermore, the isolation procedure involve multiple steps like neutralization using strong cation exchange resin (Dowex), distillation to obtain residue, 5-6 times adding large amount of water, charcoalization, evaporating charcoalized solution to obtain concentrated solution, maintaining concentrated solution at 4°C for 1 day to obtain crystals of Zidovudine.
The disadvantages of the process which makes it less feasible on industrial scale can be listed as follows
a) use of water soluble solvent like dioxane whose recovery is difficult

b) use of cation exchange resin and requirement of regeneration of resin
c) use of large amount of water and
d) large amount of energy requirement for evaporating the water to obtain concentrated solution
The process is depicted in Scheme III

US5220003 discloses a process for preparation of Zidovudine by using crotonaldehyde as starting material. Crotonaldehyde was converted into a mixture of the E and Z isomers of l-(trimethylsilyloxy)-l,3-butadiene. The later is condensed with methyl orthoformate using zinc chloride as catalyst to obtain an enal acetal which on reduction gave an allylic alcohol. The allylic alcohol was subjected to epoxidation by treatment with (-)-diisopropyl tartrate, tert-butyl hydroperoxide and titanium tetraisoproxide at -20°C for 2 days to afford epoxy alcohol after workup and chromatography. The epoxy alcohol was subjected to regioselective opening by treating with azidotrimethylsilane in presence of diethylaluminium fluoride to obtain

desired azido diol which was then cyclised to obtain mixture of a and β-anomers of
methyl furanoside. The methyl furanoside obtained was silylated with tert-
butylchlorodiphenylsilane-imidazole in DMF and then converted into Zidovudine by
coupling with trimethylsilyl thymine followed by deprotection. This process is
lengthy, time consuming, uses expensive reagents like titanium tetra-isoproxide and
hence is unviable on commercial scale. The reaction scheme is given below in
Scheme IV

US5466787 describes a process for preparation of Zidovudine from 5-methyluridine. The 5-methyluridine was tri-O-mesylated using methanesulphonyl chloride in pyridine, the tri-O-mesylated product was heated to 115°C with sodium benzoate to give anhydrouridine which on treatment with acetyl bromide in methanol gave a key intermediate, 5'-0-benzoyl-3'-0-methanesulfonyl-2'-bromothymidine. The 5'-0-benzoyl-3'-0-methanesulfonyl-2,-bromothymidine was subjected to debromination using tributyltin hydride and catalytic amount of azobisisobutyronitrile (AIBN) in solvent like ether/ester or ketone to afford 5'-0-benzoyl-3'-

methanesulfonylthymidine. The denominated product was converted in to Zidovudine by reacting with sodium azide in presence of lithium carbonate followed by deprotection using sodium methoxide in methanol. After neutralizing the reaction mixture with acidic resin, the Zidovudine was isolated in 71% yield from 5'-0-benzoyl-3'-methanesulfonylthymidine. The process disclosed in this patent involves several steps, uses expensive reagents like tributyltin hydride and azobisisobutyronitrile (A1BN) and hence, is not suitable for commercial scale. The reaction scheme is shown below in Scheme V

Furthermore, apart from above discussed references some of the other references related to process for the preparation of Zidovudine are Tetrahedron Letters 29(42), 5349-5352, (1988), Chemical Communications (15), 997-998, (1989), Synthesis (6), 451-454, (1991), Journal of Chemical Research, Synopses (8), 326-327, (1993), Journal of Chemical Research (8), 326-327, (1993), Nucleosides & Nucleotides 15(4), 899-906, (1996), Tetrahedron 57(35), 7513-7517, (2001), Synthesis (9), 1337-1340, (2001), US4937329, US4921950, US4916218, US5384396,

US5414078, US5384396, US5220003, US5633366, EP280128 and EP292101 The processes mentioned in prior art suffers from one or more drawbacks, as aforementioned. Hence, there is a need to develop an improved, simple, environment friendly and industrially feasible process for the preparation of Zidovudine. The inventors of present invention have rationally designed an improved process for preparation of Zidovudine with superior quality.
OBJECT OF THE INVENTION
1) The object of the present invention is to provide an improved process for preparation of Zidovudine in high yield and purity
2) Another object of the present invention is to provide Zidovudine having HPLC purity of more than 99.5%.
3) Another object of the present invention is to provide an improved process for preparation of 5'-0-pivaloyl-2,3'-anhydrotriymidine, an key intermediate in preparation of Zidovudine
4) Yet another object of the present invention is to provide a process for preparation of Zidovudine wherein the solvent used in the process can be recovered and reused.
5) Yet another object of the present invention is to provide simple, safe, environment friendly and industrially feasible process for preparation of Zidovudine

SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an improved process for preparation of Zidovudine of Formula I having HPLC purity of more than 99.5%, from 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV

wherein, Piv represents Pivaloyl group, comprising,

c) reacting the 5'-O-pivaloylo'-azido-O'-deoxythymidine of Formula V with
a) reacting 5;-0-pivaloyl-2,3'-anhydrothymidine of Formula IV with sodium azide in presence of ammonium chloride in an aprotic solvent at temperature ranging from 90-120°C
b) cooling the reaction mixture of step a) to 20-30°C and adding the reaction mixture to water to precipitate 5'-0-pivaloyl-3'-azido-3'-deoxythymidine of Formula V

aqueous alkali metal hydroxide solution in methanol at temperature ranging from 25-40°C
d) adjusting pH of the reaction mixture of step c) to 6 to 7.5 followed by charcoalization to obtain a charcoalized solution
e) evaporating the charcoalized solution to dryness to obtain crude Zidovudine of Formula I
f) crystallizing the crude Zidovudine of Formula I from water to obtain crystals of pure Zidovudine of Formula I having HPLC purity of more than 99.5%
According to another aspect of present invention there is provided an improved process for preparation of 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV, used as starting material in preparation of Zidovudine of Formula I

wherein, Piv represents Pivaloyl group, comprising,
i) reacting p-thymidine with pivaloyl chloride in pyridine at temperature ranging from 0-10°C to afford 5'-0-pivaloylthymidine of Formula II

Formula II
ii) insitu reacting 5'-0-pivaloylthymidine of Formula II with mesyl chloride
at temperature ranging from 25-30°C iii) distilling off pyridine to obtain a residue, adding water to the residue and
heating the mixture to 60-75°C iv) cooling the mixture of step iii) to 25-30°C and isolating the crude 5'-0-
pivaloyl-3'-0-mesylthymidine of Formula III by filtration

wherein Ms represents mesyl group
v) recrystallizing the crude 5'-O-pivaloyl-3'-O-mesylthymidine of Formula
III using toluene as solvent to obtain 5'-O-pivaloyl-3'-O-mesylthymidine
of Formula III having HPLC purity of more than 97% vi) reacting 5'-0-pivaloyl-3'-0-mesylthymidine of Formula III with an alkali
metal hydroxide in a C3 to C8 aliphatic alcohol at temperature ranging
from 35-55°C vii) isolating crude 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV from
reaction mixture of step vi) viii) purifying the crude 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV
by treatment with dichloromethane followed by toluene to obtain 5'-0-
pivaloyl-2,3'-anhydrothymidine of Formula IV having HPLC purity of
more than 99%.

According to another aspect of present invention, the Zidovudine of Formula I prepared by the process of present invention has HPLC purity of more than 99.5% and single maximum unknown impurity of less than 0.1%.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, commercially viable and simple process for preparation of Zidovudine of Formula I and its intermediates. The process of the present invention eliminates the risk of handling hazardous chemicals, thus making the process more environment friendly and industrially viable.
According to an aspect of the present invention, there is provided an improved process for preparation of Zidovudine of Formula I having HPLC purity of more than 99.5%, from 5'-0-pivaloyI-2,3'-anhydrothymidine of Formula IV

wherein, Piv represents Pivaloyl group, comprising,
a) reacting 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV with sodium azide in presence of ammonium chloride in an aprotic solvent at temperature ranging from 90- 120°C
b) cooling the reaction mixture of step a) to 20-30°C and adding the reaction


mixture to water to precipitate 5'O-pivaloyl-3'-azido-3'-leoxythymidme of Formula V
c) reacting the 5'-0-pivaloyl-3'-azido-3'-deoxythymidine of Formula V with aqueous alkali metal hydroxide solution in methanol at temperature ranging from 25-40°C
d) adjusting pH of the reaction mixture of step c) to 6 to 7.5 followed by charcoalization to obtain a charcoalized solution
e) evaporating the charcoalized solution to dryness to obtain crude Zidovudine of Formula I
f) crystallizing the crude Zidovudine of Formula I from water to obtain crystals of pure Zidovudine of Formula I having HPLC purity of more than 99.5%
In an embodiment of the present invention, the molar ratio of the sodium azide used in step a) with respect to 5'-0-pivaloyl-2.3'-anhydrothymidine of Formula IV is in range of 2 to 4.
The aprotic solvent used in step a) is selected from N, N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, preferably N, N-dimethylformamide is used.
The amount of aprotic solvent used in step a) with respect to 5'-0-pivaloyl-2,3'-anhydrothymidine is in range of 2 to 6 volumes.

The molar ratio of the ammonium chloride used in step a) with respect to 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV is in range of 1 to 3.
According to an embodiment of the present invention, the amount of water used in step b) with respect to 5'-0-pivaloyl-2,3!-anhydrothymidine of Formula II is in range of 10 to 20 volumes.
According to another embodiment of the present invention, the aqueous alkali metal hydroxide used in step c) is selected from sodium hydroxide or potassium hydroxide.
The concentration of aqueous alkali metal hydroxide used is in the range of 2 to 8M.
The molar ratio of alkali metal hydroxide used with respect to 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV is in range of 1.5 to 2.5.
According to an embodiment of the present invention, in step d) the pH of reaction mixture is adjusted to 6 to 7.5 using an acid like acetic acid, formic acid, sulfuric acid and hydrochloric acid, preferably hydrochloric acid is used.
According to another aspect of the present invention, there is provided an improved process for preparation of 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV, used as starting material in preparation of Zidovudine of Formula I


wherein, Piv represents Pivaloyl group, comprising,
i) reacting α,β-thymidine with pivaloyl chloride in pyridine at temperature ranging from 0-10°C to afford 5'-0-pivaloylthymidine of Formula II

ii) insitu reacting 5'-0-pivaloylthymidine of Formula II with mesyl chloride
at temperature ranging from 25-30°C iii) distilling off pyridine to obtain a residue, adding water to the residue and
heating the mixture to 60-75°C iv) cooling the mixture of step iii) to 25-30°C and isolating the crude 5'-0-
pivaloyl-3'-0-mesylthymidine of Formula III by filtration

wherein Ms represents mesyl group
v) recrystallizing the crude 5'-0-pivaloyl-3'-0-mesylthymidine of Formula
III using toluene as solvent to obtain 5'-0-pivaloyl-3'-0-mesylthymidine
of Formula III having HPLC purity of more than 97%

vi) reacting 5'-0-pivaloyl-3'-0-mesylthymidine of Formula III with an alkali metal hydroxide in a C3 to C% aliphatic alcohol at temperature ranging from 35-55°C
vii) isolating crude 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV from reaction mixture of step vi)
viii) purifying the crude 5'-0-pivaloyl-2,3'-arihydrothymidine of Formula IV by treatment with dichloromethane followed by toluene to obtain 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV having HPLC purity of more than 99%
According to an embodiment of the present invention, the molar ratio of pivaloyl chloride used in step i) with respect to p-thymidine is in range of 1 to 1.5.
The amount of pyridine used in step i) with respect to respect to p-thymidine is in range of 4 to 7 volumes.
The 5'-hydroxy group of p-thymidine was protected with pivaloyl group by reacting p-thymidine with pivolyl chloride in pyridine at temperature ranging from 0-10°C for 2 to 4 hours.
According to another embodiment of the present invention, the molar ratio of mesyl chloride used in step ii) with respect to p-thymidine is in range of 1 to 1.5.
According to another embodiment of the present invention, in step iii) pyridine is quantitively recovered and reused.
The amount of water added to the residue in step iii) with respect to p-thymidine is in range of 3 to 8 volumes.

In step iii) the mixture is heated to 65-70°C for 0.5 to 2 hours.
According to yet another embodiment of the present invention, the alkali metal hydroxide used in step vi) is selected from sodium hydroxide or potassium hydroxide, preferably potassium hydroxide is used.
The molar ratio of alkali metal hydroxide used in step vi) with respect to 5'-0-pivaloyl-3'-0-mesylthymidine of Formula III is in range of 1 to 1.5.
The C3 to Cg aliphatic alcohol used in step vi) is selected from n-propanol, iso-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol and the like, preferably n-butanol is used.
The amount of C3 to Cg aliphatic alcohol used in step vi) used with respect to 5'-0-pivaloyl-3'-0-mesylthymidine is in range of 10 to 20 volumes.
The C3 to Cg aliphatic alcohol used in step vi) is recovered and reused.
According to an embodiment of the present invention, in step vii) the crude 5'-0-pivaloyl-2,3:-anhydrothymidine of Formula IV is isolated by cooling the reaction mixture of step vi) to 0-10°C followed by filtration and drying.
According to another embodiment of the present invention, in step vii) the crude 5'-O-pivaloyl-2,3-anhydrothymidine of Formula IV is isolated by evaporating the reaction mixture of step vi) to dryness.
According to an embodiment of the present invention, in step viii) treatment of the

crude 5'-0-pivaloyl-2,3'-arihydrothymidine of Formula IV with dichloromethane followed by toluene, ensures removal of inorganic and organic impurities.
The present process for the preparation of Zidovudine of Formula I can be depicted as in scheme VI

According to another aspect of present invention, the Zidovudine of Formula I prepared by the process of present invention has HPLC purity of more than 99.5%, and single maximum unknown impurity of less than 0.1%
The Zidovudine of Formula I obtained by the present invention is free from organic impurities.
It was observed by inventors of present invention, that in the present process for the

preparation of Zidovudine, the formation of impurities like 1 -[(2R,5S)-5-
(hydroxymethyl)-2,5-dihydroruran-2-yl)-5-methylpyrimidine-2,4(lH,3H)-dione
(Impurity A), l-(3-chloro-2,3-dideoxy-p-D-erythro-pentofuranosyl)-5-
methylpyrimidine-2,4(lH,3H)-dione (Impurity B) and thymine (Impurity C) are controlled to the great extent.
The Zidovudine obtained from the process of present invention, complies with the quality standard established by the British, European, International and U.S. Pharmacopoeia.
The HPLC purity of Zidovudine of Formula I is determined using following
parameters:
Column : Zorbax Eclipse XDB, C18,250 mm x 4.6 mm, 5 urn
Column temperature : 30°C
Flow rate : 1.2 ml/min
Detection wavelength : 265 nm
Diluent : Methanol/Water (20:80)
Injection volume : 10 ul
Run time : 35 min
Method : Isocratic
Furthermore, the HPLC purity of 5'-0-pivaloyl-2, 3'-anhydrothymidine of Formula
IV and its intermediates are determined using following parameters:
Column : Zorbax Eclipse XDB, C18, 250 mm x 4.6 mm, 5 urn
Column temperature : 35°C
Flow rate : 1.1 ml/min
Detection wavelength : 265 nm

Diluent " : Methanol/Water (90:10)
Mobile phase A : 0.1% aqueous solution of o-Phosphoric acid
Mobile phase B : Methanol
Injection volume : 10 μl
Runtime : 35min
Method : Gradient

Time (min) Mobile Phase A Mobile Phase B
0.0 90 10
2.0 90 10
20.0 10 90
26.0 10 90
30.0 90 10
35.0 90 10
The detail of the invention provided in the following examples is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 5'-0-pivaloyl-3'-0-mesylthymidine
To a stirred solution of 250g of p-thymidine in 1500ml of pyridine was slowly added 152.53ml of pivaloyl chloride at temperature of about 0-5°C. After protecting 5'-hydroxy group with pivaloyl group, 87.86ml of mesyl chloride was added. The temperature of the reaction mixture was then raised to 25-30°C and maintained for 2 to 3 hours with stirring. Pyridine was distilled out from the reaction mixture under vacuum to obtain a residue. To the residue obtained was added 1250ml of water and the mixture was heated to 65-70°C for 1 to 1.5 hour. Further, the mixture was cooled

to 25-30°C and the solid was filtered and dried to obtain 405g of crude 5'-0-pivaloyl-3'-0-mesylthymidine having HPLC purity of 88.66% and HPLC assay 90.4%. The crude 5'-0-pivaloyl-3'-0-mesylthymidine was recrystallized using toluene as solvent and dried to obtain 363g (Yield: 87%) of 5'-0-pivaloyl-3'-0-mesylthymidine having HPLC purity 98.01% Melting Point: 140-142°C
1HNMR in CDC13 (δ ppm): 8.97 (s, 1 H, 3-NH), 7.20 (s, IH, 6-H), 6.29-6.24 (dd, 1H, l'-H), 5.26-5.24 (m, IH, 3'-H), 4.48-4.46 (m, 1H, 4'-H), 4.39-4.30 (m, 1H, 5a,b-H), 3.12 (s, 3H, methanesulphonyl group), 2.69-2.67 (m, IH, 2' a-H), 2.26-2.24 (m, IH, 2' b-H), 1.93 (s, 3H, 5-CH3), 1.24 (s, 9H, pivaloyl group) Mass spectrum (DI): 404 (M+)
Example 2: Preparation of 5'-0-pivaloyl-2,3'-anhydrothymidine
To a suspension of 350g of 5'-0-pivaloyl-3'-0-mesylthymidine in 5250ml of n-butanol was added 45.13g of potassium hydroxide (Assay: 86.07%) at 25-30°C. The temperature of the reaction mixture was then raised to 48-52°C and maintained for 2 hours with stirring. Further, additional 11.28g of potassium hydroxide (Assay: 86.07%) was added in two equal portions within a period of 4 hours. After completion of reaction, the mixture was cooled to 0-5°C, filtered and dried to obtain crude 5'-O-pivaloyl-2,3'-anhydrothymidine. The crude 5'-O-pivaloyl-2,3'-anhydrothymidine was then extracted with 5250ml of dichloromethane. The dichloromethane was then removed by distillation and the residue obtained was treated with 420ml of toluene, cooled to 0-5°C and dried to obtain 242.80g (Yield: 91%) of 5'-O-pivaloyl-2,3-anhydrothymidine having HPLC purity 99.88%. Melting Point: 216-218°C
1HNMR in CDC13 (δ ppm): 6.99 (s, IH, 6-H), 5.56-5.55 (d, IH, l'-H), 5.20 (m, IH, 3'-H), 4.42-4.39 (m, IH, 4'-H), 4.26- 4.23 (m, 2H, 5' ab-H), 2.83-2.79 (m, IH, 2' a-H), 2.51-2.45 (m, IH, 2' b-H), 1.92 (s, 3H, 5-CH3), 1.19 (s, 9H, pivaloyl group)

Mass spectrum (DI): 308 (M+)
Example 3: Preparation of 5'-0-pivaloyl-2, S'-anhydrothymidine
To a suspension of 350g of 5'-0-pivaloyl-3'-0-mesylthymidine in 5250ml of n-butanol was added 45.13g of potassium hydroxide (Assay: 86.07%) at 25-30°C. The temperature of the reaction mixture was then raised to 48-52°C and maintained for 2 hours with stirring. Further, additional 11.28g of potassium hydroxide (Assay: 86.07%) was added in portions within a period of 4 hours. After completion of reaction, n-butanol was distilled out under vacuum from the reaction mixture to obtain a crude 5'-0-pivaloyl-2,3'-anhydrothymidine. The crude S'-O-pivaloyl-2,3-anhydrothymidine was then extracted with 5250ml of dichloromethane. The dichloromethane extract was washed with 700ml of water. The dichloromethane was then removed by distillation and the residue obtained was treated with 420ml of toluene, cooled to 0-5°C and dried to obtain 240.6g (Yield: 90.17%) of 5'-0-pivaloyl-2,3'-anhydrothymidine having HPLC purity 99.72%.
Example 4: Preparation of 5'-0-pivaloyl-2,3'-anhydrothymidine
The procedure is carried out as in example 2 starting with 110.22g of crude 5'-0-pivaloyl-3'-0-mesylthymidine having HPLC purity 87.26% and HPLC assay 90.72% to obtain 66g (Yield: 86.57%) of 5'-0-pivaloyl-2,3'-anhydrothymidine having HPLC purity 99.97%.
Example 5: Preparation of Zidovudine
To a suspension of 200g of 5'-0-pivaloyl-2,3'-anhydrothymidine in 800ml of dimethylformamide was added 126.5g of sodium azide and 62.45g of ammonium chloride. The mixture was heated to 100-115°C for 7-8 hours. After completion of reaction, the reaction mixture was cooled to 20°C. The reaction mixture was then added to water to precipitate 5:-0-pivaloyl-3'-azido-3'-deoxythymidine. The 5'-0-

pivaloyl-3'-azido-3'-deoxythymidine was filtered and washed with 400ml of water.
The wet cake of 5'-0-pivaloyl-3'-azido-3'-deoxythymidine was then dissolved in
1000ml of methanol and 220.5ml of 5M aqueous sodium hydroxide solution was
added. The mixture was then stirred at 30-35°C for 2 hours. The pH of the mixture
was adjusted to 6 to 6.5 using concentrated hydrochloric acid and the resulting
solution was subjected to charcoalization to obtain a charcoalized solution. The
charcoalized solution was filtered and the filtrate was evaporated to dryness to obtain
crude Zidovudine. To the crude Zidovudine was added 400ml of water and the
suspension was heated to 45-50°C for 0.5 hours. The suspension was then cooled to
0-5°C for 3-4 hours, filtered and dried to obtain 130g (Yield: 75.05%) of Zidovudine
having HPLC purity 99.87%.
Melting Point: 123-124oC
IR (KBr): 3462.34, 3159.51,3024.48,2818.09,2495.97,2114.05,2085.12, 1685.84,
1654.98, 1465.95, 1437.02, 1280.78, 1261.49, 1111.03, 1089.82, 1064.74, 898.86,
846.78 and 761.91 cm-1.
1HNMR in CDC13 (δ ppm): 8.46 (br V, 1H, 3-NH), 7.37 (s, 1H, 6-H), 6.07-6.03 (t,
1H, l'-H), 4.42- 4.38 (m, 1H, 3'-H), 4.02-3.95 (m, 2H, 5' a-H & 4'-H), 3.83-3.80 (m,
1H, 51 b-H), 2.58-2.51 (m, 1H, 2' a-H), 2.43-2.36 (m, 2H, 2' b-H & 5'-OH), 1.92 (s,
3H, 5-CH3).
Mass spectrum (DI): 267 (M+)
Specific optical rotation: +62.56 [Lit.: +60.5 to +63.0]

We claim
1. An improved process for preparation of Zidovudine of Formula I having HPLC
purity of more than 99.5%, from 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula IV

wherein, Piv represents Pivaloyl group, comprising,

c) reacting the 5,-0-pivaloyl-3,-azido-3,-deoxythymidine of Formula V with
a) reacting 5'-0-pivaloyl-2,3,-anhydrothymidine of Formula IV with sodium azide in presence of ammonium chloride in an aprotic solvent at temperature ranging from 90- 120°C
b) cooling the reaction mixture of step a) to 20-30°C and adding the reaction mixture to water to precipitate 5'-0-pivaloyl-3'-azido-3'-deoxythymidine of Formula V

aqueous alkali metal hydroxide solution in methanol at temperature ranging from 25-40°C
d) adjusting pH of the reaction mixture of step c) to 6 to 7.5 followed by charcoalization to obtain a charcoalized solution
e) evaporating the charcoalized solution to dryness to obtain crude Zidovudine of Formula I
f) crystallizing the crude Zidovudine of Formula I from water to obtain crystals of pure Zidovudine of Formula I having HPLC purity of more than 99.5%

2. The process as claimed in claim 1, wherein the molar ratio of the sodium azide used in step a) with respect to 5'-0-pivaloyl-2,3'-anhydrothymidine of Formula II is in range of 2 to 4.
3. The process as claimed in claim 1, wherein the aprotic solvent used in step a) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, preferably N,N-dimethylforrnamide is used.
4. The process as claimed in claim 1, wherein the molar ratio of the ammonium chloride used in step a) with respect to 5'-O-pivaloyl-2,3-anhydrothymidine of Formula IV is in range of 1 to 3.
5. The process as claimed in claim 1, wherein the Zidovudine of Formula I prepared has HPLC purity of more than 99.5% and single maximum unknown impurity of less than 0.1%
6. An improved process for preparation of 5'-0-pivaloyl-2.3'-anhydrothymidine of Formula IV, used as starting material in preparation of Zidovudine of Formula I


wherein, Piv represents Pivaloyl group, comprising,
i) reacting (3-thymidine with pivaloyl chloride in pyridine at temperature ranging from 0-10°C to afford 5'-0-pivaloylthymidine of Formula II

ii) insitu reacting 5'-0-pivaloylthymidine of Formula II with mesyl chloride
at temperature ranging from 25-30°C iii) distilling off pyridine to obtain a residue, adding water to the residue and
heating the mixture to 60-75°C iv) cooling the mixture of step iii) to 25-30°C and isolating the crude 5'-0-
pivaloyl-3' -O-mesylthymidine of Formula III by filtration


wherein Ms represents mesyl group
v) recrystallizing the crude 5'-0-pivaloyl-3'-0-mesylthymidine of Formula
III using toluene as solvent to obtain 5'-0-pivaloyl-3'-0-mesylthymidine
of Formula III having HPLC purity of more than 97% vi) reacting 5'-0-pivaloyl-3'-0-mesylthymidine of Formula III with an alkali
metal hydroxide in a C3 to C8 aliphatic alcohol at temperature ranging
from 35-55°C vii) isolating crude 5,-0-pivaloyl-2,3'-anhydrothymidine of Formula IV from
reaction mixture of step vi) viii) purifying the crude S'-O-pivaloyl,2,3-anhydrothymidine of Formula IV
by treatment with dichloromethane followed by toluene to obtain 5'-0-
pivaloyl-2, 3'-anhydrothymidine of Formula IV having HPLC purity of
more than 99%
7. The process as claimed in claim 6, wherein the alkali metal hydroxide used in step vi) is selected from sodium hydroxide or potassium hydroxide, preferably potassium hydroxide is used.
8. The process as claimed in claim 6, wherein the molar ratio of alkali metal hydroxide used in step vi) with respect to 5'-0-pivaloyl-3'-0-mesylthymidine of Formula III is in range of 1 to 1.5.

9. The process as claimed in claim 6, wherein the C3 to Cg aliphatic alcohol used in
step vi) is selected from n-propanol, iso-propanol, n-butanol, n-pentanol, n-hexanol,
n-heptanol and the like, preferably n-butanol is used.
10. The process as claimed in claim 6, wherein the amount of C3 to Cg aliphatic
alcohol used in step vi) used with respect to S'-O-pivaloyl-3'-O-mesylthymidine is in
range of 10 to 20 volumes.